FERTILITY AND STERILITY威

IN VITRO FERTILIZATION VOL. 73, NO. 2, FEBRUARY 2000

Copyright ©2000 American Society for Reproductive Medicine
Published by Elsevier Science Inc.
Printed on acid-free paper in U.S.A.

Prospective, randomized, controlled study

of in vitro fertilization-embryo transfer with
a single dose of a luteinizing hormone-
releasing hormone (LH-RH) antagonist
(cetrorelix) or a depot formula of an
LH-RH agonist (triptorelin)
François Olivennes, M.D., Ph.D.,* Joëlle Belaisch-Allart, M.D.,†
Jean-Claude Emperaire, M.D.,‡ Hervé Dechaud, M.D.,§ Sylvia Alvarez, M.D.,㛳
Laurence Moreau, M.D.,¶ Bernard Nicollet, M.D.,** Jean-René Zorn, M.D.,††
Philippe Bouchard, M.D.,‡‡ and René Frydman, M.D.*

A. Béclère Hospital, Clamart; J. Rostand Hospital, Sèvres; Clinique St. Sernin, Bordeaux; A. de Villeneuve
Hospital, Montpellier; CMCO, Schiltigheim; Clinique Ste. Marie-Thérèse, Brin; and Tenon Hospital, Cochin
Hospital, and Ste. Antoine Hospital, Paris, France

Received August 31, 1999;

revised and accepted Objective: To confirm the value of a single dose of 3 mg of cetrorelix in preventing the occurrence of
October 25, 1999. premature LH surges.
Reprint requests: François Design: Multicenter randomized, prospective study.
Olivennes, M.D., Ph.D.,
Service de Gynécologie- Setting: Reproductive medicine units.
Obstétrique, Hôpital A. Patient(s): Infertile patients undergoing ovarian stimulation for IVF-ET.
Béclère, 157, rue de la
Porte De Trivaux, 92140 Intervention(s): A single dose of 3 mg of cetrorelix (Cetrotide; ASTA Medica, Frankfurt, Germany) (115
Clamart Cedex, France patients) was administered in the late follicular phase. A depot preparation of triptorelin (Decapeptyl;
(FAX: 33-1-45-37-49-80). Ipsen-Biotech, Paris, France) was chosen as a control agent (39 patients). Ovarian stimulation was conducted
* Department of Obstetrics with hMG (Menogon; Ferring, Kiel, Germany).
and Gynecology, A. Main Outcome Measure(s): Premature LH surges (LH level ⬎10 IU/L), progesterone level greater than 1
Béclère Hospital. ng/L, and IVF results.
†
Department of Obstetrics
and Gynecology, J.
Result(s): No LH surge occurred after cetrorelix administration. The patients in the cetrorelix group had a
Rostand Hospital. lower number of oocytes and embryos. The percentage of mature oocytes and fertilization rates were similar
‡
Clinique St. Sernin.
in both groups, and the pregnancy rates were not statistically different. The length of stimulation, number of
§ hMG ampules administered, and occurrence of the ovarian hyperstimulation syndrome were lower in the
Department of Obstetrics
and Gynecology, A. de
cetrorelix group. Tolerance of cetrorelix was excellent.
Villeneuve Hospital. Conclusion(s): A cetrorelix single-dose protocol prevented LH surges in all patients studied. It compares
㛳 favorably to the “long protocol” and could be a protocol of choice in IVF-ET. (Fertil Steril威 2000;73:314 –20.
Department of Obstetrics
and Gynecology, Tenon ©2000 by American Society for Reproductive Medicine.)
Hospital.
¶
Key Words: IVF-ET, LH-RH antagonist, single dose
Department of Obstetrics
and Gynecology, CMCO.
** Clinique Ste. Marie-
Thérèse.
One of the main reasons for the increased (ARTs). The combination of luteinizing hor-
††
Clinique Universitaire success rate of IVF-ET is the use of controlled mone-releasing hormone (LH-RH) agonist
Baudelocque, Cochin ovarian stimulation. Multifollicular develop- (LH-RH-a) and human menopausal gonadotro-
Hospital. ment allows the collection of a large number of
‡‡
pin (hMG) proved to be the most successful
Department of oocytes that can yield several embryos for mul-
Endocrinology, St. Antoine and is the most frequently used. In France,
Hospital. tiple embryo transfers. LH-RH-a are used in over 90% of the IVF-ET
Different stimulation regimens have been cycles, and the so-called “long protocol” is the
0015-0282/00/$20.00
PII S0015-0282(99)00524-5 used in assisted reproductive technologies most common (1).

