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GnRH agonists and antagonists in IVF

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                   GnRH agonists and antagonists for follicle stimulation in IVF


                           C.A.M. Jansen MD, PhD, K.E. Tucker PhD, HCLD


              Department of IVF, Reinier de Graafgroep, loc Diaconessenhuis Voorburg
                                            The Netherlands


ABSTRACT


Gonadotropin-releasing hormone (GnRH) and its analogues have been extensively used in clinical
medicine. Pulsatile secretion of native GnRH stimulates gonadotrophs of the anterior pituitary and
exogenous administration has been used for induction of ovulation. GnRH agonists initially produce a
stimulation of pituitary gonadotrophs resulting in secretion of follicle-stimulating hormone and
luteinizing hormone and the expected gonadal response, whilst continuous administration gives the
same initial effect, however followed by down regulation and inhibition of the pituitary-gonadal axis by
clustering and internalization of the receptor. The GnRH antagonists promptly suppress pituitary
gonadotropin by competitive GnRH-receptor binding, thereby avoiding the initial stimulatory phase of
the agonists. This binding is a dose dependent action. Discontinuation of GnRH antagonist treatment
leads to a rapid and predictable recovery of the pituitary-gonadal axis.

The GnRH analogues are potent therapeutic agents that are considerably useful in a variety of clinical
indications. Much of their appeal is based on the fact that they prevent the occurrence of a premature
luteinization, thereby reducing its negative effect on the cohort of growing follicles. A premature LH rise
occurs in about 15% of all IVF cycles. This pronounced elevation of LH before the administration of
hCG does not necessarily have to lead to an inadvertent ovulation, but it does lead to follicle
luteinization and diminished fertilization, implantation and pregnancy rates.

Although a meta-analysis of several prospective and randomized studies comparing down-regulated
and non-down-regulated treatments as first choice in IVF has revealed that a significant difference in
                                                                      1
pregnancy rates exits between these two types of stimulation protocols , the differences are due to
exceptionally low results in the non analogue arm, much lower than previously published in
comparable studies performed by the same groups for other reasons.

So far results with the GnRH antagonists in ART have been lower than with agonists, but it is too early
to draw conclusions form the phase III studies alone; more experience is needed to assess the proper
value of these new compounds. This article deals with the introduction of these compounds in clinical
reproductive medicine, and gives a critical appraisal

THE INTRODUCTION OF GNRH AGONISTS IN REPRODUCTIVE MEDICINE

Whenever a new medication is introduced into clinical practice, elaborate and time consuming
investigations need to be performed in a fixed sequence: phase I studies for establishment of action,
phase II studies for dose finding and phase III studies for the determination of efficacy and efficiency.
Even so starting at this last phase the complication rate is also determined. During this investigation
process intended for registration side effects are reported The seriousness of these are judged in
relation to the expected health benefits and to the seriousness of the disease for which the medication
is intended. For instance even fatal side effects of the drug itself may be acceptable, when the
condition itself is so serious that overall life expectancy in patients having the disease is markedly
improved by the medication.

This is usually the case for carcinoma with metastases, and it should be clear that these conditions
cannot be set in line with non- life threatening diseases such as infertility. However, once the FDA or
other regulating authorities have approved the medication for clinical use, the prescribing physician

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has no obligation whatsoever to justify its use for indications other than the intended one.

GnRH agonists are a typical example of this: originally intended and used to achieve castrate levels of
sex steroids, especially estradiol and testosterone, for instance in case of metastasized prostate
carcinoma, they were suddenly, without any dose finding studies and without any proper health gain-
to cost studies introduced into artificial reproductive programs, based on the finding that they could
prevent premature luteinization. This peculiar type of introduction was only possible because the
substances were already available, intended for prostate carcinoma. As such it is surprising that it has
taken longer than 10 years after the entry into the field of ART before the first proper dose finding
studies were performed.

Introduction of a new medication can only be justified when either the medication is more effective, or
when it has fewer side effects or both. In addition, at equal effectiveness, there should at least be a
cost benefit. Agonists have not truly fulfilled these requirements. The primary goal of the use of
agonists is to achieve better results during stimulation for IVF. It is clear that these drugs exert their
effect by the prevention of a premature LH surge, the incidence of which is dependent on the size of
the dominant follicle. Ultimately, LH surges will be detected in all patients. Thus, the incidence of a
premature peak can be is directly dependent on the accuracy of follicular monitoring. Treating all
patients with agonists means a pharmacological “overkill” in about 85% of patients undergoing IVF in
centers with accurate monitoring. Agonists act more as an “umbrella”, if you will, against the potential
“rainfall” of premature luteinization. It seems strange, however, to always have an umbrella put up
when one knows it will only rain 15% of the time.

There is no conclusive evidence that agonists act by synchronizing follicle growth, preventing
dominance or improve a poor response. The purported synchronization is based on the fact that it is
possible to allow large follicles to grow beyond the size at which they would stimulate an endogenous
LH peak. This makes it possible for more subordinate follicles to achieve a sufficient size and maturity.
On ultrasound, it may appear that GnRH agonists have made it possible for more follicles to be
synchronized, since the relative differences in size between the largest follicles will decrease.

Premature luteinization a reason for cancellation?
In the era before the introduction of agonists, many centers would cancel a stimulation cycle if a
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premature or mature LH peak had occurred. The scientific basis for this decision, however, is weak . It
is possible for the patient to become pregnant despite the occurrence of a premature LH peak. The
decision to cancel might be justified in the time of the follicle puncture by laparoscopy, when the
patient had to be subjected to general anesthesia and a fairly invasive surgical procedure. Nowadays,
in light of the transvaginal puncture as a much less involved, outpatient procedure, this decision
cannot be properly defended. Many clinicians have based their policies on that of the Jones Center in
Norfolk. The Jones‟ Institute has published their cancellation policies in a book chapter to which many
other clinics refer and cite as their justification for cycle cancellation. It is possible, therefore, that in
canceling the cycles where a premature LH peak is observed, they inadvertently bias the differences
observed between the agonist versus the non-agonist groups based mostly on the differences in
cancellation rates.

