LINEBURG


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pregnancy rates in IVF cycles in those women who underwent coasting (Grace
et al., 2005). The decrease in implantation and pregnancy rates was not
statistically signi¬cant. The clinical pregnancy rate for the non-coasted patients
was 34.4% per cycle (22 out of 64) compared with 20% per cycle (6 out of 30).
However, in the subset of patients who received a lower dose of hCG
(5000 versus 10 000 IU), the difference was statistically signi¬cant. The
pregnancy rate was 9% per cycle (1 out of 11) compared with 34.4% (p ¼ 0.04).
In the reported publications, ovulation was induced in three studies by
administering 5000 units of hCG (Waldenstrom et al., 1999; Dechaud et al.,
2000; Ohata et al., 2000), but more often with 10 000 units (Sher et al., 1995;
Dhont et al., 1998; Tortoriello et al., 1998a; Egbase et al., 1999; Fluker et al.,
1999; Aboulghar et al., 2000; Al-Shawaf et al., 2001). The fertilization rate was
signi¬cantly lower compared to the non-coasted group (59.4% vs. 73.9%,
164 PREVENTION OF OVARIAN HYPERSTIMULATION SYNDROME




respectively). The rate of cell division was also signi¬cantly slower and the
mean and median cumulative embryo index (EI) and the mean number of
blastomeres was also signi¬cantly lower (p < 0.0001). In our experience,
coasting abolished severe OHSS. However, the clinical pregnancy rate was
signi¬cantly lower in the coasted patients who received a lower dose of hCG.
Therefore, the question is raised: should we adjust our expectations and accept
a safer but less successful outcome? That question has to be asked every time
this clinical scenario arises.

COASTING: CONCLUSIONS
Coasting is the most popular method for preventing OHSS. Prospective
randomized studies regarding its ef¬cacy are limited because it is unacceptable
to have a control group subjected to the risk of severe hyperstimulation
syndrome. The exact point at which coasting should start or ¬nish varies
from one group to another, which limits the ability to compare outcomes.
Levinsohn-Tavor et al. (2003), after a critical review of the data in the different
protocols, recommended avoiding certain pitfalls in the coasting protocol in
order to achieve the best formula. Coasting should be initiated when the serum
estradiol exceeds 3000 pg/ml, but not unless the leading follicles reach
a diameter of 15“18 mm. The duration of coasting should be limited to less
than four days to avoid a decrease in implantation and pregnancy rates that
would occur after longer periods of coasting.
Opinion is divided about the impact of coasting on pregnancy outcome.
In my opinion, there is no question that, by utilization of this approach, many
cases of severe OHSS can be prevented. I believe that such a policy is useful;
however, I also believe that the application of coasting to the point of complete
prevention will result in a decrease in the number and the quality of oocytes
and a lower pregnancy rate.


DECREASE IN HCG DOSAGE

It is amazing that there is only one clinical trial published in the literature
regarding the impact of the dose of hCG on the occurrence of OHSS. Abdalla
et al. (1987) reported a signi¬cantly lower successful oocyte recovery in patients
who received 2000 IU of hCG (77.3%) compared with patients who received
either 5000 IU of hCG (95.5%) or 10 000 IU of hCG (98.1%), p < 0.001.
It is very interesting to review the details of the ¬rst article on the
classi¬cation of OHSS (Rabau et al., 1967). The authors listed seven cases
with mild OHSS and another seven cases with severe OHSS, and the dose
of hCG that was used ranged from 10 000 to 29 000 IU. Most of the patients
received around 25 000 IU, which is an amazingly high dose by today™s
standards. During that period, the ¬rst report to suggest that hCG
administration after ovarian stimulation with hMG resulted in pregnancy
with simultaneous ovarian cyst formation was published by Pascetto and
Montanino in 1964. The authors administered a total of 25 000 IU of hCG
165
RECOMBINANT hCG