314
 Treatment with LH-RH-a induces a medical, reversible
hypophysectomy and prevents premature LH surges, result-
ing in cycle cancellation and poor IVF outcome (2, 3). Preg-
nancy rates have increased mainly through an increase in the
number of collected oocytes and embryos (4). Treatment
with LH-RH-a allows programming of treatment cycles,
which helps to organize more efficiently the activities of
large IVF centers. However, LH-RH-a has drawbacks. The
long protocol is associated with side effects related to hor-
monal depletion (such as hot flashes, bleeding, and vaginal
dryness). The length of the treatment period is increased,
because 2–3 weeks are usually needed to obtain desensiti-
zation, and stimulation requires a greater amount of hMG
(5). The latter factor increases the cost of the procedure and
the risk of hyperstimulation syndrome, a rare but serious
complication (6).
Recently developed LH-RH antagonist compounds are
devoid of the side effects associated with earlier compounds
(7). The competitive properties of LH-RH antagonists induce
an immediate and rapid decrease in LH and FSH levels
without “flare-up.” Their administration in the late follicular
phase can prevent (or interrupt) the LH surge, as shown with
Nal-Glu and cetrorelix (8 –11). Their use in IVF-ET has been
suggested to achieve similar results as those obtained with
LH-RH-a, without the associated drawbacks.
Various stimulation protocols that incorporate the use of
LH-RH antagonists have been suggested. The multiple-dose
regimen requires daily injections of LH-RH antagonists
starting on day 5 or 6 of the stimulation period until the
administration of human chorionic gonadotropin (hCG)
(12, 13). On the basis of our previous studies with Nal-Glu
(14, 15), we proposed a single-dose protocol designed to
inject the LH-RH antagonist cetrorelix in the late follicular
phase, when the LH surge is most feared (16 –18). This
protocol was effective in preventing premature ovulation
while requiring a lower dose of hMG compared (albeit
retrospectively) to the long protocol using LH-RH-a in a
depot preparation (17). However, we treated a small number
of patients, and there were no prospective, randomized,
controlled clinical trials that compared this regimen to pro-
tocols using LH-RH-a.
The aim of this prospective, multicenter, randomized
study was to assess, in a large group of patients, the efficacy
of a single-dose regimen of the LH-RH antagonist cetrorelix
in preventing premature LH surges compared with that of a
depot preparation of the LH-RH-a triptorelin used as a con-
trol agent.
MATERIALS AND METHODS
Design
The study was open, randomized, and prospective and
multicentered. In view of the very different mode of admin-
istration of the cetrorelix and of the LH-RH-a in the long
FERTILITY & STERILITY威
protocol, it was impossible to design a double-blind study.
The major objective of this study was to determine the
response rate to cetrorelix (prevention of LH surges). A
control group that received triptorelin was included to vali-
date the design and the IVF variables (oocyte and embryo
quality and pregnancy rates). For this purpose, the random-
ization was performed using a 3:1 ratio in favor of cetrorelix.
The study and informed consent form were approved by
the ethics committee of Paris-Sud University (CCPPRB-
Kremlin-Bicêtre). The patients were provided with detailed
information about the study, and each one signed a consent
form.
Patients
Patients were recruited in eight French IVF centers (De-
partment chairs are listed in parentheses): A. Béclère Hos-
pital, Clamart (Pr. R. Frydman); J. Rostand Hospital, Sèvres
(Dr. J. Belaisch-Allart); Clinique St. Sernin, Bordeaux (Dr.