Studies on the effectivity and efficacy of GnRH agonists

GnRH agonists have never been tested in a double blind prospective randomized way. In all RCT‟s the
investigator was aware of the used medication. In addition consciously or subconsciously, the
investigator may be tempted to cancel more cycles when faced with a non-analogue arm. The
incidence of cycle cancellations in both arms of these trials may have lead to an unwittingly biased
                                                                     3,7
conclusion. Sometimes not even the cancellation rate is mentioned.

Many studies only contain small numbers of patients. Some comparative studies that contain larger
numbers of patients do not adhere to the most elementary requirements, especially with respect to the
                                                     4 5
selection of patients for the groups being compared , . They must be carefully evaluated and possibly
be discarded. For instance, Macnamee and co-workers compared a group of patients stimulated with
and without agonists. All patients in the non-agonist group were allowed to start, whilst the patients in


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the agonist group were selected based on a number of factors (i.e. no cysts, very low plasma
progesterone at cycle start, etc.). Strangely enough, this issue is not addressed at all. There is no
mention of the number of patients that dropped out in the agonist group due to the selection process.
It is surprising that the peer referees of a journal such as Fertility and Sterility accept this type of
omissions. In still other studies the choice of the stimulation scheme (with or without agonists) was left
                    6
to the investigator . Some studies do not randomize or are inconsistent in their treatment. For
instance, stimulations were begun with hMG alone and then end exclusively with GnRH down-
                                           7
regulated cycles by the end of the study .

The results of a current literature search resulted in only 11 studies which were prospective and
              8 9 10 11 12 13 14 15 16 17 18
randomized , , , , , , , , , , . One study was only concerned with low responders, and since
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this was not the “first choice” medication scheme it was not included . One study was prospective, but
                                                               12
not truly randomized; selection took place on alternate days . In addition, this study initially involved
both IVF as well as GIFT. Three out of the eleven studies found a significant difference in pregnancy
rates per cycle, but they also found a significant difference in cancellation rates. The only important
parameter is the “take-home-baby” rate. A number of authors do not mention this, so we obtained or
calculated this information from related publications by these same groups. The only author that found
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a significant difference in live births was Neveu and co-workers . This difference was based, however,
on only 10 patients per arm (1/10 in the HMG group, 6/10 in the down-regulated group). It is clear that
the numbers are too small for these data to be truly representative.

A meta-analysis has been published that purely confines itself to the description of the differences
                                                    1
rather than the analysis of the underlying causes . When combined and re-evaluated as a meta-
analysis taken together, these 11 studies resulted in a significant difference in results, which,
incidentally, is mainly due to the differences in cancellation rates. Figure 1 depicts the reported or
calculated “take-home-baby” rate per started cycle in studies with the use of GnRH agonists as a first
choice. In terms of delivery rate per aspiration the difference is 13 versus 16% (p < 0.03)(Figure 2).
The most striking finding in all of these studies, however, is not so much that the results in the down-
regulated cycles are so superior, but that the results in the non down-regulated cycles are so poor that
there is ultimately a significant difference between these two groups (Table I). It‟s curious that some
centers can achieve satisfactory results without the use of agonists, whilst others do not seem to be
able to. The difference may lie to the quality of the follicular monitoring.


year/ author          No anal THB/cy      %       Canc   With Anal THB/cy     %      Canc
         1987 Neveu                  1/10 10,0 %    20 %                 6/10   60 %     0%
        1990 Antoine                 9/90 10,0 %    15 %                15/90 16,7 %     8%
      1990 Benadiva                 14/88 15,9%     20 %                10/68 14,7 %    14 %
         1990 Ferrier                4/43   9,3 %   26 %                 0/30    0%     23 %
        1990 Abdalla                 3/58   5,1 %   19 %                 7/48 14,6 %     9%
        1990 vd Berg                 4/52   7,7 %   17 %              16/101 15,8 %     14 %
          1990 Kubik                 2/26   7,7 %   39 %                 5/34 14,7 %    15 %
       1991 Maroulis                11/93 11,8 %    23 %                11/99 11,1 %    12 %
         1991 Ron El               11/151   7,2 %   27 %              21/151 13,9 %      3%
      1992 Kingsland               19/158 12,0 %    11 %              24/150 16,7 %      5%
        1992 Corson                  3/33   9,0 %   30 %                 8/34 23,5 %     8%
                Total              81/802 10,1 % 20,3 %              123/815 15,1 % 10,4 %

TABLE 1:
Take home baby rate per started cycle (as in fig 1) and cancellation rates of prospective, randomized
studies in IVF with and without GnRH analogues as first choice. Column 1: year of publication, first
author; column 2 and 5: rate per cycle in cycles without and with GnRH analogues; column 3 and 6:
percentages; column 4 and 7: cancellation rates in these groups.



                                                    3
                                                                                                                                          4
                                                                                                                                Rec FSH


            TAKE HOME BABY RATE PER CYCLE: GnRH Analogs                                                  P value (2 sided)




               Neveu

              Antoine

             Benadiva

               Ferrier

              vd Berg

                Kubik

             Maroulis

               Ron El

            Kingsland

              Abdalla

              Corson

               Overall

                         0 ,001   0 ,01               0,1                1                 10          100                   1000
                                          Odds- ratio (MLE estimation) with 95 % Conf int, log scale


                                                                                                       CAM JANSEN, Fertinet 1997




Fig 1: Odds ratio and 95 % Confidence Intervals of the “take-home-baby” rate (THBR) per started
cycle in prospective randomized studies in IVF with or without GnRH as first choice (ref 2-12). THBR
was published, communicated, or calculated from the pregnancy and abortion rates reported. p-
values depicted on the right.