for their ovarian stimulation protocol. Schenker and Weinstein (1978) in their
review summarized their experience in the 1960s and 1970s with some
fascinating remarks about hCG administration. The dose and timing of hCG
varied from 1000 to 25 000 IU or more, and from one to several doses, which
could either overlap or not overlap with the administration of hMG. They
found similar ovulation rates following any dosage of hCG but the pregnancy
rate was highest after 6000 to 15 000 IU. Very interestingly, they noted the
frequency of OHSS to be lower in patients given 1000“5000 IU or more than
25 000 IU, than in patients given 6000“25 000 IU. Data on the regimens of hCG
which did not overlap hMG showed a signi¬cantly lower incidence of OHSS
than when hCG overlapped (Thompson and Hansen, 1970; Schenker and
Weinstein, 1978).
In the routine IVF cases, most centers in the United States administer one
dose of hCG at 10 000 IU, whereas, in Europe, some centers administer 5000
only, while others administer 10 000 IU. In the past, some authorities have
recommended a dosage of up to 25 000 IU to induce ovulation (Lunenfeld
and Insler, 1978). I recommend a dose of 10 000 IU to trigger ovulation.
If there are clinical or endocrinological suspicions of OHSS, I reduce the dose
of hCG by one-third to one-half. I believe that this could at least help
in decreasing the severity of OHSS.


RECOMBINANT hCG

Recombinant hCG, at a dose of 250 mg, is as effective as 10 000 IU urinary
hCG in triggering ovulation. It also has the advantage of subcutaneous
administration (Rizk and Abdalla, 2006). The pregnancy and implantation rates
and the incidence of OHSS were comparable between recombinant and urinary
hCG (Chang et al., 2001; Driscoll et al., 2000; European Recombinant Human
Chorionic Gonadotrophin Group, 2000). Induction of ovulation in WHO
group II anovulatory women undergoing ovulation induction using recom-
binant FSH produced comparable results between 250 mg recombinant hCG
and 5000 IU urinary hCG (International Recombinant Human Chorionic
Gonadotrophin Study Group, 2001).


Alternatives to hCG
The Use of GnRH-Agonist to Trigger Ovulation
Alternatives to hCG have been explored for the last two decades (Rizk et al.,
1991a, 2002). These include GnRH agonists, native GnRH, and recombinant
LH. GnRH agonist has been used to trigger ovulation in assisted conception for
15 years. The widespread use of the long protocol of pituitary down-regulation
has practically limited its use to a minority of cycles where gonadotrophins only
are used. If the next decade witnesses a signi¬cant increase in GnRH antagonist
cycles, then the use of the GnRH agonist will be revisited extensively.
166 PREVENTION OF OVARIAN HYPERSTIMULATION SYNDROME




IN GONADOTROPHIN CYCLES
The use of GnRH agonists to trigger ovulation has been investigated since
the late 1980s. Gonen et al. (1990) and Itskovitz et al. (1991) used the initial
¬‚are-up effect of the agonist to achieve ovulation and subsequent pregnancies.
In patients at risk of OHSS, intranasal buserelin (200 mg three times
at 8 h intervals) was used to trigger ovulation, and a 22% pregnancy rate
resulted without any cases of OHSS. Imoedemhe et al. (1991) used GnRH-a
in 38 women considered at risk of OHSS, having serum estradiol levels of
44000 pg/ml, with 11 pregnancies and no cases of OHSS. Emperaire and Ruf¬e
(1991) utilized buserelin 200 mg 3 ‚ at 8 h intervals in a series of 126 cycles in
48 patients with primary infertility treated with gonadotrophins for anovula-
tion. In the 37 cycles where buserelin was used, no OHSS occurred despite high
preovulatory levels of serum estradiol. The pregnancy rate per cycle was 21.6%
using buserelin, compared with 16.8% when hCG was used. Van der Meer et al.
(1993) could not prevent OHSS by using GnRH agonist to trigger ovulation.
Gerris et al. (1995) triggered ovulation in hMG stimulated cycles by using
GnRH agonist and observed a high frequency of luteal phase insuf¬ciency.
OHSS could not be prevented by using this approach. The major limitation of
the use of GnRH agonist is that it could not be used in cycles where ovarian
stimulation with hMG was performed after pituitary desensitization using
GnRH agonist (Rizk, 2001, 2002).
Revel and Casper (2001) carefully analyzed the use of GnRH agonist
instead of hCG to trigger ovulation in cycles where gonadotrophins and
clomiphene citrate have been used for ovulation induction. They evaluated
the ef¬cacy of GnRH agonist and pursued the concept of whether GnRH
agonist would prevent OHSS. They analyzed the data from uncontrolled
clinical trials as well as controlled studies comparing GnRH agonist with hCG
in terms of its ability to trigger the LH surge (Tables VII.12, VII.13) or to
prevent OHSS (Tables VII.14, VII.15). In uncontrolled studies when GnRH
agonist was used to trigger ovulation, the incidence of OHSS was 0.9% (3 out
of 334) (Table VII.14). In controlled studies, the incidence of OHSS was
1.5% in the hCG group, compared with 0.7% in the GnRH agonist group
(Table VII.15). It appears therefore that GnRH agonist is as effective as hCG in
triggering ovulation in gonadotrophin-only cycles with only half the incidence
of OHSS.