J.C. Emperaire); A. de Villeneuve Hospital, Montpellier (Pr.
B. Hedon); Tenon Hospital, Paris (Pr. J. Salat-Baroux);
CMCO, Schiltigheim (Pr. A. Dellenbach); Clinique Ste.
Marie-Thérèse, Bron (Dr. B. Nicollet); and Clinique Univer-
sitaire Baudelocque, Paris (Pr. J.R. Zorn).
The study inclusion criteria were as follows: patients
18 –39 years old who required infertility treatment by con-
trolled ovarian stimulation and IVF-ET with or without
intracytoplasmic sperm injection (ICSI) and had normal
menstrual cycle with a range of 24 –35 days with intra-
individual variation of ⫾3 days, FSH levels ⱕ10 IU/L done
at cycle day 2 ⫾ 1, normal uterus, and no more than three
previous IVF-ET attempts. Women with the polycystic ovar-
ian syndrome and patients with severe endometriosis (Amer-
ican Fertility Society stage III and IV) were excluded.
A total of 169 patients were randomized (126 in the
cetrorelix group and 43 in the triptorelin group). However,
15 patients did not receive the medication (11 in the cetro-
relix group and 4 in the triptorelin group). Intracytoplasmic
sperm injection was done in 12 patients of the cetrorelix
group (10.6%) and in 5 patients in the triptorelin group
(13.9%).
Treatment Procedures
LH-RH Antagonist Protocol
The cetrorelix single-dose protocol, in which the LH-RH
antagonist is administered in the late follicular phase, was
used as described in previous studies (16 –18). Ovarian stim-
ulation was started on day 2 of the menstrual cycle with 2
ampules per day of hMG (Menogon; Ferring, Kiel, Ger-
many) for the first 4 days of treatment. The dose of hMG was
thereafter adapted to the ovarian response. Monitoring of the
cycle was done by daily assessment of plasma levels of LH,
FSH, E2, and P in conjunction with ultrasonography starting
on stimulation day 5. A single dose of 3 mg of the LH-RH
antagonist cetrorelix (Cetrotide; ASTA Medica, Frankfurt,
315
Germany) was administered on day 7 of hMG stimulation
unless the E2 level was below 400 pg/mL, in which case the
injection was delayed. If triggering of ovulation was not
done within 4 days of administration of the 3-mg dose of
cetrorelix, a daily injection of 0.25 mg was given until hCG
administration. The LH-RH antagonist protocol was as-
signed to 115 patients.
LH-RH-a Protocol
The long protocol consisted of administration of a depot
formula of 3.75 mg of triptorelin (Decapeptyl LP 3.75;
Ipsen-Biotech, Paris, France) in the midluteal phase (days
18 –22) before the stimulation cycle. Stimulation of hMG
was commenced at least 15 days after LH-RH-a injection,
when desensitization was confirmed by plasma E2 level ⱖ50
pg/mL, FSH and LH levels ⱕ10 IU/L, P levels ⱕ1 ␮g/mL,
and absence of ovarian cysts on ultrasonography. Adminis-
tration of hMG was started at 2 or 3 ampules per day
(according to previous response to ovarian stimulation) dur-
ing the first 4 days of the stimulation regimen and was then
adapted to ovarian response. Monitoring of the cycle was
similar to the LH-RH antagonist protocol. The agonist pro-
tocol was assigned to 39 patients.
Cancellation, Triggering of Ovulation, and
Luteal Support
The cycle was cancelled and hCG was not administered
if more than 12 follicules had a diameter ⱖ15 mm or E2
levels were ⱖ4,000 pg/mL. Human chorionic gonadotropin
(Gonadotrophine Chorionique “Endo”; Organon, Puteaux,
France) (10,000 IU) was given when at least one follicle
greater than or equal to 18 mm was observed on ultrasonog-
raphy and the E2 plasma level was greater than or equal to
1,200 pg/mL. Luteal phase support was systematically given by
daily vaginal administration of 300 to 600 mg of micronized P
(Utrogestan; Besins Iscovesco Pharmaceuticals, Paris, France).
