mini-dose long gonadotropin-releasing hormone (gnrh) agonist versus agonist flare stimulation...

Middle East Fertility Society Journal (2013) xxx, xxx–xxx

Middle East Fertility Society

Middle East Fertility Society Journal

www.mefsjournal.orgwww.sciencedirect.com

ORIGINAL ARTICLE

Mini-dose long gonadotropin-releasing

hormone (GnRH) agonist versus agonist flare

stimulation protocol for in vitro fertilization poor

responders

Abbreviations: GnRH, gonadotropin releasing hormone; IVF, in vitro

fertilization; ICSI, intracytoplasmic sperm injection; HCG, human

chorionic gonadotropin; FSH, follicular stimulating hormone; E2,

estradiol; COH, controlled ovarian hyper stimulation; AFC, antral

follicle count; hMG, human menopausal gonadotropin* Tel.: +20 1001078586.E-mail addresses: [email protected], drmonashaban@

gmail.com.

Peer review under responsibility of Middle East Fertility Society.

Production and hosting by Elsevier

1110-5690 � 2013 Production and hosting by Elsevier B.V. on behalf of Middle East Fertility Society.

http://dx.doi.org/10.1016/j.mefs.2013.10.001

Please cite this article in press as: Shaban MM Mini-dose long gonadotropin-releasing hormone (GnRH) agonist versus agonist flare stimprotocol for in vitro fertilization poor responders, Middle East Fertil Soc J (2013), http://dx.doi.org/10.1016/j.mefs.2013.10.001

Mona Mohamed Shaban *

Department of Obstetrics and Gynecology, Faculty of Medicine, Cairo University, Egypt

Received 16 May 2013; accepted 8 October 2013

KEYWORDS

Mini-dose GnRH long ago-

nist;

GnRH agonist flare;

Poor responders;

IVF/ICSI

Abstract Objectives: To compare 2 stimulation protocols, mini-dose long gonadotropin releasing

hormone (GnRH) agonist versus agonist flare for in vitro fertilization poor responders.

Design: Prospective comparative nonrandomized clinical trial.

Setting: Dr. Samir Abasss IVF center, Jeddah, Kingdom of Saudi Arabia from april 2012 to

December 2012 on 50 women undergoing IVF/ICSI fulfilling the criteria of poor responders.

Material and methods: Patients were allocated into 2 groups, group 1 (n= 25) received mini-

dose long agonist and group 2 (n= 25) received agonist flare protocol.

Main outcome: Number of oocytes retrieved (primary outcome), duration of stimulation (days),

peak E2 level on the day of hCG injection, number of fertilized oocytes, number of transferred

embryos and pregnancy rate/cycle.

ulation

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2 M.M. Shaban

Please cite this article in press as: Shabaprotocol for in vitro fertilization poor r

Results: Both groups were comparable regarding age, body mass index and duration of infertil-

ity (years). The difference in basal FSH and duration of stimulation (days) does not reach statistical

significance (p value 0.833 and 0.373 respectively). There was a high statistical difference between

both groups regarding peak E2 on day of hCG injection, number of oocytes retrieved, number

of fertilized oocytes, number of transferred embryos; which is higher in the mini-dose agonist group

(p value 0.00).

Pregnancy rate/cycle was higher in the mini-dose agonist group (9/25 vs. 6/25) however this

difference does not reach statistical significance (p value 0.355) which may be attributed to small

sample size or advanced maternal age.

Conclusion: Mini-dose long GnRHa stimulation protocol appears to be more beneficial for poor

responders than GnRHa agonist flare.

� 2013 Production and hosting by Elsevier B.V. on behalf of Middle East Fertility Society.

1. Introduction

Poor response is one of the frustrating problems which is faced

in COH (controlled ovarian hyper stimulation); it occurs in 10–25% of all IVF cycles (1); and unfortunately associated withhigh cancelation rate, low pregnancy rate and in young womenit is the first sign of ovarian aging and early menopause.

There is still no universal definition of poor responders andseveral criteria were used which is badly reflected on its man-agement (2).