The popularity of GnRH agonists

There is no doubt that using agonists is extremely convenient: There are almost no constraints of the
follicle size at which one can administer hCG. That is, it does not differ whether hCG is given at
different follicle sizes between 16 and 24 mm. Aspirations can be scheduled during convenient days,
work load can be equalized and weekend procedures can be avoided. Although GnRH agonists can
simplify IVF scheduling, agonists may also mask inaccuracy in follicular monitoring. This applies
mostly to those clinicians with little expertise in follicle monitoring. Normally there is a penalty to pay for
inaccurate follicle measurements (in the form of premature luteinization), but agonists mask this. So,
especially in those centers that have a rapid turnover IVF doctors, such as those with residents, are
more likely to benefit from the use of agonists. This aspect and those mentioned earlier must be the
cause of the eager acceptance of agonists in IVF.

SIDE EFFECTS

OHSS (Ovarian HyperStimulation Syndrome)

The incidence of OHSS varies per center. It is dependent on nomenclature and diagnostics. The
literature concerning OHSS in agonist cycles suggests an increased risk, with reported figures of 6.6
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to 8.4% of cycles resulting in this side effect . Half of these were severe forms. In cycles with HMG
alone an incidence of 0.7% was found. In one study an ICU (intensive care unit) admission rate of
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patients with OHSS resulting from GnRH down-regulation of 0.6 % was mentioned . Unfortunately, in
order to properly show a significant difference in OHSS occurrence between the two treatments, a
prospective study involving a large number of patients would be needed. No such study has been
performed.

The hospital admission rate due to OHSS in non-analogue cycles can be estimated to be at about 0.1
to 0.05%. In a prospective randomized assessor blind study using hMG or recombinant FSH in the
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absence of agonists there were no cases of severe OHSS . This is in contrast to 2 and 3,2 % in the
largest prospective randomized multicenter study ever performed, using down-regulation for
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stimulation with either urinary FSH or recombinant FSH (Puregon) . This study has revealed a
number of interesting findings: one of these was that there were large differences e.g. in oocyte yield
even when exactly the same inclusion criteria and the same stimulation protocol were used. In spite of
this, the oocyte yield ranged from a mean of 7 to 16 between different centers. One other interesting
finding in both studies was that the results in terms of ongoing pregnancy rates were exactly the same
in our study without down-regulation and the large study. The ongoing pregnancy rates were 17.1 %
and 22.2 % per cycle in the non-analogue study for HMG and rec FSH respectively, versus 18.1 %

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and 22.2 % in the analogue study.

The multiple pregnancy rate

It appears that the multiple pregnancy rate is increased with the use of agonists. In the study of
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Chetowksi et al. there was a 44% multiple rate in the agonist arm versus 8% in the hMG alone group .
It is important to consider that the increase in multiples may due to an increase in implantation rates
when agonists are used. This feature must be carefully analyzed and the proper steps must be taken
to ensure that fewer embryos are replaced in an agonist-stimulated cycle.

Other side effects?

Not very much is known concerning long-term effects of any of the compounds used in IVF. There are
reports on the absence of short-term effects when GnRH agonists were inadvertently administered
during pregnancy. These reports are incidental and should be judged with caution as they may
represent a publication bias typical for such cases. That is, occasionally, authors may be more inclined
to publish results when no side effects are present.
                                       24                                        25
Agonists are present in follicular fluid and they can easily pass the placenta . It has been
demonstrated that in rabbits there is a direct adenylcyclase-independent effect on the oocyte, which
                                                   26
may lead to premature resumption of the meiosis . This effect is via the protein kinase C system, but
it is not known whether there are long-term consequences.

Standard toxicological and teratological tests.

With the use of GnRH analogues, there are no obvious signs of an increase in congenital
abnormalities. It is not certain, however, whether the standard toxicological or teratological tests are
sufficient to exclude a possible influence. Analogues are small polypeptides. If one might envisage any
effect it might be on brain tissue. A possible influence on brain development and behavioral aspects is
not excluded. If such an influence might exist, however, it may take years to express itself.
Administration of analogues to rats 28 days after ovulation does not lead to demonstrable effects in
behavior and development in female rats. In male rates, however, administration of an antagonist
leads to clear disturbances, only expressed after puberty. There was a significant reduction in
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testicular size, disturbed pubertal development, diminished fertility and aberrant sexual behavior ,
which may be the resultant of either an influence on brain development or on testicular development.
This could also be the case for humans. Agonists present at a sensitive moment in brain development
could result in an influence that only will express itself after puberty. In addition, if the effect also
directly affected the testes, the fetus would be vulnerable at about 8 to 12 weeks. Although with the
short-acting agonists such an influence is unlikely, this does present a clear warning for the depot-
preparations, that may sometimes last as long as 8 weeks or longer in the body.

Swaab and co-workers have introduced the concept of functional teratology, stressing the possibility of
                                                                                                28 29
influences of substances during pregnancy that may affect behavior many years after birth , .
Especially with the use of neuropeptides, it is clear that caution is warranted. Interestingly, in many
published case-reports of the inadvertent use of agonists in pregnancy, basic information, such as the
sex of the child born, was not mentioned. If these babies are male, it is imperative that these patients
are subjected to a follow-up examination until after puberty. Recently it has been published that there
was a remarkable incidence (4 out of six) of children that showed attention deficit and hyperactivity
                                                                                                   30
disorder (ADHD) after inadvertent administration of GnRH analogues during early pregnancy .

Despite some claims that the treatment with agonists might lead to savings there is no doubt that there
is an increase in cost. The advantages in terms of cost goes back to the fact that one may reschedule
working times to exclude weekends, and that one might decrease the frequency of ultrasound
monitoring. As the number of days of stimulation is approximately 4 days longer, however, there is no
decrease in the absolute number of appointments.