Data Analysis
The primary task was to assess the efficacy of the single-
dose protocol in preventing premature ovulation indicated by
LH surges. Luteinizing hormone surges were defined as an
LH value greater than or equal to 10 IU/L and a subsequent
increase in the P level (ⱖ1 ng/mL). Plasma LH values
greater than or equal to 10 IU/L without increase in the P
level were considered increases in the LH level and were
also analyzed.
The tolerability of both the LH-RH antagonist and the
LH-RH-a was evaluated by observation of the injection site
and self-report of adverse events by the patients.
The following IVF-ET variables were compared between
the two protocols: dose of hMG; days of stimulation; E2
levels; number and size of follicles on the day of hCG;
number of oocytes; number of metaphase II oocytes in ICSI
cycles and number of mature oocytes evaluated 24 hours
after insemination in cycles without ICSI; fertilization rate;
316 Olivennes et al. Single-dose cetrorelix protocol
number of embryos, pregnancies, miscarriages, and ectopic
pregnancies; and incidence of the ovarian hyperstimulation
syndrome (OHSS). Clinical pregnancies were defined as
fetal heart beat on ultrasonography. Ongoing pregnancies
were defined as pregnancies ongoing after 12 weeks of
amenorrhea.
Statistical Analysis
The response rate was defined as the percentage of pa-
tients who did not experience an LH surge. A 95% lower
confidence limit was to be determined for this rate. Assum-
ing a response rate of at least 95% for cetrorelix and a width
of 5% for the confidence interval, 107 patients were neces-
sary. To achieve this number of evaluable patients, it was
planned to recruit 120 cetrorelix patients. The control group
that received triptorelin was included to validate the trial
design and to assess IVF variables, such as oocytes and
embryo quality. The randomization was performed using a
3:1 ratio in favor of cetrorelix.
Confidence intervals for single proportions were calcu-
lated according to the Clopper-Pearson method. The results
of comparisons between treatment groups, performed as
secondary analyses, are presented using confidence intervals
rather than P values. P values were considered inappropriate
because they depend not only on the observed differences
and variability but also on the sample size and the treatment
allocation ratio, so that nonsignificant results would have
been uninformative.
Confidence intervals for differences in proportions were
calculated according to the method of Mantel-Haenszel ad-
justing for study center, except for the incidence of OHSS
and miscarriages. Because of low incidence, no center-
adjusted analysis was performed for these two variables. For
the rate of ectopic pregnancies, the numbers were so low that
no comparison was made. For all other treatment compar-
isons, analyses of variance by study center and treatment
were used.
RESULTS
No difference was observed between the LH-RH-a and
LH-RH antagonist groups for demographic and baseline data
(Table 1). The distribution of the causes of infertility were
also similar for tubal pregnancy, male sex, endometriosis,
and other factors; respective values were 52.2%, 16.5%,
1.7%, and 29.6% in the cetrorelix group vs. 48.7%, 17.9%,
5.1%, and 28.1% in the triptorelin group.
Cetrorelix Administration
One hundred fifteen patients (90.4%) received a single
3-mg dose of cetrorelix. Nine of these women (7.9%) were
given one additional dose of 0.25 mg of cetrorelix and 2
women (1.7%) received two additional doses of 0.25 mg,
because criteria for triggering of ovulation were not reached
within 4 days of the 3-mg administration.
Vol. 73, No. 2, February 2000
 TABLE 1

