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Comparison of GnRH agonist and antagonist protocols in normoresponder

patients who had IVF-ICSI

Article  in  Archives of Gynecology and Obstetrics · May 2013

DOI: 10.1007/s00404-013-2903-z · Source: PubMed

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Arch Gynecol Obstet (2013) 288:1413–1416
DOI 10.1007/s00404-013-2903-z
REPRODUCTIVE MEDICINE
Comparison of GnRH agonist and antagonist protocols
in normoresponder patients who had IVF-ICSI
Mustafa Kara • Turgut Aydin • Turhan Aran •
Nurettin Turktekin • Betul Ozdemir
Received: 15 January 2013 / Accepted: 13 May 2013 / Published online: 26 May 2013
Ó Springer-Verlag Berlin Heidelberg 2013
Abstract
Purpose To measure the estradiol (E2) and progesterone
levels on day of human chorionic gonadotropin (hCG) and
to assess follicular development, pregnancy rates and IVF-
ICSI outcomes comparing gonadotropin releasing hormone
(GnRH) agonist and antagonist protocols.
Methods A total 195 women were included in the study.
The patients were treated with agonist or antagonist pro-
tocol according to the clinician’s and patient’s preference.
GnRH agonist and antagonists were administered to 77 and
118 patients, respectively.
Results Retrieved oocyte number (RON), metaphase two
oocyte number (MON), E2 and progesteron levels on day
of hCG, and fertilization rate were significantly higher in
agonist group than antagonist group (p \ 0.05). Implanta-
tion rate (IR), clinical pregnancy rate (CPR), and ongoing
pregnancy rate (OPR) were significantly higher in antag-
onist group than agonist group (p \ 0.05). However, there
was no significant difference between both groups in
relation with total follicle stimulating hormone (FSH).
M. Kara (&)
Department of Obstetrics and Gynecology, Bozok University
Medical Faculty, Adnan Menderes Boulevard No 44,
66200 Yozgat, Turkey
e-mail: opdrmustafakara@hotmail.com;
mustafa.kara@bozok.edu.tr
T. Aydin
B. Ozdemir
Acibadem In Vitro Fertilization Center, Kayseri, Turkey
T. Aran
Department of Obstetrics and Gynecology, Karadeniz Technical
University Medical Faculty, Trabzon, Turkey
N. Turktekin
Kayseri In Vitro Fertilization Center, Kayseri, Turkey
Conclusion GnRH agonist treatment seems to be associ-
ated with higher serum E2 and progesterone levels and
resulted in lower pregnancy rates than antagonist treatment.
Keywords GnRH agonist
GnRH antagonist
IVF-ICSI

Pregnancy
Introduction
IVF-ICSI has been utilized for many years in infertility and
the success of the treatment depends on many factors.
Retrieved oocyte number (RON) and follicular maturation
are important for a successful pregnancy. With the onset of
gonadotrophin releasing hormone (GnRH) agonists in
controlled ovarian hyperstimulation (COH), the pregnancy
rates were increased [1]. GnRH agonists have been used in
numerous treatment protocols to improve IVF-ICSI out-
come. Long protocol is usually used to suppress anterior
hypophysis and to prevent premature luteinizing hormone
(LH) surge. But, the duration of treatment is long and total
follicle stimulating hormone (FSH) dose required for the
stimulation is high in this regime [2]. Besides, estradiol
(E2) levels are high in GnRH agonist protocol. There are
studies showing that high E2 levels might have a negative
effect on implantation [3, 4].
Later, GnRH antagonists were presented for COH. Short
stimulation period and low gonadotrophin dosages are the
advantages of antagonist treatment [5]. In spite of the
superiority of these agents, management of ovulation
induction is still a challenge; especially, there are con-
flicting data about the normoresponder patients. Al Inany
et al. [6]. reported that RON and clinical pregnancy rate
(CPR) were lower in GnRH antagonist cycles However,
other reports suggested that live birth rates were higher in
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1414 Arch Gynecol Obstet (2013) 288:1413–1416

antagonist treatment than agonist protocol [7, 8]. In the
highlight of the current concepts, it was thought that
success of the GnRH treatment could be increased with
flexible regime. The aim of this study was to compare the
IVF-ICSI outcome between agonist and antagonist proto-
cols. To our best knowledge, there are few studies available
comparing IVF-ICSI outcome of agonist and antagonists
whose embryo transfer was done at the fifth day.
Switzerland) starting on the oocyte pickup (OPU) day and
lasted for 12 days (until the serum b hCG measurement
day). If pregnancy occurred, progesterone was given until
the 12th gestational week. Clinical pregnancy is accepted
as pregnancy, that is confirming the gestational sac or heart
beat of the fetus using TV USG.
Statistical analysis