The overall costs of an IVF cycle are comprised initially of the price of the agonist itself, then the


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added cost of the extra ampoules of hMG or FSH. Depending on the length of the down-regulation
(long or short scheme), one may require about 10 to 20 more amps. The cost of IVF should be
analyzed as the cost per healthy child. Even if one takes into account the diminished pregnancy rates
in those cycles with a premature LH surge, the cost per baby born is still considerably higher when
agonists are used. Based on our own data in a program where the cost per baby born equals between
HFL12.500 and HFL 15.000 (including cost of medication but excluding the cost of pregnancy itself),
which at the present US dollar rate is between 5000 and 6000 US dollars, we calculated the added
cost, when all patients had been treated with agonists per extra child born, at fl 97.750.00 (~ US
$40.000) for the short scheme, and fl 195.500.00 (US $80,000) for the long protocol.
         In addition to the costs directly attributable to the use of agonists is the increased cost due to
the increased complication rate, which would require admissions to a hospital or ICU because of the
OHSS. These costs may add considerably to the total.

Various GnRH agonist protocols

There are a number of protocols, all meant to achieve down regulation. These will be mentioned
briefly.
The ultrashort protocol consists of the administration of an agonist from day 1 for three days, and then
follicle stimulation with gonadotropins.
The short protocol: the agonist is given from day 1 to the day of hCG, concomitantly with the follicle
stimulation.
The long protocol, which mainly has two variants: Start of the agonist either on day 21 of the previous
cycle with mostly stimulation on day 3, or the agonist on day 1 of the cycle, after which the stimulation
can start any day once proper down-regulation is achieved, usually assessed by either LH or estradiol
levels. A number of studies have focused on a prospective randomized comparison between these
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different modalities, and a meta- analysis has been published . In terms of pregnancy rates, the
highest results are achieved with the long protocol, with a common odds ratio of 1.32 (95% CI 1.10-
1.57). However none of the studies are large enough to include the incidence of side effects, such as
cyst formation or the complication rate, thus these are invariably excluded from the analysis.

One author studied the endogenous dimeric LH as well as free  subunit levels after cessation of the
agonist on day seven of the cycle. In some cases the endogenous LH fell to extremely low levels,
below 0.1 IU/l, far below the generally assumed level of about 1 IU/l necessary for adequate follicle
        32
growth . This may be undetected once stimulation is achieved with HMG as there will always be
sufficient exogenous LH or hCG, but it may pose a problem for some patients when recombinant FSH
is used.
Some authors advocate the use of a contraceptive pill during the month preceding the treatment,
during which the agonist is also given in the second half of the pill cycle, claiming that this will reduce
               33
cyst formation . One advantage is that with the use of the pill, inadvertent administration of the
agonist during an undetected pregnancy is unlikely.

Selective use of agonists?
          There may be something to be said for defining selection criteria for the use of agonists as
well as for that of antagonists, instead of completely down-regulating all patients with agonists and
then overdosing them with hMG or FSH. It is clear that it is feasible to achieve satisfactory results
even when agonists are not used as first choice. Efforts should be directed towards trying to recognize
those patients that will specifically benefit from agonists or antagonists. One predictor might be the
early follicular Inhibin-B level (the dimeric form of B inhibin). It has been stated that a low inhibin B can
pinpoint poor responders and it has been suggested that a high inhibin B is seen in PCO patients.
Another feature could be identification of patients with an elevated chance of the occurrence of a
                      34
premature LH peak .

Dose finding in agonists

         It is questionable whether castrate levels estradiol are required in standard IVF or ICSI
treatments, in contrast to the necessity for such levels of testosterone in prostate carcinoma. In view of
the fact that agonists have been used for more than ten years it is surprising that only recently, dose


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                                                                                                            7
finding studies have been performed to investigate the effect of various degrees of down regulation by
the administration of different doses of triptorelin. A prospective, randomized, double blind, placebo
controlled study between various doses of triptoreline (15, 50 and 100 g / daily) showed that the
minimal dose to sufficiently suppress estradiol concentrations and to increase the number of follicles
during stimulation was 50 g. In addition there was a linear relationship between the duration of the
stimulation and the degree of suppression: the higher the triptorelin dose, the longer the stimulation
lasted. However, even 15 g was sufficient to prevent the occurrence of a LH surge, and although a
premature LH surge occurred in 23 % of the placebo treated groups, there was no difference in
                                             35
pregnancy rates between the four groups.


GnRH ANTAGONISTS

The GnRH antagonists promptly suppress pituitary gonadotropin by competitive GnRH-receptor
binding, thereby avoiding the initial stimulatory phase of the agonists. This binding is a dose dependent
action. Discontinuation of GnRH antagonist treatment leads to a rapid and predictable recovery of the
pituitary-gonadal axis. Antagonists can be- and usually are- given during the stimulation phase, either
on a fixed day in the cycle, after five or six days of stimulation or at a fixed size of the leading follicle.

GnRH antagonists directly bind to the pituitary LH receptor to form binding in competition with GnRH
itself. They have a direct effect, in contrast to the agonists that act through down regulation of the
receptors after an initial flare-up. However they may bind to receptors elsewhere in the body such as
at the endometrial level, and at the level of the granulosa cell in the follicle. It has been described that
prolonged exposure of antral follicles to GnRH antagonists in heifers may lead to an increase in follicle
atresia with a decrease in estradiol production without a concomitant effect on the oocyte, or later in
                           36
embryonic development , whilst in sheep it was shown that injection of the GnRH antagonist antarelix
in a relative high concentration (0.5 mg per about 40 kg) led to a decrease estradiol production but
also in oocyte quality and in blastocyst formation rate, which could be prevented by the simultaneous
                                                                                                          37
restoration of LH pulsatility by exogenous administration the day before the LH peak was mimicked .
As such it does not suggest a direct detrimental effect on the oocyte but an indirect effect through
relative lack of LH activity. This is in accordance with a report of a normal pregnancy rate after transfer
                                                                                              38
of cryopreserved embryos from cycles in which a high dose of the antagonist was used