Poor response is due topoor ovarian reservewhichmaybe dueto woman’s age P40 years, previous ovarian surgery or irradia-tion, chromosomal anomalies such as turner syndrome, endome-

triosis, benign or malignant ovarian tumors, chemotherapy,decreased number of FSH receptors available in granulosa cells,(3) the presence of a special FSH receptor-binding inhibitor in the

follicular fluid, and the presence of autoantibodies against gran-ulosa cells (4); and can be predicted from number of developingfollicles and/or the number of oocytes retrieved after conven-tional stimulation protocol, total dose of gonadotropins used

for ovarian stimulation; Eric et al. define poor response as num-ber ofmature follicles<2–5; number ofmature oocytes retrieved63; single dominant follicle; mean daily gonadotropin dose

P300 IU; total gonadotropin dose >40 ampules (5). And alsopoor response can be predicted if patient age P40 years (6), pre-vious canceled IVF cycle due to poor response (7), peak E2 level

at time of trigger <300–500 pg/ml, day 3 FSH >15 l/ml (8),poor or no response to clomiphine challenge test, anti-mullerianhormone (AMH) which correlates with antral follicles (9).

Sonographic assessment of ovarian reserve includes de-

creased antral follicle count, decreased ovarian volume and de-creased stromal blood flow (10,11).

Treatment of poor responders to COH who are undergoing

IVF remains a challenge and many protocols were proposed toimprove the outcome including increasing the dose of gonado-tropins; but it was found ineffective, use of recombinant puri-

fied FSH instead of HMG, luteal initiation of gonadotropinsdepending on the recruitment of the growing follicles startsin the luteal phase but the results were disappointing (8,12,13).

GnRH agonist flare including short, ultrashort and lutealphase agonist including long protocol, agonist stop, mini-doseagonist, antagonist were also tried (14–16).

Addition of adjuvant therapy to the stimulation protocol as

growth hormone, corticosteroids, testosterone, aromataseinhibitors and DHEA (dehydro epiandro sterone) were alsotried but unfortunately the improvement of the pregnancy rate

n MM Mini-dose long gonadotropesponders, Middle East Fertil Soc

is quite low and up till now no single protocol is universallyperfect for poor responders (17–19).

In our study we compare 2 stimulation protocols (mini-dose

longGnRH agonist vs. agonist flare) in poor responders regard-ing peak E2 (Estradiol) level at time of HCG injection, durationof stimulation (days), number of oocytes retrieved, fertilization

rate, number of embryos transferred and pregnancy rate.

2. Material and methods

Our study was a prospective non randomized comparativestudy which was conducted in Dr. Samir Abasss IVF center,Jeddah, Kingdom of Saudi Arabia from April 2012 to Decem-

ber 2012 on 50 women fulfilling the criteria of poor response toCOH and candidates for IVF. Group 1 (n = 25 women) re-ceived mini-dose long GnRH agonist and group 2 (n = 25 wo-men) received GnRH agonist flare.

2.1. Inclusion criteria

Ovarian volume <3 (20), antral follicle count (AFC) < 6

(21,22), day 3 FSH >8 IU/l (23) and history of previous can-celed IVF trial due to poor response.

2.2. Exclusion criteria

Single ovary, severe endometriosis, endocrine or metabolicdisorders.

Our study was approved by the ethics committee of the cen-ter and fulfilling the ethical considerations in accordance withthe declaration of Helsinki for medical research involving hu-man subjects. An informed consent was taken from all women

who agreed to participate in our study.

2.3. Stimulation protocol

In both groups pretreatment was done with oral contraceptivepills (Gynera, Schering-plow: plough) in the cycle precedingstimulation. In group (1) triptorelin (decapeptyl depot

3.75 mg, Ferring, Malmo, sweden) was taken once IM on day21 of the OCP cycle, in group (2) treptorelin (decapeptyl0.1 mg) was administrated SC daily from 1st of withdrawal

bleeding till the day of hCG administration.In both groups gonadotropin (hMG) (Menogon, ferring

pharmaceuticals, Germany) was initiated on day 3 of the cyclein a dose of 450 IU daily intramuscular injection. Once 2 or

in-releasing hormone (GnRH) agonist versus agonist flare stimulationJ (2013), http://dx.doi.org/10.1016/j.mefs.2013.10.001


Mini-dose long gonadotropin-releasing hormone (GnRH) agonist versus agonist flare 3

more leading follicles reached 17–18 mm hCG 10,000 IU(Pregnyl; NV Organon) was administrated IM.

2.4. Cycle monitoring

Serial transvaginal ultrasound to assess follicular growth andserum E2 were done starting on day 6 of the cycle and onward,

with adjustments of gonadotropin dose and monitoring fre-quency based on patient response.

2.5. Oocyte retrieval

It was performed 35 h from HCG injection using transvaginalultrasound guided double lumen needle aspiration under gen-

eral anesthesia followed by ICSI.

2.6. Embryo transfer

2–3 days after ovum pick up depending on the number and

quality of available embryos using labotec catheter (Labotec,Gottingen Germanny) under ultrasound guidance.