IN GnRH-ANTAGONIST/GONADOTROPHIN CYCLES
Rizk (2002) reviewed the approaches that have been successfully used to
induce the ¬nal stages of oocyte meiosis maturation in GnRH antagonist
and gonadotrophin cycles. These include hCG, GnRH agonist, native GnRH,
recombinant LH and withdrawal of GnRH antagonist. GnRH agonist has been
successfully shown to induce these ¬nal stages of oocyte maturation in monkeys
and humans, Felberbaum et al. (1995) and Olivennes et al. (1996) elegantly
demonstrated ovulation triggering by GnRH agonist after GnRH antagonist
treatment.
167
RECOMBINANT hCG




Table VII.12 Effectiveness of GnRH agonist in uncontrolled studies
Reproduced with permission from Revel and Casper (2001). Infertility and Reproductive
Medicine Clinics of North America 12:105“18

Pregnancy rate
Study Criteria No. LH surge, no. (%)* per ET no. (%)**

Lanzone et al. (1989) 8 8 (100) “
E2{41200 pg/ml
Emperaire and Ruf¬e (1991) 126 “ 27 (22)
E244000 pg/ml
Imoedemhe et al. (1991) 27 “ 11 (29)
Itskovitz et al. (1991) 12 12 (100) 4 (29)
Tulchinsky et al. (1991) pilot study 13 11 (85) 4 (36)
van der Meer et al. (1993) pilot study 48 44 (92) 10 (23)
Balasch et al. (1994) cycles that would otherwise 23 17 (74) 4 (17)
have been cancelled
E243500 pg/ml
Shalev et al. (1994) 12 “ 6 (50)
All 261 88% 29%

* LH ¼ luteinizing hormone
** ET ¼ embryo transfer
{
E2 ¼ 17b-estradiol



Table VII.13 Effectiveness of GnRH agonist versus hCG in controlled studies
Reproduced with permission from Revel and Casper (2001). Infertility and Reproductive Medicine
Clinics of North America 12:105“18

LH surge, Pregnancies LH surge, Pregnancies,
Study Stimulation* No. no. (%) no. (%) No. no. (%) no. (%) p

Gonen et al. (1990) CC“hMG 9 9 (100) 0 9 9 3 (33) NS**
Segal and Casper CC“hMG 95 “ 19 (19) 84 “ 18 (20) NS
(1992)
Scott et al. (1994) CC 21 21 (100) “ 21 21 (100) “ NS
Kulikowski et al. CC“hMG 34 “ 3 (9) 32 “ 4 (13) NS
(1995)
Gerris et al. (1995) hMG 10 10 “ 19 “ “
Schmit-Sarosi et al. CC 15 8 (53) 2 (13) 11 11 (100) 3 (27) <0.01
(1995)
Shalev et al. (1995a) CC 106 “ 14 (13) 104 “ 3 (12) NS
Shalev et al. (1995b) hMG 68 “ 18 (27) 72 “ 11 (15) NS
Romen et al. (1997) FSH 416 413 (99) 71 (17) 345 342 (99) 93 (27) 0.0007
All 753 461/471 (98) 127/734 (16.7) 676 402/405 (99) 144/657 (22) <0.05

* LH ¼ luteinizing hormone; CC ¼ clomiphene citrate; HmG ¼ human menopausal gonadotropin; FSH ¼ follicle-
stimulating hormone
** NS ¼ not signi¬cant
168 PREVENTION OF OVARIAN HYPERSTIMULATION SYNDROME




Table VII.14 Uncontrolled studies to determine whether GnRH agonists for
triggering ovulation prevent OHSS
Reproduced with permission from Revel and Casper (2001). Infertility and
Reproductive Medicine Clinics of North America 12:105“18

No. with
Study Criteria No. cycles OHSS Comments

E2*41200 pg/ml or
Emperaire and Ruf¬e (1991) 37 10
43 follicles of 17 mm
E244000 pg/ml
Imoedemhe et al. (1991) 36 0
Itskovitch et al. (1991) E2 5000“13000 pg/ml 8 0
Van der Meer et al. (1993) “ 48 3 mild to moderate
Balasch et al. (1994) cycles to be cancelled 23 0
owing to high risk
Balasch et al. (1995) 30 0
Lanzone et al. (1989) PCOS 40 0 some GnRh
agonist, some hCG
Lewit et al. (1995) High risk? 80 0
E2 43500 pg/ml,
Shalev et al. (1994) 12 0 not IVF
no of follicles 420
Total 334 3(0.9%)