All agonists as well as antagonists are formed by the substitution of one or more amino acids in the
decapeptide chain. The first generation of antagonists were unsuitable for clinical use in the human,
because of their histamine releasing effect of the mast cells, leading to a high incidence of allergic
          39
reactions . However at present at least two preparations are devoid of such activity, and are used in
clinical medicine: ganirelix and cetrorelix

It should be noted that all phase II and III studies concerning the antagonist cetrorelix were performed
           40 41 42
with hMG , , . This means that in all cases there will always be sufficient amounts of LH by
exogenous administration. For the daily dose of 0,25 mg this is probably of limited consequence, but
for the depot preparation of 3 mg, it may mean that some patients will lack LH when the follicle
stimulation is performed with recombinant FSH. However so far it is not yet clear whether this will
influence the results. As in most cases there will still be sufficient LH, this feature may not readily show
up in prospective randomized trials.
                                                                                                    43 44
All phase II and III studies with the antagonist ganirelix were performed with recombinant FSH , .
One serendipitous but unwanted observation in the dose finding study was that when recombinant
FSH was combined with a high daily dose of 2 mg, some patients showed undetectable LH levels, in
conjunction with a considerable drop in estradiol levels, a cessation or even reversal of follicle growth
                                                                                                      45
or both. This effect could be reversed immediately by switching over to hMG for follicle stimulation .
This shows that this effect is most likely due to deprivation of LH once the antagonist was
administered.

So far all prospective randomized controlled trials have shown lesser results in IVF in the antagonist
group, in comparison to the long agonist scheme. Although many patients feel better, side effects are


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negligible, and there may be a lesser risk of OHSS, these compounds have met with considerable
resistance of many clinicians to use this medication. It is likely that many patients will not benefit from
these compounds, but there will be a subgroup for which this medication is preferable, without the
decrease in results.

One report suggested that poor responders might benefit from antagonists; however as the results
from previous stimulations were compared to next one, the possibility of regression to the mean is
      46
likely . In a prospective study that included a larger group results were equally in the low response
                    47
group disappointing .

It has been suggested that the use of GnRH antagonist would obviate the need for luteal support. In
fact, although widely practiced in the early days of IVF, the need for luteal support has never been
proven for non-analogue cycles. However it seems that the effect of the antagonist may last as long as
                                                                                 48
7 days, and it may be that in some patients there still is a luteal insufficiency . One other suggestion
is that specific patients may benefit from the gain in time due to shorter treatment duration such as
                                                     49
women that need cancer treatment at short notice

One clear distinction with GnRH agonists is that patient compliance, which plays hardly any role when
agonists are used, can be critical for antagonists: even the omission of one day may lead to a
                                                        50
premature LH surge, thereby influencing results in IVF

It is clear that the clinician has to abandon the idea that there is something as a „holy grail‟ for
everybody. Future stimulations will have to become more personalized: some patients respond
differently to different stimulation protocols. In future it should be possible to select a proper
stimulation protocol for an individual patient, whether it is with agonists, with antagonists or altogether
without.

Conclusion

It is clear that agonists have become ubiquitous in IVF; however, it is questionable whether or not their
use should aim to achieve castrate levels, should be first and indiscriminate. The differences between
groups of patients treated with or without agonists can, at least in part, be explained by the difference
in cancellation rate. Agonists do not improve pregnancy rates in centers with already good pregnancy
rates, but they may normalize results in centers with poor rates. They allow unrivalled flexibility, but
with the same token, they can conceal incompetence in follicle monitoring as they do not just prevent
premature LH peaks, but also mature LH peaks. The complication rate, especially with regard to the
incidence of OHSS, is increased, and the cost- benefit ratio is worsened.

Future follicle stimulation schemes should become much more individualized; instead of completely
and indiscriminately down-regulating all patients, clinicians should search for selection criteria to
distinguish those patients that really need GnRH agonists from those that do not.

REFERENCES

1
  Hughes EG, Fedorkow DM, Daya S e.a.: The routine use of gonadotropin releasing hormone agonist
prior to in vitro fertilization and gamete intrafallopian transfer: a meta-analysis of randomized controlled
trials, Fertil.Steril. 58:888, 1992
2
 Jansen CAM en Burgers S. Do follicle number, presence of cysts or LH peaks justify cancellation of
an IVF cycle? Hum.Reprod. 1990; 5S: 96
3
 Gonen Y, Dirnfeld M, Goldman S et al: The use of long acting gonadotropin releasing hormone
agonist (GnRH-a, Decapeptyl) and gonadotropins versus short acting GnRH-a (Buserelin) and
gonadotropins before and during ovarian stimulation for in vitro fertilization. J IVF-ET: 8: 254, 1991.
4
 Macnamee, MC, Tayler, PJ, Howles, CM et. al: Short term luteinizing hormone-releasing hormone
agonist treatment: prospective trial of a novel ovarian stimulation regimen for in vitro fertilization. Fertil.

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                                                                                                            9

