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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
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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
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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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