* E2 ¼ 17b-estradiol




Table VII.15 Controlled studies to determine whether GnRH agonist for triggering ovulation
prevents OHSS
Reproduced with permission from Revel and Casper (2001). Infertility and Reproductive Medicine
Clinics of North America 12:105“18

GnRH HCG

Study Criteria No. OHSS No. OHSS Comments

Gonen et al. (1990) 9 0 9 0
Segal and Casper (1992) randomized 84 0 95 0
Gerris et al. (1995) controlled 28 1 10 0 on native GnRH
Kulikowski et al. (1995) non-randomized 48 0 34 4 moderate OHSS
Shalev et al. (1995b) randomized 72 4 84 8 not signi¬cant
Shalev et al. (1995a) randomized 104 0 106 0 clomiphene cycles
Romeu et al. (1997) prospective, 345 0 416 0 FSH, IUI
non-randomized
Penarrubia et al. (1998) prospective, 26 0 26 0 2 doses of hCG and of LH
non-randomized
All 716 5 (0.7%) 780 12 (1.5%) signi¬cant, p ¼ 0.047 (z test)
169
RECOMBINANT hCG




Focusing on OHSS prevention, recent studies suggested the safe use
of GnRH agonist to trigger ovulation in women who underwent ovulation
induction with recombinant FSH and the GnRH antagonist. Itskovitz-Eldor
et al. (2000) reported the use of a single bolus of GnRH agonist (decapeptyl)
0.2 mg to trigger ovulation in women at risk for OHSS after treatment with
recombinant FSH and ganirelix. All women had serum estradiol levels greater
than 3000 pg/ml and more than 20 follicles; none developed signs or symptoms
of OHSS and four conceived.
Bracero et al. (2001) studied 19 women who underwent controlled ovarian
hyperstimulation for IVF using gonadotrophins and ganirelix, 0.5 mg. All 19
patients had serum estradiol greater than 3000 pg/ml with 20 or more follicles
more than 15 mm in diameter. In eight patients, leuprolide acetate, 1 mg, was
given twice, 12 h apart, and in 11 women, hCG, 10 000 IU, was administered
and oocytes were retrieved 36 h later. In the ¬rst group, none of the patients
developed symptoms or signs of OHSS, whereas two of the 11 patients in the
second group developed mild OHSS, p ¼ 0.05. The authors concluded that
leuprolide acetate instead of hCG should be used for triggering ovulation
to prevent OHSS in cycles where gonadotrophins and GnRH antagonist has
been used.
More recently, several prospective randomized trials evaluated the use
of GnRH agonist to trigger ¬nal oocyte maturation instead of hCG in patients
undergoing IVF with GnRH antagonists. Humaidan et al. (2005) recently
evaluated the use of an agonist as an alternative to hCG in 122 patients
undergoing IVF. The authors used buserelin 0.5 mg subcutaneously to trigger
ovulation. A signi¬cantly lower pregnancy rate was reported in the agonist
arm. This might be associated with discontinuation of luteal support in the
presence of a positive pregnancy test.
Kolibianakis et al. (2005) randomized 106 patients to receive either 10 000
IU urinary hCG or 0.2 mg triptorelin for triggering ¬nal oocyte maturation.
Ovarian stimulation for IVF was performed using recombinant FSH at a
¬xed dose of 200 IU, and GnRH antagonist was started on the sixth day of
ovarian stimulation. Luteal phase support was established using micronized
vaginal progesterone and oral estradiol. The authors observed no signi¬cant
differences in the number of cumulus“oocyte complexes, metaphase II oocytes,
fertilization rates or the number and quality of embryos replaced. However,
a signi¬cantly lower probability of ongoing pregnancy rate in the GnRH agonist
arm prompted discontinuation of the trial (OR ¼ 0.11; 95% CI, 0.02“0.52).


