GnRH Microdose stimulation in CO by fjwuxn



In: ‘The art and science of Assisted Reproductive Techniques (ART)’. Ed. G. Allahbadia and R. Basuray- Bas,
Publ Jaypee Medical Publishers; Chapter 12; 2003: 73 -7

                                              Microdose GnRH for the
                                         Stimulation of Low responders
                                                                           C.A.M. Jansen, K.E. Tucker
                              Department of IVF, Reinier de Graafgroep, loc Diaconessenhuis Voorburg
                                                                                     The Netherlands

OVERVIEW                                                  more the result of the promotion policy, or the
                                                          lack thereof by the pharmaceutical companies,
Gonadoptrophin-releasing hormone (GnRH)                   rather than of scientifically founded data.
agonists have initially been introduced in the            Interestingly, the large-scale use of depot
field of reproductive medicine on an „off label           formulas seems mainly to have been confined
use‟ basis without preceding proper dose                  to certain countries such as France and Israel.
finding studies. As a result doses that were              In these countries the fear of a possible long-
required for the original indication (i.e.                term influence of depot preparations seems to
prostate carcinoma) were used, begging the                have been less prominent.
question whether these schemes would not                  In addition there is insufficient evidence to
lead to LH levels that were too low for the               compare the different GnRH agonists in terms
maintenance of proper follicle growth in some             of efficiency and efficacy. Most prospective
patients. During the era of follicle stimulation          randomized studies compare one agonist with
with HMG- a combination of FSH and LH (or                 another, without any preceding necessary dose
hCG)- this aspect might stay unnoticed as there           finding studies. The only real dose-finding
will always be a sufficient exogenous                     study was initiated by dr Mak and performed
administration to sustain follicle growth, but            at the Free University in Amsterdam, in a
this may change for some patients since the               prospective, double blind placebo controlled
wide scale use of recombinant FSH devoid of               (unique in this field), randomized study. It was
any LH activity. Some authors have                        clear that much lower doses, even up to 5
appropriately questioned the dosing for GnRH              µg/day of triptorelin could suffice in obtaining
agonists: they have coined the term “micro                pituitary desensitization2. In a further study
dose”, but one should question this term as it            there turned out to be no influence on
may well be that what is considered normal                pregnancy rates between any of the dosages
may actually be a “macro dose”. Dose finding              used (placebo, 15, 50 and 100 μg/ day), and
studies have only recently been performed, but            even the placebo led to a similar pregnancy
uncontrolled studies with lower dosage have               rate3. Additional details of this study have
suggested an improvement in response for                  been published previously4
certain specific groups such as previous low
responders. However none of these studies are             ‘Micro dose’ protocols in IVF
prospective, randomized and controlled. So                The first to suggest that some patients might
far, although it is possible that certain patients        benefit from micro dose GnRH protocols (40
may benefit from lower dosages, there still is            μg per day instead of the usual 1000 μg
no proper scientific basis for either attitude.           leuprolide acetate) was Richard Scott5.
Therefore there is an urgent need for                     However in this study the subsequent response
randomized controlled trials.                             with the microdose protocol was compared to
                                                          the previous response with the standard GnRH
Methods and results                                       dose, leaving the study open to the criticism
The first to suggest the benefit of GnRH                  that this may be due to the phenomenon of
agonists for prevention of premature                      „regression to the mean‟. The same holds for a
luteinization in reproductive medicine was                similar study of almost identical design that
Richard Fleming as early as 198.1 Several                 was published later6. In addition in this second
dosages with several GnRH agonists are used,              study, where patients received 80 μg leuprolide
most commonly buserelin, nafarelin, triptorelin           per day the previous low responders also
and leuprolide. Originally buserelin was used             received Growth Hormone (GH) as
universally, as this was the first and only               supplementation in the subsequent treatment,
available product. The subsequent increase in             thus having different stimulation schemes in
the use of leuprolide (mainly in the USA) and             both arms.
triptorelin (mainly in Europe and many other              A third study is open to the same criticism:
countries) at the expense of buserelin was                cycle analysis was performed before and after