2.7. Luteal phase support

Using progesterone vaginal pessaries (Cyclogest, Alpharma,UK) 400 mg twice daily from the day of egg collection till

the day of the pregnancy test and continued till 12 week gesta-tion if pregnancy is documented.

2.8. Pregnancy test

It was done 2 weeks after oocyte pick-up and ultrasound wasdone at 6–8 week gestation to document gestational sac and fe-tal pulsation.

In this study a pregnancy was defined as a positive serumHCG test and a sac on ultrasound scan, or an ectopic pregnancy.

The primary outcome is number of oocytes retrieved, sec-

ondary outcomes are serum E2 level at time of hCG injection,duration of stimulation, fertilization rate per oocytes, numberof embryos transferred and pregnancy rate/cycle.

2.9. Statistical analysis

Data were statistically described in terms of mean ± standard

deviation (±SD), median and range, or frequencies (numberof cases) and percentages when appropriate. Comparison ofnumerical variables between the study groups was done usingStudent’s t test for independent samples in comparing 2 groups

when normally distributed and Mann Whitney U test for inde-pendent samples when not normally distributed. For compar-ing categorical data, Chi square (v2) test was performed. Exact

test was used instead when the expected frequency is less than5. P values less than 0.05 were considered statistically signifi-cant. All statistical calculations were done using computer pro-

grams SPSS (statistical package for the social science; SPSSInc., Chicago, IL, USA) version 15 for Microsoft Windows.

3. Results

50 infertile women fulfilling the criteria of poor responders toCOH were enrolled in the study and assigned into 2 groups,

Please cite this article in press as: Shaban MM Mini-dose long gonadotropprotocol for in vitro fertilization poor responders, Middle East Fertil Soc

group 1 (n = 25 women) received mini-dose long GnRH ago-nist, group 2 (n = 25 women) received agonist flare protocol.

Both groups were comparable regarding age, duration of

infertility and body mass index (BMI). Mean age in group(1) was 39.04 ± 1.76 vs. 39.04 ± 1.76 in group (2), p value0.750.

Duration of infertility was 3.24 ± 1.2 in group (1) vs.3.48 ± 1.4 in group (2) with p value 0.521.

BMI was 25.75 ± 1.69 in group (1) vs. 25.96 ± 1.699 in

group (2) with p value 0.660 in Table 1.There is no statistical difference between both groups

regarding basal FSH level (10.68 ± 1.14 vs. 10.75 ± 1.25; pvalue 0.833) and days of stimulation (10.5 ± 1.35 vs.

10.8 ± 1.22; p value 0.373).There was a difference in reaching statistical significance be-

tween both groups regarding serum E2 levels on the day of

hCG injection (784 ± 1.66, 534 ± 1.3 pg/ml respectively withp value 0.00), number of oocytes retrieved (4.52 ± 1.9 vs.2.36 ± 1.3; p value 0.00), number of fertilized oocytes

(2.8 ± 1.5, 1.4 ± 1.0; p value 0.00) and number of transferredembryos (2.5 ± 1.12 vs. 1.4 ± 1.0; p value 0.00) in Table 2.

The difference in clinical pregnancy/cycle in both groups

does not reach statistical significance (9/25 vs. 6/25; p value0.355) in Table 3.

Among group (1) one ET (embryo transfer) was canceleddue to failure of fertilization. Among group (2) 4 ET were can-

celed due to failure of fertilization.

4. Discussion

Although there is a lack of uniform definition of poor respond-ers, the most common criteria are elevated day 3 FSH, low an-tral follicle count, low peak E2, large dose of gonadotropins is

required for stimulation, low number of oocytes retrieved andhistory of previous canceled cycle due to poor response (24).

Unfortunately poor responders are associated with low

pregnancy rate and high cancelation rate, many protocols weretried to improve the pregnancy rate and implantation rate inpoor responders including increasing the dose of gonadotro-

pins, GnRH agonist (longstop, micro-dose flare protocols),antagonist protocol, addition of adjuvant therapy to stimula-tion protocols (growth hormone, testosterone, DHEA, aroma-tase inhibitors) but none of them are ideal for all patients (25).

The comparison between short and long protocols in COHfor IVF has been studied for many years; In long protocoldown regulation of the pituitary was achieved by mid-luteal

administration of GnRHa injection and once down regulationhas been achieved exogenous gonadotropins commences whileGnRHa is continued till the day of hCG injection.