Statistical analysis was performed using SPSS 17.00 (SPSS

Materials and methods Inc., Chicago). The Chi square test was used for categorical
variables and an independent sample t test was used for
This study was designed as a prospective cohort trial. The continuous variables that were normally distributed.
ethical consent was reviewed and approved by the Ethical p value \ 0.05 was considered significant. Results were
Committee of Bozok University Medical Faculty. Agonist expressed as mean ± SD.
and antagonist protocols were chosen according to the
clinician’s choice and the patient’s preference. The distri-
bution of the groups was homogenous. Normoresponder Results
patients were included in the study. Exclusion criteria were
having FSH [15 IU/l, having antimullerian hormone level One hundred and ninety-five women were included in the
\1.5 ng/ml and antral follicle number \4 on the second study. Seventy-eight patients were administered GnRH
day of menstruation. Testicular sperm extraction (TESE) agonist and 117 ones were given GnRH antagonist. All the
performed patients and the patients performed frozen- women were on their first cycle of IVF-ICSI cycle. Both
thawed embryo transfer were not included in the study. agonist and antagonist treatments were very well tolerated
GnRH agonists were used as long protocol. In long by the patients. No systemic adverse effects were observed
protocol, Leuprolide acetate (LucrinÒ daily 0.25 mg and no severe ovarian hyperstimulation syndrome (OHSS)
Abbott, USA) was given on the 21st day of the previous occurred.
menstrual cycle. Highly purified-urinary FSH (Fostimon The patients’ age, duration of infertility, basal E2 levels,
HPÒ 75 IBSA, Switzerland) was administered on the sec- basal FSH levels, basal AMH levels were analyzed but
ond day of the cycle after down-regulation of the pituitary. there were no statistical difference between agonist and
Ovarian response was assessed using transvaginal ultraso- antagonist groups. Characteristics of the patients are shown
nography (TV USG) and serum E2 was measured to in Table 1.
demonstrate pituitary suppression. In antagonist regime, The follicular development was better in agonist group.
pituitary suppression was managed with Cetrorelix RON and MON were significantly higher in agonist group
(CetrotideÒ 0.25 Merck-Serono, Switzerland). Flexible than antagonist group, respectively (p = 0.001 and
regime was preferred with Cetrorelix starting on the sixth p = 0.016). FR and IR were significantly lower in agonist
or seventh day of the cycle according to the follicular
growth (when the leading follicle reached to 13–14 mm) Table 1 Characteristics of the patients
and E2 level (when the level exceeded 600–800 pg/ml).
Agonist Antagonist p 95 % CI
Agonist and antagonist protocols were performed as (n = 78) (n = 117)
described previously [9, 10]. Monitorization of the cycle
was performed using TV USG and serum E2 assessment. Age (year) 29.60 ± 4.65 28.98 ± 4.64 0.36 -0.72 to
1.96
IVF-ICSI was done in all patients.
DI (year) 5.21 ± 0.66 5.70 ± 1.12 0.28 -0.52 to
Embryo culturing was done using G-MOPS plus, G-IVF 1.36
plus, G1-plus, G2-plus (Vitrolife, Sweden AB, Kungsba- Basal E2 level 43.14 ± 10.31 46.33 ± 8.27 0.95 4.55 to
cka, Sweden). Embryos were classified according to the (pg/ml) 11.76
number of blastomeres, percentage of fragmentation and Basal AMH 2.25 ± 0.48 2.61 ± 0.63 0.85 -0.26 to
blastomere appearences as type I, II, III or IV on first, third, level (ng/ml) -0.04
or fifth days. Blastocytes having no fragmentation and Basal FSH level 6.11 ± 0.51 6.73 ± 0.62 0.19 -0.62 to
containing equal blastomeres were selected for embryo (iu/l) 1.25
transfer. All embryos were transferred on fifth day fol- p statistical significance
lowing OPU. Luteal phase support was given by vaginal CI confidence interval, DI duration of infertility, AMH antimullerian
progesterone (Crinone %8 vaginal gelÒ Merck-Serono, hormone, FSH follicular stimulating hormone