the micro dose treatment in poor responders           do not respond to the stimulation with
whilst patients were subsequently divided             recombinant FSH under GnRH suppression
according to their age (above or below 40             may be „rescued‟ by switching over to HMG 13.
years).7                                              In this study patients that did not respond to
                                                      the combination of a GnRH agonist and
The ‘poor responder’                                  recombinant FSH were randomized to either
                                                      an increase in rec FSH or to stimulation with
In all studies concerning micro dose GnRH the         the same original dose HMG. The oocyte yield
group of patients was emphasized that pose the        as well as the oestradiol concentration was
greatest challenge to all of us, i.e. the so-called   significantly higher in the HMG group. The
„poor responders‟. In an overview of the              authors ascribe this to the lack of sufficient
proposed stimulation regimes in poor                  LH, needed for adequate follicle growth that
responders it was first concluded that so far         can be overcome by the administration of
there is no uniform definition of the word            exogenous LH, but then one might equally
„poor‟ responder.8 Various authors use                expect a favorable effect from a decrease the
different definitions of the word, ranging from       dosage of the GnRH agonist. Similarly
the number of follicles on ultrasound, (ranging       Westergaard et al have described an increase in
from 2 to 5), the maximal E2 level (ranging           miscarriage rates in patients that showed very
from 100- 660 pg/ml) on the day of hCG, the           low LH levels (below 0.5 IU/l in a sensitive
mean daily gonadoptrophin used, the total             assay with a detection limit of 0,05 IU/l) after
number of ampoules and so on. In addition it          GnRH down regulation in comparison to those
was concluded that there is no RCT to show            with higher LH levels14. This suggests that
that the micro dose GnRH is of benefit to poor        indeed there is a minimum concentration of
responders, that at best only some patients           LH necessary for adequate follicle growth. In
might benefit from it, and that in any case it is     the past, when stimulation was performed with
not possible to identify this patient in advance.     hMG this was a moot point as exogenously
In another retrospective analysis between the         administered LH (and/or hCG) was present in
standard midluteal long protocol and a micro          the hMG formulation (mandatory 1:1 - FSH:
dose of 40 μg daily dose of leuprolide it was         LH ratio by the pharmacopoeia) which was
concluded that except for a significant increase      always sufficient to allow for proper
in cancellation rate in the micro dose group          folliculogenesis. In this study the GnRH dose
there were no significant differences in the          was decreased considerably after down
other variables such as the oocyte yield or the       regulation was achieved from 0,5 mg to 0,2 mg
pregnancy rate9.                                      buserelin per day when ovarian stimulation
In one study the ovarian volume before the            was commenced with recombinant FSH. The
start of stimulation was taken into account, and      philosophy behind this dose decrease is that
results were compared in the different groups.        one may do with less GnRH agonist; however
However the stimulation scheme was not                LH levels were not measured in the first days
randomized: patients with a small volume (less        after dosage decrease. It has been published
than 3 cc) received a micro dose agonist              that LH levels may fall to undetectable levels
scheme, whilst women with a normal volume             after midfollicular cessation of the agonist
had a standard dose agonist scheme. 10 In             thereby compromising the sustenance of
addition in this study there was a surprisingly       follicle growth15.
large group with very small ovaries: 28 % of          Ideally before the introduction of any
all patients had a mean volume of less than 3         medication, dose finding studies should be
cc, which means (with the ellipsoid formula of        performed to establish the minimum effective
D1 x D2 x D3 x 0.526 or 0.523 depending on            dose to achieve any effect with a minimum in
the publication) a mean size of the complete          complications and cost. This has never taken
ovary of less than 18 mm. The authors                 place with GnRH agonists. Their rapid and
suggested that the ovarian response would             widespread introduction was due to the instant
have been less if a standard dose was used,           universal recognition of their ability to prevent
citing previous literature 11,12 However in only      luteinization and ovulation before follicle
one of these there is a decrease in oocyte            aspiration. This peculiar type of drug
numbers in small ovaries and in neither of            introduction was only possible because these
these there is a decrease in pregnancy rate.          substances were already available, as
Furthermore the incidence of small ovaries            mentioned previously. As such it is surprising
(less than 3 ml) ranged between 9 and 12 % in         that it has taken longer than 10 years after their
these studies, a considerably lower incidence         entry into the field of ART before the first
than the present study.                               proper dose-finding studies for COH in IVF
It has recently been suggested that patients that     were performed3