Steril, 52: 264, 1989
5
 Garcia, JE, Padilla, SL, Bayati, J. et al: Follicular phase gonadotropin-releasing hormone agonist and
human gonadotropins: a better alternative for ovulation induction in in vitro fertilization. Fertil. Steril.
53:302,1990.
6
 Thanki, KH., Schmidt. Follicular development and oocyte maturation after stimulation with
gonadotropins versus leuprolide acetate/gonadotropins during in vitro fertilisation. Fertil. Steril, 54:
656, 1990
7
 Chetowski, RJ, Kruse, LR en Nass, TE: Improved pregnancy outcome with the addition of leuprolide
acetate to gonadotropins for in vitro fertilization. Fertil.Steril, 52: 250, 1989
8
 Neveu, S., Arnal, F., Hedon, B. et al.:Ovarian stimulation by a combination of gonadotropin-releasing
hormone agonist and gonadotropins for in vitro fertilization. Fertil. Steril. 47: 639, 1987
9
  Antoine, JM, Salat-Baroux, J., Alvarez, S. et al.: Ovarian stimulation using human menopausal
gonadotropins with or without LHRH agonists in a long protocol for in-vitro fertilization: a prospective
randomized comparison. Human Reprod. 5: 565, 1990
10
   Benadiva, CA, Mastroianni, L., Blasco, L et al.: Comparison of different regimens of a gonadotropin-
releasing hormone analogue during ovarian stimulation for in vitro fertilisation. Fertil Steril. 53: 479,
1990.
11
   Ferrier, A., Prey, K., Rasweiler, JJ et al.: Evaluation of leuprolide acetate and gonadotropins versus
clomiphene citrate and gonadotropins for in vitro fertilization or gamete intrafallopian transfer. Fertil.
Steril. 54: 90, 1990
12
   Abdalla, HI, Morris, NN, Ahuja, KK et al: Comparative trial of luteinizing hormone-releasing hormone
analogue/human menopausal gonadotropin and clomiphene citrate/human menopausal gonadotropin
in an assisted conception program. Fertil. Steril. 53: 473, 1990
13
  van de Berg- Helder A, Helmerhorst FM, Blankhart A, Brand R, Waegemaekers C, Naaktgeboren
N.: Comparison of ovarian stimulation regimens for in vitro fertilization (IVF) with and without a
gonadotropin releasing hormone (GnRH) agonist: results of a randomized study. J.IVF-ET: 7: 358,
1990.
14
  Kubik, CJ, Guzick, DS, Berga, SL et al: Randomized, prospective trial of leuprolide acetate and
conventional superovulation in first cycles of in vitro fertilization and gamete intrafallopian transfer.
Fertil. Steril.54: 836, 1990
15
   Maroulis, GB, Saphier, A., Emery, M. et al: Prospective randomized study of human menotropin
versus a follicular and a luteal phase gonadotropin-releasing hormone analogue-human menotropin
stimulation protocols for in vitro fertilization. Fertil.Steril.55:1157,1991
16
  Ron El, R, Nachum, H, Herman, A et al: Gonadotropins and combined gonadotropin-releasing
hormone agonist--gonadotropins protocols in a randomized prospective study. Fertil.Steril, 55: 574,
1991
17
  Kingsland, C., Mason, B, Tan, SL et al. The routine use of gonadotropin-releasing hormone agonists
for all patients undergoing in vitro fertilization. Is there any medical advantage? A prospective
randomized study. Fertil.Steril 57: 804, 1992
18
  Corson SL , Batzer FR, Gocial B, Eisenberg E, Huppert LC, Nelson JR. Leuprolide acetate-prepared
invitro fertilization- gamete intrafallopian transfer cycles: efficacy versus controls and cost analysis.
Fertil. Steril. 57: 601-5, 1992


                                                      9
                                                                                                        10

19
  MacLachlan, V., Besanko, M., O'Shea, F. et al: A controlled study of luteinizing hormone-releasing
hormone agonist (buserelin) for the induction of folliculogenesis before in vitro fertilization. New
Engl.J.Med. 320: 1233, 1989
20
   Golan, A, Ron-El, R., Herman A. et al: Ovarian hyperstimulation syndrome following D-Trp-6
luteinizing hormone-releasing hormone microcapsules and menotropins for in-vitro fertilization.
Fertil.Steril., 50: 912, 1988
21
  Smitz, J., Camus, M., de Vroey, P. et al: Incidence of severe hyperstimulation syndrome after GnRH
agonist /HMG superovulation for in vitro fertilization. Hum.Reprod. 5: 933, 1990
22
  Jansen CA, van Os HC, Out HJ, Coelingh Bennink HJ A prospective randomized clinical trial
comparing recombinant follicle stimulating hormone (Puregon) and human menopausal
gonadotrophins (Humegon) in non-down-regulated in-vitro fertilization patients. Hum Reprod
1998;13:2995-9
23
 Out HJ, Mannaerts BM, Driessen SG, Bennink HJ A prospective, randomized, assessor-blind,
multicentre study comparing recombinant and urinary follicle stimulating hormone (Puregon versus
Metrodin) in in-vitro fertilization. Hum Reprod 1995;10:2534-40
24
  Loumaye, E., Vankrieken, L., Coen, G. et al.: Use of gonadotropin-releasing hormone agonist during
ovarian stimulation leads to significant concentrations of peptide in follicular fluids. Fertil. Steril. 52:
256, 1989.
25
  Skopelak, VIM. and Hodgen, G.D.: Infusion of gonadotropin-releasing hormone agonist during
pregnancy: Maternal and fetal responses in primates. Am.J.Obstet.Gynecol. 156: 755, 1987.

26
  Yoshimura, Y., Ubukata, Y., Nakamura, Y. et al.: Gonadotropin-releasing hormone agonists induce
meiotic maturation and degenerated oocytes in the in vitro perfused rabbit ovary. Fertil. Steril. 55: 177,
1991.
27
  van den Dungen, H.M., LHRH and gonadotropins in rat pubertal development. Academic thesis,
Free University Amsterdam, the Netherlands, 1990
28
  Swaab, D.F., G.J. Boer en Feenstra, M.F., Concept of functional neuroteratology and the
importance of neurochemistry. Prog. Brain Res, 73: 3, 1988.
29
  Boer, G.J., Sijdewint, G.M. en Swaab, D.F., Neuropeptides and functional neuroteratology. Prog.
Brain Res. 73: 245, 1988
30
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  Daya S. Gonadotropin releasing hormone agonist protocols for pituitary desensitization in in vitro
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  Cedrin-Durnerin I, Bidart JM, Robert P, Wolf JP, Uzan M, Hugues JN. Consequences on
gonadotrophin secretion of an early discontinuation of gonadotrophin-releasing hormone agonist
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33
  Buckett WM, Tan SL Use of luteinizing hormone releasing hormone agonists in polycystic ovary
syndrome. Baillieres Clin Obstet Gynaecol 1998 Dec; 12(4): 593-606



