Iranian Journal of Reproductive Medicine Vol.6. No.1.

pp: 33-37, Winter 2008

GnRHa stop protocol versus long protocol in poor

responder IVF patients
Ensieh Shahrokh Tehrani nejad M.D., Behnaz Attar Shakeri M.D., Batool Hoseini Rashidi M.D.,
Fatemeh Ramezanzade M.D., Mamak Shariat M.D.

Vali-e-Asr Reproductive Health Research Center (V.R.H.R.C), Tehran University of Medical Sciences
(T.U.M.S), Vali-e-Asr Hospital, Imam Khomeini Hospital, Tehran, Iran.

Received: 9 January 2008; accepted: 10 March 2008

Abstract
Background: Recently different studies suggested that discontinuation of
gonadotrophin releasing hormone analogue (GnRHa) at beginning of ovarian
stimulation (improvement of ovarian response to gonadotrophins) may have some
benefit to poor responder patients in invitro fertilization (IVF) cycles.
Objective:The efficacy of GnRHa stop protocol in poor responder patients in IVF
cycles was assessed.
Materials and Methods: This study was a prospective, randomized controlled trial that
40 poor responder patients (less than three mature follicles in a previous cycle) with
normal basal follicle stimulating hormone (FSH) were randomly allocated into two
protocols: 1) Non-stop protocol: long GnRHa suppression, and start gonadotrophins
from day 3 of mense. 2) Stop-protocol: GnRHa is stopped with the onset of menses,
and gonadotrophin doses remained similar to group 1.
Results: A significantly higher number of follicles, oocytes, embryos and fertilization
rate also shorter stimulation days and lower human menopausal gonadotropins (HMG)
ampoules were recorded in the stop protocol compared to the control group. Both
protocols resulted in a similar cancellation rate, pregnancy rate, estradiol level and LH
level.
Conclusion: Early follicular cessation of GnRHa permitted the retrieval of a
significantly higher number of follicles, oocytes and embryos, and can reduce the
number of HMG and stimulation days.

Key words: GnRHa long protocol, IVF, Poor respondr, GnRHa stop protocol.

Introduction oocytes and transferred embryos. These patients

have lower pregnancy rates compared to normal
A reasonable percentage of women undergoing responders (2).
infertility treatment respond poorly to the usual Among patients undergoing IVF treatment,
gonadotrophin stimulation protocol (1). Garcia et prevalence of low response is 9% to 24% (3). The
al (1983) first described poor responders as optimal approach for poor responders to ovarian
patients with peak estradiol (E2) level of <300 stimulation is still controversial. There are
pg/ml and decreased follicular response, who different ways for this, such as using high doses of
expressed low number of retrieved and fertilized gonadotrophins, co-treatment with estrogens,
growth hormone or contraceptive pills, and even
Correspondence Author: natural cycle (4, 5).
Dr. Behnaz Attar Shakeri, Vali-e-Asr Reproductive In a prospective analysis in 182 low responders
Health Research Center, Tehran, University of Medical undergoing 224 IVF-ET cycles, down-regulation
Sciences, Vali-e-Asr Hospital, Imam Khomeini was obtained with the administration of leuprolide
Hospital, Keshavarz Blvd, Tehran, 14194, Iran.
acetate, beginning in the mid-luteal phase and
E-mail: [email protected]
ending with the onset of menses. Daily
 Shahrokh Tehrani Nejad et al

administration of 6 ampoules of FSH alone or in gonadotropins beginning with GnRH-a on day 2 at