Demographic data, duration of infertility, and FSH level at screening in the two groups of patients.

No. of Mean value P

Variable Treatment patients (⫾SD) value

Duration of infertility (mo) Cetrorelix 115 59.3 ⫾ 35.0 .434

Triptorelin 39 55.3 ⫾ 38.1
FSH level at screening (U/L) Cetrorelix 110 6.3 ⫾ 2.0 .889
Triptorelin 38 6.3 ⫾ 1.9
Age (y) Cetrorelix 115 31.4 ⫾ 3.7 .378
Triptorelin 39 31.8 ⫾ 3.8
Broca index (sex corrected) Cetrorelix 114 1.1 ⫾ 0.2 .521
Triptorelin 39 1.1 ⫾ 0.2
Height (cm) Cetrorelix 114 164.5 ⫾ 6.1 .635
Triptorelin 39 163.9 ⫾ 6.0
Weight (kg) Cetrorelix 115 60.3 ⫾ 9.5 .766
Triptorelin 39 60.8 ⫾ 9.7

Olivennes. Study of IVF-ET. Fertil Steril 2000.

None of the 115 patients experienced an LH surge after
cetrorelix administration. However, according to the proto-
col definition, 3 of these patients (2.6%) exhibited an LH
surge before LH-RH antagonist administration. In all these
cases, E2 levels were already high (⬎800 pg/mL) on the day
of cetrorelix administration. The LH-RH antagonist injection
interrupted the surge, and stimulation was continued for 2–3
days until criteria for hCG administration were reached.
Oocyte pick-up was successfully performed in all cases, and
embryos were obtained. One of these patients achieved an
ongoing pregnancy. One patient in the triptorelin group
(2.8%) experienced an LH surge.
A total of 18 patients in the cetrorelix group (15.7%) had
an LH level ⱖ10 IU/L on the day of cetrorelix injection. The
administration of cetrorelix interrupted any further LH in-
crease. The mean plasma LH levels dropped significantly,
from 17.4 ⫾ 4.6 IU/L on the day of cetrorelix administration
to 1.0 ⫾ 0.3 IU/L the following day.
Plasma LH levels are presented in Figure 1. As expected,
LH plasma levels were lower at the onset of the stimulation
(day 1) in the group with down-regulated cycles (the LH-
RH-a group) (1.6 ⫾ 1.3 IU/L) compared with the cetrorelix
group (4.8 ⫾ 2.0 IU/L).

FIGURE 1

Serum LH concentration (mean ⫾ SD) in the two groups of patients.

Olivennes. Study of IVF-ET. Fertil Steril 2000.

FERTILITY & STERILITY威 317

 TABLE 2

IVF-ET results in the two groups of patients.

Treatment
Center-adjusted
Variables Cetrorelix Triptorelin 95% CI

No. of patients undergoing ovum pick-up (% of treated patients) 113 (98.3) 36 (92.3) ⫺0.4 to ⫺12.5
Stimulation length (d) 9.4 ⫾ 1.4 10.7 ⫾ 1.7 ⫺1.9 to ⫺0.7
No. of ampules 24.3 ⫾ 7.4 35.6 ⫾ 15.1 ⫺14.2 to ⫺7.2
E2 level on day of hCG administration (pg/mL)* 1,786 ⫾ 808 2,549 ⫾ 1,194 ⫺1,042 to ⫺368
Total no. of oocytes retrieved 9.2 ⫾ 5.1 12.6 ⫾ 7.4 ⫺5.6 to ⫺1.3
No. of mature oocytes/no. of metaphase II oocytes 7.2 ⫾ 4.9 10.3 ⫾ 7.4 ⫺5.3 to ⫺1.2
No. of embryos obtained 5.4 ⫾ 3.5 7.5 ⫾ 4.9 ⫺3.7 to ⫺0.6
No. of embryos transferred 2.6 ⫾ 0.9 2.7 ⫾ 0.6 ⫺0.3 to ⫺0.3
Clinical pregnancy rate/OPU (%) 22.6 28.2 ⫺23.9 to 12.3
Miscarriage rate (%) (no. of miscarriages/no. of pregnancies) 15.4 (4/26) 27.3 (3/11) ⫺41.6 to 17.9
Ectopic pregnancy rate (%) (no. of ectopic pregnancies/no. of pregnancies) 7.7 (2/26) 0 (0/11) —
Ongoing pregnancy rate/OPU (%) 18.3 23.1 ⫺20.2 to 8.9
Ongoing pregnancy rate/ET (%) 21.2 27.3 ⫺22.9 to 11.0
Rate of OHSS (%) 3.5 11.1 ⫺18.4 to 3.2
OHSS patients requiring hospitalization (%) 1.8 5.6 ⫺11.7 to 4.1
Note: All values are means ⫾ SD unless otherwise indicated. OHSS ⫽ ovarian hyperstimulation syndrome.
* Determined by a local laboratory.
Olivennes. Study of IVF-ET. Fertil Steril 2000.