                                                    10
                                                                                                           11
34
  Lockwood GM, Muttukrishna S, Ledger WL, Groome NP, Dolfing J and Jansen CAM Optimisation of
non-analogue IVF: a role for inhibin B in predicting patients liable to premature LH surge or inadequate
response. Hum. Reprod. 1997; 12S: 157-8
34
  Hughes EG, Fedorkow DM, Daya S e.a.: The routine use of gonadotropin releasing hormone
agonist prior to in vitro fertilization and gamete intrafallopian transfer: a meta-analysis of randomized
controlled trials, Fertil.Steril. 58:888, 1992
34
  Jansen CAM en Burgers S. Do follicle number, presence of cysts or LH peaks justify cancellation of
an IVF cycle? Hum.Reprod. 1990; 5S: 96
34
  Gonen Y, Dirnfeld M, Goldman S et al: The use of long acting gonadotropin releasing hormone
agonist (GnRH-a, Decapeptyl) and gonadotropins versus short acting GnRH-a (Buserelin) and
gonadotropins before and during ovarian stimulation for in vitro fertilization. J IVF-ET: 8: 254, 1991.
34
  Macnamee, M.C., Tayler, P.J., Howles, C.M. et. al: Short term luteinizing hormone-releasing
hormone agonist treatment: prospective trial of a novel ovarian stimulation regimen for in vitro
fertilization. Fertil. Steril, 52: 264, 1989
34
  Garcia, J.E., Padilla, S.L., Bayati., J. et al: Follicular phase gonadotropin-releasing hormone agonist
and human gonadotropins: a better alternative for ovulation induction in in vitro fertilization. Fertil.
Steril. 53:302,1990.
34
  Thanki, K.H. en Schmidt, Follicular development and oocyte maturation after stimulation with
gonadotropins versus leuprolide acetate/gonadotropins during in vitro fertilisation. Fertil. Steril, 54:
656, 1990
34
  Chetowski, R.J., Kruse, L.R. en Nass, T.E.: Improved pregnancy outcome with the addition of
leuprolide acetate to gonadotropins for in vitro fertilization. Fertil.Steril, 52: 250, 1989
34
   Neveu, S., Arnal, F., Hedon, B. et al.:Ovarian stimulation by a combination of gonadotropin-relea-
sing hormone agonist and gonadotropins for in vitro fertilization. Fertil. Steril. 47: 639, 1987
34
  Antoine, J.M., Salat-Baroux, J., Alvarez, S. et al.: Ovarian stimulation using human menopausal
gonadotropins with or without LHRH agonists in a long protocol for in-vitro fertilization: a prospective
randomized comparison. Human Reprod. 5: 565, 1990
34
  Benadiva, C.A., Mastroianni, L., Blasco, L et al.: Comparison of different regimens of a gonadotro-
pin- releasing hormone analogue during ovarian stimulation for in vitro fertilisation. Fertil Steril. 53:
479, 1990.
34
   Ferrier, A., Prey, K., Rasweiler, J.J. et al.: Evaluation of leuprolide acetate and gonadotropins versus
clomiphene citrate and gonadotropins for in vitro fertilization or gamete intrafallopian transfer. Fertil.
Steril. 54: 90, 1990
34
  Abdalla, H.I., Morris, N.N., Ahuja, K.K. et al: Comparative trial of luteinizing hormone-releasing
hormone analogue/human menopausal gonadotropin and clomiphene citrate/human menopausal
gonadotropin in an assisted conception program. Fertil. Steril. 53: 473, 1990
34
  van de Berg- Helder A, Helmerhorst FM, Blankhart A, Brand R, Waegemaekers C, Naaktgeboren
N.: Comparison of ovarian stimulation regimens for in vitro fertilization (IVF) with and without a
gonadotropin releasing hormone (GnRH) agonist: results of a randomized study. J.IVF-ET: 7: 358,
1990.
34
  Kubik, C.J., Guzick, D.S. Berga, S.L. et al: Randomized, prospective trial of leuprolide acetate and
conventional superovulation in first cycles of in vitro fertilization and gamete intrafallopian transfer.


                                                     11
                                                                                                         12