combination with hMG was initiated on cycle day 1 mg/d for 3 days, followed by 250 µg/d until the
3. The clinical PR per transfer, the ongoing PR per day of hCG administration. None of the
transfer, and the implantation rate were 32%, 24%, comparisons reached statistical significance;
and 9%, respectively. Short-term ovarian however, the microdose group demonstrated a
suppression begun in the luteal phase and trend toward a higher completed pregnancy rate
discontinued with the onset of menses followed by (8). In Schachter study 63 patients enrolled IVF
high-dose stimulation with gonadotropins yields program were treated in two consecutive cycles.
favorable pregnancy results in low responders. In Starting with a standardized protocol utilizing
another study, Drinfield (1999) studied 63 patients midluteal administration of Nafarelin (N) 600 µg/d
with previous poor response to COH and/or high continued throughout the stimulation phase with
basal FSH level (>=9 mIU/mL) undergoing 78 human menopausal gonadotropin (hMG) until
IVF-ET cycles. follicles of 20 mm were identified by transvaginal
In both groups, administration of GnRH-a was ultrasound (standard group).
started in the midluteal phase. Whereas in the Patients with a poor response in the standard
study group (40 cycles), it ended before cycle were treated in the subsequent cycle with N
administration of gonadotropins, in controls (38 and hMG initially in a similar manner, and then N
cycles) GnRH-a treatment was continued was stopped after 5 days of hMG stimulation (N-
throughout the follicular phase. A significantly stop group). The change in each parameter in the
higher cancellation rate was noted in the study N-stop cycle was expressed as the percent change
group than in the controls. The new and control as compared with the standard protocol cycle for
regimens resulted in similar stimulation each patient. Peak estradiol (E2) and the number
characteristics and clinical pregnancy rates (7). of aspirated oocytes were increased in the N-stop
Recent evidence confirms that early GnRHa cycle, but insignificantly. The percentag of
cessation is still effective in the prevention of a cleaving embryos was significantly increased in
premature rise in LH (9). the N-stop cycle, as embryo morphology was
In Garcia study (2000) 70 low responder improved. The efficacy of gonadotropin treatment
patients (less than three mature follicles in a was enhanced in the N-stop cycle, as expressed by
previous cycle) with normal basal follicle a 32.5% increase in oocytes retrieved per hMG
stimulating hormone concentrations and a ampoule administered (21).
previous cancelled IVF cycle were randomly In this prospective randomizes clinical trial the
allocated into two protocols: 1) non-stop protocol: benefit of withholding GnRHa in early follicular
long GnRHa suppression with high doses of phase in women who previously had insufficient
gonadotrophins, and 2) stop protocol, in which ovarian response to complete an IVF attempt was
GnRHa administration was stopped with the onset evaluated.
of menses, while gonadotrophin doses remained
similar to the non-stop protocol. A significantly Materials and methods
higher number of mature oocytes were obtained in
the study group (stop protocol) compared to the This study was performed on 40 poor
control group (non-stop protocol). The stop responders' patients (previous poor response)
protocol reduced the number of ampoules of undergoing IVF cycle treated at Vali-e-Asr
gonadotrophins required. Both protocols resulted Reproductive Health Center, Tehran University,
in a similar cancellation rate, pregnancy rate, and between November 2004, and February 2006. All
implantation rate (10). couples were required to sign a written informed
In Detti retrospective study, women diagnosed consent after the provision of complete
as poor responders underwent three different information. Including criteria were: patients with
stimulation regimens during IVF cycles: 1) stop at least one previous cancelled IVF cycle, with
protocol: GnRH-a 500 µg/d administered from the fewer than three follicles>18mm in diameter and
midluteal phase to the start of menses, then basal FSH <12mIu/ml. There was no age limit. In
gonadotropins from day 2 of cycle, 2) microdose our standard long protocol, after pituitary
flare: GnRH-a 20 µg administered twice daily with desensitization with Buserelin 0.5 mg daily
gonadotropins from day 2 to the day of hCG subcutaneously (Suprefact, 1mg/cc, Aventis,
administration, or 3) regular dose flare: Germay), on days 3 of cycle four ampoules of
human menopausal gonadotrophin (HMG 75 Iu,

34 Iranian Journal of Reproductive Medicine Vol.6. No.1. Winter 2008

 A comparison of GnRHa stop protocol with long protocol in poor responder IVF patients

Merional, IBSA) was administered to patients and Statistical analysis

number of HMG were regulated according to Data were expressed as mean ±SEM. Statistical
transvaginal ovarian ultrasound on 7th day of analysis was performed using commercially
stimulation. Twenty patients were treated with a available software packages (SPSS). Number of
stop protocol with Buserelin cease on the onset of follicles, oocytes, embryos, fertilization rate and
mense and twenty patients stimulated with long cancellation rate were compared between two
protocol that Buserelin was continued until HCG groups with Mannwhitney U test. Chemical and
administration (half dose after mense). The criteria clinical pregnancy rate and quality of embryos
for HCG 10,000 Iu (Pregnyl, ORGANON, Iran) were compared with chi-square.
administration, was at least three follicles
measuring ≥ 18mm in diameter. Oocyte retrieval Results
was scheduled for 34-36 hours after HCG
injection and Cyclogest 400mg (Actoverco, Iran) After randomization, 20 patients were included
BD was administrated as luteal support. Then in 2 groups. Group І non- stop protocol and group
standard IVF procedure was done (11). Three ІІ stop protocol. Table 2 shows that in patients
types of embryos were established, ranging from undergoing ovarian stimulation with the stop
type A to C. Type A embryos were the best and protocol a significantly higher number of follicles,
were defined as round and well-shaped oocyetes embryos and fertilization rate were
blastomeres without fragments. Type C was found, no differences were found in cancellation
defined as irregular blastomeres with many rate (5% versus 0%) and grade of embryos.
fragments, and type B was intermediate. Only Obviously, a higher number of HMG ampoules
patients with freshly transferred embryos were and Stimulation days were found in the non–stop
included in the study. Serum estradiol and LH protocol. Pregnancy rate was higher in stop
level were analyzed on day of HCG injection. protocol but the differences were not significant.