IVF-ET Results The plasma E2 levels are presented in Figure 2. The E2

The IVF-ET results are presented in Table 2. One hun-
dred thirteen patients (98.3%) in the cetrorelix group and 36
(92.3%) in the triptorelin group had an oocyte pick-up. The
mean length of stimulation was significantly lower in the
cetrorelix group (9.4 vs. 10.7 days). The mean number of
ampules administered was significantly higher in the trip-
torelin group (35.6 vs. 24.3).
levels on the day of hCG administration were significantly
lower in the cetrorelix group (1,786 ⫾ 808 pg/mL) than in
the triptorelin group (2,549 ⫾ 1,194 pg/mL). The mean
number of follicles ⱖ18 mm was similar between the two
groups on the day of hCG administration (4.6 ⫾ 2.8 vs.
5.6 ⫾ 4.4 in the cetrorelix and triptorelin groups, respective-
ly). The total number of follicles greater than or equal to 15

FIGURE 2

Serum E2 concentrations (mean ⫾ SD) in the two groups of patients.

Olivennes. Study of IVF-ET. Fertil Steril 2000.

318 Olivennes et al. Single-dose cetrorelix protocol Vol. 73, No. 2, February 2000
mm and greater than or equal to 17 mm was higher in the
triptorelin group (5.0 ⫾ 3.9 vs. 3.4 ⫾ 2.6, CI 0.5–2.8).
The total number of retrieved oocytes, as well as the
number of mature or metaphase II oocytes, was higher in the
triptorelin group. This difference was not observed when the
analysis was restricted to the small number of ICSI cases.
The proportion of mature or metaphase II oocytes was sim-
ilar in the two groups (81.9% vs. 77.3%), as was the fertil-
ization rate (fertilized oocytes/oocytes inseminated or in-
jected) (50.5% vs. 54.7% in the cetrorelix and triptorelin
groups, respectively).
The total number of embryos obtained was also higher in
the triptorelin group (7.5 ⫾ 4.9) as compared with the
cetrorelix group (5.4 ⫾ 3.5). The number of embryos trans-
ferred was comparable in the two groups of patients (2.6 ⫾
0.9 vs. 2.7 ⫾ 0.6 for the LH-RH antagonist and agonist
groups, respectively).
The incidence of OHSS (World Health Organization
stage II–III) was higher in the triptorelin group (11.1%) than
in the cetrorelix group (3.5%), as was the number of OHSS
cases requiring hospitalization (5.6% vs. 1.8% for the ago-
nist and antagonist groups, respectively).
The clinical pregnancy rates per patient were statistically
comparable in the LH-RH-a group (28.2%) and in the
LH-RH antagonist group (22.6%), as were ongoing preg-
nancy rates per embryo transfer (23.1% vs. 27.3% for the
cetrorelix and triptorelin groups, respectively). The miscar-
riage rate was not different in the two groups.
DISCUSSION
This study was performed using a randomized, open, and
controlled parallel group design with a 3:1 distribution be-
tween the LH-RH antagonist single-dose protocol and the
LH-RH agonist long protocol. It was not intended to com-
pare the two groups but to validate the clinical model of our
single-dose 3-mg cetrorelix protocol.
Following injection of a depot formulation of triptorelin,
one surge in LH level was observed. The cetrorelix single-
dose protocol successfully prevented LH surge; no surge was
observed after antagonist administration. Three LH surges
occurred before cetrorelix administration. These surges were
interrupted by the antagonist. Stimulation was continued for
2 or 3 days, hCG was administered, and oocyte pick-up was
successfully performed. One of these three patients became
pregnant.
It was surprising to note that 18 patients had an LH rise
(LH level ⱖ10 IU/L) on the day of cetrorelix administration.
These rises were also immediately interrupted by LH-RH
antagonist administration, and all these patients had oocyte
pick-up and mature oocytes and embryos. Four of them
became pregnant (22.2%). These interrupted LH rises seemed
to have no measurable deleterious effect in this study.
FERTILITY & STERILITY威
In this single-dose protocol, antagonist administration
should be performed on stimulation day 7 to prevent early,
premature LH surges. In this study, 0.25 mg of cetrorelix
was administered daily if hCG was not given 4 days after the
first 3-mg administration. One hundred four patients (90.4%)
received only a single 3-mg dose of cetrorelix. Additional
0.25-mg doses were given to 11 patients (9.6%), 9 of whom
received this smaller dose on the morning of hCG adminis-
tration. In this study, 4 days was chosen as a maximum
protection period after a 3-mg cetrorelix administration. This
interval was selected from previous studies, since a large
number of patients had a 4-day interval between cetrorelix
administration and hCG administration without an LH rise or