Fertil. Steril.54: 836, 1990
34
   Maroulis, G.B., Saphier, A., Emery, M. et al: Prospective randomized study of human menotropin
versus a follicular and a luteal phase gonadotropin-releasing hormone analogue-human menotropin
stimulation protocols for in vitro fertilization. Fertil.Steril.55:1157,1991
34
  Ron El, R., Nachum, H., Herman, A. et al: Gonadotropins and combined gonadotropin-releasing
hormone agonist--gonadotropins protocols in a randomized prospective study. Fertil.Steril, 55: 574,
1991
34
  Kingsland, C., Mason, B., Tan, S.L. et al. The routine use of gonadotropin-releasing hormone
agonists for all patients undergoing in vitro fertilization. Is there any medical advantage? A prospective
randomized study. Fertil.Steril 57: 804, 1992
34
   Corson SL , Batzer FR, Gocial B, Eisenberg E, Huppert LC, Nelson JR. Leuprolide acetate-prepared
in vitro fertilization- gamete intrafallopian transfer cycles: efficacy versus controls and cost analysis.
Fertil. Steril. 57: 601-5, 1992
34
  MacLachlan, V., Besanko, M., O'Shea, F. et al: A controlled study of luteinizing hormone-releasing
hormone agonist (buserelin) for the induction of folliculogenesis before in vitro fertilization. New
Engl.J.Med. 320: 1233, 1989
34
   Golan, A, Ron-El, R., Herman A. et al: Ovarian hyperstimulation syndrome following D-Trp-6
luteinizing hormone-releasing hormone microcapsules and menotropins for in-vitro fertilization.
Fertil.Steril., 50: 912, 1988
34
  Smitz, J., Camus, M., Devroey, P. et al: Incidence of severe hyperstimulation syndrome after GnRH
agonist /HMG superovulation for in vitro fertilization. Hum.Reprod. 5: 933, 1990
34
  Jansen CA, van Os HC, Out HJ, Coelingh Bennink HJ A prospective randomized clinical trial
comparing recombinant follicle stimulating hormone (Puregon) and human menopausal
gonadotrophins (Humegon) in non-down-regulated in-vitro fertilization patients. Hum Reprod
1998;13:2995-9
34
 Out HJ, Mannaerts BM, Driessen SG, Bennink HJ A prospective, randomized, assessor-blind,
multicentre study comparing recombinant and urinary follicle stimulating hormone (Puregon versus
Metrodin) in in-vitro fertilization. Hum Reprod 1995;10: 2534-40
34
  Loumaye, E., Vankrieken, L., Coen, G. et al.: Use of gonadotropin-releasing hormone agonist during
ovarian stimulation leads to significant concentrations of peptide in follicular fluids. Fertil. Steril.1989;
52: 256.
34
  Skopelak, VM, Hodgen, G.D.: Infusion of gonadotropin-releasing hormone agonist during
pregnancy: Maternal and fetal responses in primates. Am.J.Obstet.Gynecol.1987;156: 755,
34
  Yoshimura, Y., Ubukata, Y., Nakamura, Y. et al.: Gonadotropin-releasing hormone agonists induce
meiotic maturation and degenerated oocytes in the in vitro perfused rabbit ovary. Fertil. Steril. 55: 177,
1991.
34
  van den Dungen, H.M., LHRH and gonadotropins in rat pubertal development. Academic thesis,
Free University Amsterdam, the Netherlands, 1990
34
  Swaab, D.F., G.J. Boer en Feenstra, M.F., Concept of functional neuroteratology and the
importance of neurochemistry. Prog. Brain Res, 73: 3, 1988.
34
     Boer, G.J., Sijdewint, G.M. en Swaab, D.F., Neuropeptides and functional neuroteratology. Prog.


                                                     12
                                                                                                      13

Brain Res. 73: 245, 1988
34
  Lockwood GM, Muttukrishna S, Ledger WL, Groome NP, Dolfing J and Jansen CAM Optimisation of
non-analogue IVF: a role for inhibin B in predicting patients liable to premature LH surge or inadequate
response.
Hum. Reprod. 1997; 12S: 157-8
35
   Janssens RMJ, Lambalk CB, Vermeiden JPW, Schats R, Schoemaker J, Mak S. Dose finding study
of triptorelin acetate for prevention of premature LH surge: a prospective, double blind, placebo-
controlled study. Hum. Reprod. 1998; 13S: 49-50
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  Oussaid B, Lonergan P, Khatir H, Guler A, Monniaux D, Touze JL, Beckers JF, Cognie Y, Mermillod
P Effect of GnRH antagonist-induced prolonged follicular phase on follicular atresia and oocyte
developmental competence in vitro in superovulated heifers. J Reprod Fertil 2000 Jan;118(1):137-44
37
   Oussaid JRF 1999 7 Oussaid B, Mariana JC, Poulin N, Fontaine J, Lonergan P, Beckers JF, Cognie
Y.Reduction of the developmental competence of sheep oocytes by inhibition of LH pulses during the
follicular phase with a GnRH antagonist. J Reprod Fertil. 1999 Sep;117(1):71-7.
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  Kol S, Lightman A, Hillensjo T, Devroey P, Fauser B, Tarlatzis B, Mannaerts B, Itskovitz-Eldor J
High doses of gonadotrophin-releasing hormone antagonist in in-vitro fertilization cycles do not
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   Morgan JE, O'Neil CE, Coy DH, Hocart SJ, Nekola MV Antagonistic analogs of luteinizing hormone-
releasing hormone are mast cell secretagogues. Int Arch Allergy Appl Immunol 1986;80(1):70-5
40
   Albano C, Smitz J, Camus M, Riethmuller-Winzen H, Van Steirteghem A, Devroey P Comparison of
different doses of gonadotropin-releasing hormone antagonist Cetrorelix during controlled ovarian
hyperstimulation. Fertil Steril 1997 May;67(5):917-22
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   Albano C, Felberbaum RE, Smitz J, Riethmuller-Winzen H, Engel J, Diedrich K, Devroey P Ovarian
stimulation with HMG: results of a prospective randomized phase III European study comparing the
luteinizing hormone-releasing hormone (LHRH)-antagonist cetrorelix and the LHRH-agonist buserelin.
European Cetrorelix Study Group. Hum Reprod 2000 Mar;15(3):526-31
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Bouchard P, Frydman R.Prospective, randomized, controlled study of in vitro fertilization-embryo
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   The ganirelix dose-finding study group. A double-blind, randomized, dose-finding study to assess
the efficacy of the gonadotrophin-releasing hormone antagonist ganirelix (Org 37462) to prevent
premature luteinizing hormone surges in women undergoing ovarian stimulation with recombinant
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  The European Orgalutran study group. Simplification of treatment with the gonadotropin-releasing
hormone antagonist ganirelix (Orgalutran®) in women undergoing controlled ovarian hyperstimulation
with recombinant follicle stimulating hormone (Puregon®): results of a controlled, randomized,
multicenter trial. Human Reproduction 2000; 15: (in print)
45
     Devroey P, personal communication
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  Craft I, Gorgy A, Hill J, Menon D, Podsiadly B.Will GnRH antagonists provide new hope for patients
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second line approach in IVF. Hum. Reprod. Suppl. 2000; 15 (in print)

48
     Albano C, Smitz J, Tournaye H, Riethmuller-Winzen H, Van Steirteghem A, Devroey P. Luteal


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phase and clinical outcome after human menopausal gonadotrophin/gonadotrophin releasing hormone
antagonist treatment for ovarian stimulation in in-vitro fertilization/intracytoplasmic sperm injection
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