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Arch Gynecol Obstet (2013) 288:1413–1416
Table 2 Comparison of IVF-ICSI outcome of agonist and antagonist protocols
Agonist (n = 78)
RON 19.63 ± 5.89
NTE 1.61 ± 0.72
MON 13.99 ± 4.12
FR, n (%) 10.3/19.6 (54.08)
IR, n (%) 46/117 (39.31)
E2 on hCG day 2946.05 ± 1059.26
P on hCG day 1.21 ± 0.44
Total FSH (iu/l) 2725.69 ± 860.37
CPR, n (%) 43 (55)
OPR, n (%) 30 (38.4)
p statistical significance
CI confidence interval, RON retrieved oocyte number, NTE number of transferred embryos, MON metaphase 2 oocyte number, FR fertilization
rate, IR implantation rate, P progesterone, FSH follicular stimulating hormone, CPR clinical pregnancy rate, OPR ongoing pregnancy rate
group than antagonist group, respectively (p = 0.05 and
p = 0.03). Also, E2 levels on hCG day were significantly
higher in agonist group than antagonist group (p = 0.001).
Premature (P) rise was higher in agonist group than
antagonist group and this difference was found to be sta-
tistically significant (p = 0.001). Interestingly, total FSH
dose was 2725.69 ± 860.37 iu/l and 2681.33 ± 921.12 iu/l
in agonist and antagonist groups, respectively. The differ-
ence between the groups was not statistically significant
(p = 0.74). Contrarily, CPR and ongoing pregnancy rate
(OPR) were significantly higher in antagonist group than
agonist group (Table 2).
Discussion
In this prospective cohort study, the IVF-ICSI outcome of
the agonist and antagonist treatment regimes were
compared. This is the first prospective randomized trial,
demonstrating blastocyst transfer results of agonist and
antagonist treatments. Our findings suggested that although
the follicular development was better in agonist group, final
IVF-ICSI outcomes were better in antagonist group than
agonist group.
Fleming et al. [1] first reported that IVF outcome started
to increase with GnRH agonist usage. Since then numerous
treatment protocols related with GnRH agonists have been
suggested to improve IVF success [11, 12]. However, most
of these therapies failed because of detrimental effects of
premature progesterone rise and high E2 levels [13, 14].
Basir et al. [15] shown that high serum E2 level led to a
disharmony between endometrial stroma and glands. As a
result, implantation could be affected negatively. Valbuena
et al. [13] pointed out that high E2 could impair embryonic
1415
Antagonist (n = 117) p 95 % CI
15.95 ± 7.85 0.001 1.62 to 5.74
1.72 ± 0.83 0.56
12.22 ± 5.45 0.016 0.33 to 3.19
9.1/15.9 (57.86) 0.05 –
84/175 (48) 0.03 –
2181.36 ± 1150.21 0.001 443.28 to 1086.10
0.93 ± 0.42 0.001 0.16 to 0.41
2681.33 ± 921.12 0.74 -214.36 to 303.08
83 (71) 0.02 –
69 (58.9) 0.01 –
cleavage. Therefore, we thought that GnRH antagonist
treatment would increase IVF-ICSI outcome due to lower
serum E2 and P level. In the present study, GnRH antag-
onist regime decreased serum E2 and P level on hCG day.
Although, the follicular development (RON and MON)
was significantly worse than agonist protocol, CPR and
OPR were significantly higher in antagonist group. Inter-
estingly, although the total FSH dose was less in antagonist
group, the difference was not statistically significant.
Another endpoint of our study was the date of the
embryo transfer. In the literature, the studies comparing
agonist and antagonist protocols had an embryo transfer
done on third day. However, in our study, embryo transfer
was performed on fifth day in all cases. Performing the
embryo transfer in blastocyst stage enhances selection of
the best qualified embryo and increases the synchrony
between embryo and endometrium [16]. Gardner et al.
[17]. reported that blastocyst transfer resulted in high
implantation rates Therefore, we hypothesized that blas-
tocyst transfer would increase the IVF-ICSI outcome.
However, the limitation of our study was not to have a
comparison between third and fifth day transfers.
Higher total FSH dose was administered in agonist
group than antagonist group but the difference between
groups was not statistically significant (p = 0.74). We did
not see OHSS or another serious complication because of
close monitorization of the patients.
In conclusion, although the higher RON and MON
yielded in the agonist treatment, CPR and OPR were better
in antagonist group. Having lower serum E2 and proges-
terone levels on hCG day could play a key role in antag-
onist cycle to obtain more successful IVF outcome than
agonist cycle. Our results demonstrate that lower E2 and P
may increase the IVF-ICSI success. Therefore, the
123
1416
clinician should take into consideration COH method,
especially antagonist protocol for a successful pregnancy.
However, large prospective randomized controlled studies
are required comparing FSH stimulation protocols with the
use of GnRH agonists versus GnRH antagonists.
Conflict of interest None.
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