                                                       incredibly short time span, mainly because of
Dose       ITT    Start     ET      Cl        Ong      the market availability and quite possibly, for
                                    preg               doctors‟ convenience. The use of GnRH
Placebo    60     59        46      10        5        analogues minimizes the need for careful
15 g/d    60     56        55      8         8        follicle monitoring, as even inaccurate
50 g/d    60     56        55      10        9        measurements are not usually penalized by
100        60     58        55      13        7        premature LH surges. The rapid acceptance of
g/d                                                   these drugs however has occurred in spite of
                                                       the increased       risk of the ovarian
Table 12.I: Results of a dose-finding study            hyperstimulation syndrome (OHSS). The
with the GnRH agonist, triptorelin. ITT:               magnitude of this risk is more difficult to
intention to treat; Started: cycles commenced;         quantify than pregnancy rate, mainly because
ET: Embryo transfer; Cl preg: Clinical                 of its lower incidence. Many prospective
pregnancy       rate-     erroneously    called        randomized studies do not mention this
implantation rate; Ong: Ongoing pregnancy              feature; in addition there is a publication bias
rate.                                                  in reporting side effects and almost a total
                                                       publication deficit with regard to the mortality
This study is characterized by two peculiar            from this syndrome. A Medline and Embase
aspects:     one       semantic,      and       one    search revealed only one two cases resulting
methodological. Firstly, the implantation rate         from the complications of the OHSS17.
(IR) is defined as others would define the
clinical pregnancy rate/ET (i.e. the presence of       Determination of down regulation
at least one gestational sac per transfer). This
means that whenever the term IR is mentioned           Often a serum estradiol level is used to
it should actually be PR. Secondly, an LH              confirm adequate down regulation and is
peak is defined in this study as a doubling from       usually below 0.2 nmol/l. It should be noted,
baseline with one later value higher than the          however, that present Enzyme Immuno Assays
doubled one. This means, according to the              are not always appropriate, as there is a wide
authors, that if baseline level is 3 IU/l, a rise to   scatter in the low range.18 The intra-assay
7IU/l, and then to 8 IU/l the next day, depicts a      variation in the low range where the cut-off
LH peak. This, as such, cannot be considered           level is present may in the range of 25 %, This
to be a full-blown LH surge, necessary to              means that when one measures E2 by EIA, one
result in all changes prior to and after               in four patients with sufficient down-regulation
ovulation (i.e. resumption of meiosis and              and E2 below 0,5 nmol/l still seemingly has
adequate luteinization) and it is known that           too high an E2 level. LH levels can be
during follicular stimulation such small LH            measured as well, but many assays have a cut-
peaks can be present. In the placebo group,            off level of 1 IU/l and do not allow for the
even after these small LH elevations, a follicle       determination of the minimum LH necessary
puncture was performed, without additional             to optimize follicle growth, as well as
HCG supplementation. It is, therefore, not             granulosa-cell estradiol synthesis after
surprising that there were surprisingly few            stimulation with recombinant FSH.
transfers in the placebo group, and this may
also explain the high miscarriage rate                 Conclusions
                                                       „Micro-dose‟ GnRH protocols are mainly
The so-called „normal‟ dose was based on the           suggested for the so-called „poor responder‟
initial assumption that the degree of down             patients. However as proper dose finding
regulation needed to be as complete as                 studies are lacking there is no proper use of the
possible. A meta-analysis of several                   word, and the so-called „normal dose‟ may
prospective and randomized studies comparing           well turn out to be „macro- dose‟. None of the
down-regulated      and     non-down-regulated         studies are randomized, and it now seems that
treatments as first choice in IVF shows that a         the GnRH antagonists have become the newest
significant difference in pregnancy rates exits        hype in the treatment of „poor responders‟. It
between these two types of stimulation                 will soon become evident that these as well
protocols16. It should be noted, however, that         will not be the panacea we are all looking for,
the differences are due to exceptionally low           and that most poor responders will just have a
results in some studies in the non-analogue            limited stock of recruitable follicles available,
group, much lower than previously published            regardless of whatever one decides to choose
in comparable studies performed by these               as stimulation regimen.
same investigators. Nevertheless, the use of
GnRH analogues has become ubiquitous in an


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