surge (18). Whether the administration of 3 mg of cetrorelix
provides more than 4 days of protection in this regard
remains to be established.
The level of E2 on the day of hCG administration was
lower in the cetrorelix group. The total number of follicles
over 15 mm was lower in this group, and the stimulation
length was shorter by 1.3 days. The higher E2 levels could
explain the higher prevalence of OHSS in the triptorelin
group (11.1% vs. 3.6%), since a high E2 level is associated
with OHSS (6). Serious OHSS requiring hospitalization was
also more frequent in the triptorelin group (5.6% vs. 1.8%).
The difference in OHSS prevalence did not reach signifi-
cance because of the sample size. However, the inclusion of
two patients of the triptorelin group who were at risk for
OHSS makes the difference significant (P⬍.019). One of
these patients received only 5,000 IU of hCG, and the other
received hCG after coasting for 7 days.
As far as IVF-ET results are concerned, the long LH-
RH-a protocol resulted in more oocytes and more embryos,
as already demonstrated in the literature when compared to
other stimulation regimens (4). The percentage of mature
oocytes, fertilization, and pregnancy rates were not statisti-
cally different in the two groups.
The trend of a slightly lower pregnancy rate observed in
the cetrorelix group may be explained by different factors.
First, the pregnancy rate among the participating centers
varied greatly. The pregnancy rate in the triptorelin group
varied from 0% to 67%. The rate of 67% obtained in one of
the centers was clearly not a usual result. Second, some
population factors were not equivalent in the two groups,
despite randomization. For example, idiopathic infertility
and patients with secondary infertility were more frequent in
the triptorelin group. Third, it is likely that a learning curve,
inherent to the use of new treatment schemes, influences
outcome. The center with previous experience with the
LH-RH antagonists had similar pregnancy rates (29% in the
LH-RH-a group vs. 30% in the LH-RH antagonist group).
Fourth, the trend toward a higher pregnancy rate in the
triptorelin group may be related to the relative higher num-
ber of obtained embryos because of the higher number of
oocytes. The latter could be related to the desensitization
319
associated with the long LH-RH-a protocol, which could
induce a synchronization of the follicular cohort (19), result-
ing in the overall larger number of follicles observed in the
triptorelin group. Finally, a possible effect of LH-RH antag-
onist on the endometrium should be ruled out, although data
on the presence of LH-RH receptors in the endometrium are
conflicting (20 –22). We find this final hypothesis question-
able on the basis of the results of our first study, which
yielded good pregnancy rates despite the use of a higher dose
of cetrorelix (5 mg), given close to the day of hCG admin-
istration (16). Therefore, a careful analysis is needed before
drawing conclusions on the pregnancy rate. A comparative
study designed to assess a 5% difference in pregnancy rate
situated in the region of 20% would require over 1,200
patients in each treatment group.
The tolerability of the LH-RH antagonist cetrorelix was
excellent. A total of 29 patients (25.2%) had a transitory
reaction at the injection site (reddening and sometimes
itching).
In conclusion, this study has confirmed the efficacy of a
single dose of 3 mg of cetrorelix, administered in the late
follicular phase, in preventing premature ovulation as indi-
cated by LH surges. Cetrorelix was tolerated well, with only
mild and transitory reactions at the injection site. The single-
dose protocol is easy to use and ensures patient compliance.
This protocol provides a shorter duration of treatment, uses
less hMG, and has a lower incidence of OHSS. In addition,
the IVF-ET results compare favorably with those obtained
with the long protocol using a depot formula of triptorelin.
The results of this study strongly suggest that the single-dose
antagonist protocol offers a valid and interesting alternative
treatment regimen for IVF-ET.
Acknowledgments: The authors thank Dr. Marcel Marzetto (ASTA Medica,
Bordeaux, France), Dr. Hilde Riethmueller-Winzen, Mr. Armin Schueler,
Professor Jurgen Engel (ASTA Medica, Frankfurt, Germany), and the staff
of ASTA Medica in France and Germany for their support in this study.
Special thanks to Professor Victor Gomel, M.D. (Paris XI University, and
Department of Obstetrics and Gynecology, University of British Columbia,
Vancouver, BC, Canada) for rewriting the manuscript.
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