Table I. Comparison of demographic characteristic in two groups.

variations Group 1 Group 2 p-value
(mean ± SD) (mean ± SD)
Age (years) 33.9±6.797 37.2±6.42 0.123(NS)
Duration of infertility (years) 8.3±5.04 11.17±7.68 0.17(NS)
BMI 26.67±3.28 25.92±2.22 0.404(NS)
BMI=Weight ⁄ (Height)2
GroupΙ: non stop protocol
GroupΙΙ: stop protocol

Table II. Comparison of quantities’ outcomes in two groups.

variations Group 1 Group 2 p-value
(mean ± SD) (mean ± SD)
Number of HMG 45.2±9.8 36.6±9.3 0.019
Number of stimulation days 10.8±2.4 9.3±2.4 0.04
Number of follicles 3.6±1.3 5.5±2.9 0.022
Number of oocytes 2.3±1.04 4±2.3 0.034
Number of M2 oocytes 1.25±0.91 2.7±2.02 0.042
Number of embryos 0.8±0.83 1.90±1.4 0.033
Number of transferred embroys 0.8±0.83 1.7±1.08 0.025
Fertilization rate 60±38.3 83.9±27.6 0.043
Serum estradiol (pg/ml) 675.15±139.3 754.2±264.17 NS
Serum LH (mIu/ml) 0.7947±0.135 0.72±0.12 NS
Endometrial thickness (mm) 9.1±1.7 9.7±1.6 NS

GroupΙ: non stop protocol

GroupΙΙ: stop protocol

Iranian Journal of Reproductive Medicine Vol.6. No.1. Winter 2008 35

 Shahrokh Tehrani Nejad et al

Table III. Comparison of grade of embryos in two groups. (p-value=1)

Grade of embryos Group 1 Group 2
number percent number percent
Good (A) 7 63.6 11 64.7
Middle (B) 4 36.4 5 29.9
Bad (C) 0 0 1 5.9

Table IV. Comparison of pregnancy between two groups. (p=NS)

outcome Group 1 Group 2
number percent number percent
Chemical pregnancy 1 5% 4 20%
Clinical pregnancy 1 5% 4 20%

Discussion Some investigators believe that follicular

growth is dependent on an appropriate vascular
The results of this prospective, randomized trial network responsible for the distribution of
showed that early cessation of GnRHa combined circulating gonadotrophins(17).
with gonadotropins, lead to a significantly higher In Schachter study, similar to our study, embryo
number of follicles, mature oocytes, embryos and cleavage rates and morphology were significantly
fertilization rate, than a conventional non-stop, improved, this may be due to improved oocyte
long down-regulation protocol but the IVF quality, which may have been responsible for
outcomes were the same in both groups. No achieving pregnancies. The efficacy of
significant differences were found comparing the gonadotropin treatment was enhanced when
two groups regarding patients age, duration of GnRH-a was discontinued (21). This results show
infertility, BMI, cause of infertility, serum that GnRH-a may have a direct negative effect on
estradiol, LH and endometrial thickness on the day folliculogenesis and oocytes, which is apparent
of HCG injection. especially in poor responder patients. In fact,
GnRHa is routinely used until oocyte retrieval, ovarian blood flow velocity after pituitary
but even with short-acting molecules pituitary suppression has been shown to be predictive of
down regulation continues following cessation of ovarian responsiveness and the outcome of IVF
GnRHa during ovarian stimulation for IVF (12). In treatment (18).
Becker's study, early follicular phase cessation of Thus it could be postulated that GnRHa early
GnRHa was still effective in the prevention of a cessation while maintaining pituitary suppression,
premature rise in LH or progesterone(9).This is in restores the diminished perifollicular blood flow,
accordance with the fact that most of the which correlates with the number of oocytes
cancellations in the study group in the current retrieved and IVF outcome (19). The primary
study as well as others (6) were not due to a efficacy result, such as a significantly higher
premature ovulation. Several mechanisms may number of mature oocytes, lower gonadotrophin
contribute to the improved ovarian response ampoule consumption in the stop protocol and
observed with the stop protocol. The pituitary GnRHa showed that the cost of the cycle in terms
gonadotrophin down regulation induced by of medication is significantly reduced. The
GnRHa, decreases cancellation rates by reduced gonadotrophin usage together with the
suppressing endogenous LH surge, although this higher number of mature oocytes retrieved and
may require significantly higher requirement of higher number of embryos, make this protocol
gonadotrophins (13). appealing, something that would be definitive if it
A direct effect of GnRHa on the ovaries has allowed higher pregnancy rates. Although a trend
been proposed; therefore reducing the dose or was observed (20% versus 0%) in this study,
even stopping the administration would remove another prospective study with pregnancy rate as
this suppression, and improve ovarian primary end-goal should be designed to prove this
responsiveness (14). This hypothesis is based on hypothesis.
the presence of GnRH receptors on the ovaries The stop protocol, in spite of having
(15). On the other hand GnRHa have been proven significantly more oocytes, had similar estradiol
to decrease blood flow assessed by pulsed Doppler concentration to those observed in the non-stop
analysis ( 16 ) . protocol, such as Garcia study (10).

36 Iranian Journal of Reproductive Medicine Vol.6. No.1. Winter 2008

 A comparison of GnRHa stop protocol with long protocol in poor responder IVF patients

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38 Iranian Journal of Reproductive Medicine Vol.6. No.1. Winter 2008