Recombinant Human LH to Trigger Ovulation
hCG is a promoter of OHSS whereas an endogenous LH surge rarely causes
OHSS (Rizk and Smitz, 1992). The idea of using leuteinizing hormone is an
old idea, not a new one. The only recent development is the development
of recombinant LH. In 1970, Vande Wiele et al. substituted puri¬ed human
pituitary LH (hLH) for hCG. They administered hLH in multiple injections
over a 24 h period, mimicking the normal LH surge. Human LH maintained
170 PREVENTION OF OVARIAN HYPERSTIMULATION SYNDROME




the corpus luteum, and by repeated injections prolonged its functional
life beyond 14 days. The authors experienced no severe cases of OHSS;
however, Schenker and Weinstein (1978) cautioned that the clinical experience
with hLH was very limited. Jewelewicz (1972) reported a case of quintuplet
pregnancy after ovulation induction with hMG and hLH.
In the experimental animal model, Gomez et al. (2004) compared the
capacity of LH, FSH and hCG to trigger ovulation, and also studied their effects
on vascular permeability and the expression of VEGF in the ovaries. As
discussed in detail in Chapter III, they stimulated immature female rats with
10 IU of pregnant mare serum gonadotrophin (PMSG) for four days and
thereafter ovulation was triggered by using 10 IU of hCG, 10 IU of FSH, 10 IU
LH, 60 IU of LH or normal saline. All the hormones utilized were equally
effective at triggering ovulation, and signi¬cantly different from the control
injection. However, only 10 IU of LH resulted in a signi¬cantly lower vascular
permeability and VEGF expression. Gomez et al. (2004) concluded that a lower
dose of LH (10 IU vs. 60 IU) prevented the undesired changes in vascular
permeability and the risk of OHSS. However, the authors encouraged clinicians
to determine the optimal dosage of LH needed to trigger ovulation in women
and at the same time to abolish OHSS. We believe that this is a very important
issue, because the clinical trials of recombinant LH have also suggested a lower
OHSS rate associated with a lower pregnancy rate, which will be discussed
in the next section. The success in determining the optimal dose or doses of
LH could be a signi¬cant step towards eliminating OHSS while retaining the
pregnancy rate.
Considering the signi¬cant differences between hCG and recombinant
human luteinizing hormone (r-hLH) and its impact on OHSS, this is the time
to revolutionize the triggering of ovulation (Emperaire and Edwards, 2004).
A European prospective randomized double-blind multicenter study evaluated
the safety and minimal effective dose of recombinant LH in patients under-
going IVF compared with 5000 IU of urinary hCG (European Recombinant
LH Study Group, 2001). The study showed that a single dose of r-hLH was
effective in inducing ¬nal follicular maturation and early luteinization in IVF
patients, and a dose between 15 000 and 30 000 IU was equivalent to 5000 IU of
hCG. There were no statistically signi¬cant differences between urinary hCG
(u-hCG) and r-hLH administration in the number of oocytes retrieved, oocyte
nuclear maturity, oocyte potential for fertilization, the number of embryos,
clinical and biochemical pregnancies and the implantation rate of the embryos.
In terms of safety, r-hLH was well-tolerated at doses of up to 30 000 IU.
Moderate OHSS occurred in 12.4% of patients who received u-hCG and 12.0%
who received two injections of r-hLH. Interestingly, there was no moderate
or severe OHSS in those patients who received a single dose of r-hLH of 30 000
IU (European Recombinant LH Study Group, 2001). A single dose of r-hLH
resulted in a highly signi¬cant reduction in OHSS.
A recent double-blind large multicenter randomized study (Trial 21447),
which compared the implantation and pregnancy rates following triggering
ovulation by r-hLH versus hCG, was discussed in a letter to the editor
171
RECOMBINANT hCG




by Aboulghar and Al-Inany (2005) in response to an article advocating the
use of LH to trigger ovulation (Emperaire and Edwards, 2004). The study is
as yet unpublished (Aboulghar and Al-Inany, 2005). A total of 437 patients
were randomly allocated in a 2 to 1 ratio to either the r-hLH treatment group
(291 patients) or the u-hCG treatment group (146 patients). The two
groups were matched for age, height, weight, BMI, race and smoking habits
at baseline. The mean ages were 31.1 + 4.5 years and 30.5 + 4.5 years, mean
height 164 + 7 cm and 161 + 7 cm, mean body weight 65.3 + 11.4 kg and
66.0 + 11.8 kg, the mean BMI was 24.4 + 4.2 kg/m2 and 24.4 + 4.1 kg/m2 in
the r-hLH and u-hCG groups respectively. The majority of patients in the study
population were Caucasian (95.9 and 97.9 in the r-hLH and the u-hCG groups,
respectively) and the majority did not smoke (78.0% and 82.2%, respectively).

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