The short protocol takes the privilege of initial stimulationof GnRHa on pituitary gonadotropins to promote folliculargrowth; in general population long protocol is found to bemore superior and more efficient than short protocol however

its use in poor responders is controversial (26,27).Feldberg et al. (1994) stated that decreasing the dose of lu-

teal GnRHa prior to ovarian stimulation (mini-dose GnRHa

protocol) decreases the extent of endogenous gonadotropinsuppression and at the same time enough to prevent prematureovulation associated with increased serum E2 level, number of

oocytes retrieved, number of embryos available for transfer,implantation, pregnancy rate and decreases the cancelation



Table 1 Demographic characteristics in both groups.

Mini-dose long agonist protocol (n= 25) Agonist flare (n= 25) P value

Age (years) 39.04 ± 1.76 39.2 ± 1.75 0.750

BMI (body mass index) kg/m2 25.75 ± 1.69 25.96 ± 1.699 0.660

Duration of infertility (years) 3.24 ± 1.2 3.48 ± 1.4 0.521

Table 2 Clinical and laboratory findings in both groups.

Mini-dose long agonist protocol (n= 25) Agonist flare (n= 25) P value

FSH level 10.68 ± 1.14 10.75 ± 1.25 0.833

Duration of stimulation (days) 10.5 ± 1.35 10.8 ± 1.22 0.373

E2 level at time of hCG injection (pg/ml) 784 ± 1.66 534 ± 1.3 0.000a

Number of oocytes retrieved 4.52 ± 1.9 2.36 ± 1.3 0.000a

Number of fertilized oocytes 2.8 ± 1.5 1.4 ± 1.0 0.000a

Number of transferred embryos 2.5 ± 1.12 1.4 ± 1.0 0.000a

a Statistically significant FSH, follicular stimulating hormone; hCG, human chorionic gonadotropin; E2, estradiol.

Table 3 Clinical pregnancy in both groups.

Mini-dose long agonist protocol (n = 25) Agonist flare (n= 25) P value

Clinical pregnancy/cycle 9/25 6/25 0.355

4 M.M. Shaban

rate in poor responders; This finding was confirmed by Oliv-

ennes et al. (28,29).Our study is a prospective non randomized study to com-

pare 2 stimulation protocols (mini-dose long GnRHa vs.GnRH agonist flare) in poor responders. 50 women fulfilling

the criteria of poor responders were recruited and allocatedinto 2 groups: group (1) (n= 25women) received mini-doselong GnRHa and group (2) (n= 25 women) received agonist

flare protocol.Both groups were comparable regarding age, BMI and

duration of infertility.

There was no difference of statistical significance betweenboth groups regarding basal FSH and days of stimulation (pvalue 0.833 and 0.373 respectively) but there was a highly sta-

tistically significant difference between both groups regardingserum E2 level on the day of HCG injection, number of oo-cytes retrieved, number of fertilized oocytes and number oftransferred embryos (p value 0.00) which goes in agreement

with Hamed et al. (30), Marco et al. (31), Madani et al. (32),Belaisch et al. (33), Toth et al. (34).

There was a difference in pregnancy rate/cycle between

both groups: higher in mini-dose long GnRHa than agonistflare (9/25 vs. 6/25); however this difference does not reach sta-tistical significance (p value 0.355). This can be explained by a

small sample size and advanced maternal age (mean age was39.04 ± 1.76 in mini-dose long agonist and 39.04 ± 1.76 inagonist flare) which in addition is associated with poorimplantation.

In our study we found that mini-dose long GnRHa is morebeneficial for poor responders especially with advanced mater-nal age and this could be explained as older women have short

follicular phase mostly due to early recruitment of follicles inthe preceding luteal phase ‘‘advanced growth’’ so the availablecohort of antral follicles is lower than younger women (35).

In agonist flare stimulation of follicular recruitment arrivestoo late because the follicular recruitment in older women had


already started in the preceding luteal phase leading to lower

number of recruited follicles in contrary to long protocol,mid lutael initiation of GnRHa leading to an increased sizeof follicle cohort recruited and in addition a longer period ofstimulation allows additional growing follicles to enter the re-

cruited cohort (31).In addition in our study we used mini dose GnRHa long

protocol which is stated by many studies that has better out-

come than conventional long protocol (28,29,36).Our results were in disagreement with Padilla et al., Span-

dorfer et al. and Akman et al. who stated that short protocol

is more effective in poor responders. However Ye et al. statedthat both protocols are equal (37–40).

5. Conclusion

Mini-dose long GnRHa is more beneficial for poor respondersespecially with advanced maternal age than GnRH agonist

flare.

Conflict of interest

Authors declare no conflicts of interest.

Acknowledgment

To all of the medical teams in Dr. Samir Abass IVF center and

to all patients who agreed to participate in our study.

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