ART

Gonadotrophin-releasing hormone-antagonists vs long agonist in in-vitro

fertilization patients with polycystic ovary syndrome: a meta-analysis

FULVIA MANCINI, ROSA TUR, FRANCISCA MARTINEZ, BUENAVENTURA COROLEU,

IGNACIO RODRIGUEZ, & PEDRO N. BARRI

Reproductive Medicine Service, Department of Obstetrics, Gynaecology and Reproductive Medicine, Institut Universitari Dexeus,

Barcelona, Spain

(Received 30 July 2010; accepted 2 September 2010)

AbstractAim. This article is a systematic review of the literature to establish whether there is an advantage in the use of GnRHantagonists (Ant) compared to the long agonist protocol (Ago) in patients with polycystic ovarian syndrome (PCOS).Material and methods. The meta-analysis was conducted using the MIX software with Mantel–Haenszel weighting methodand the fixed effect model.Results. Five studies were identified. We analyzed 269 Ant and 303 Ago cycles. Pregnancy rates and the incidence of ovarianhyperstimulation syndrome (OHSS) were analyzed in all five studies, abortion rates were analyzed on three. Pregnancy ratesdid not differ between the groups: 137/269 (Ant Group) versus 172/303 (Ago Group) (OR: 0.80 CI: [0.57–1.11]). Theincidence of OHSS per Ant (13/269) was significantly lower compared to the Ago (35/303) (OR: 0.47 CI: [0.24–0.92]). Nodifference was found between the two groups in the abortion rate: 10/77 (Ant Group) versus 9/88 (Ago Group) (OR: 1.29 CI:[0.49–3.36]).Conclusion. The limited evidence present in literature suggests that in patients with PCOS there is no difference between along Ago and an Ant protocol in terms of pregnancy and abortion rates. It seems more likely that the use of the Ant mayreduce the incidence of OHSS.

Keywords: GnRH antagonist, GnRH agonist, in-vitro fertilization, polycystic ovary syndrome, ovarian hyperstimulation syndrome

Introduction

The polycystic ovarian syndrome (PCOS) is the com-monest endocrinopathy of women in the reproductive ageand is the first cause of anovulation. Gonadotrophin-releasing hormone (GnRH) agonists (Ago) are used inin-vitro fertilization (IVF) in order to avoid the prematureLH surge before oocyte retrieval. However, in patientsaffected by PCOS the standard long Ago protocol is oftenbound to be cancelled due to multifollicular developmentand the risk of ovarian hyperstimulation syndrome(OHSS) [1]. GnRH-antagonists (Ant) competitively blockthe GnRH receptors leading to an immediate suppressiveeffect on gonadotrophin secretion. This allows a finermodulation of hormonal stimulation and a reduction oftreatment duration from weeks to days [2]. The use of Antin patients with PCOS could lead to: decreased incidenceof excessive multifollicular development, of cycle cancella-tion, and of OHSS. A meta-analysis by Griesinger et al.[3] confirmed that the duration of stimulation wasreduced in favor of Ant. No significant difference wasfound in the likelihood of pregnancy nor in the incidenceof grade I and II OHSS. However, this meta-analysis didnot consider high body mass index (BMI) as exclusioncriteria although it is now asserted that obesity isassociated with a poorer IVF outcome [4] and it includedone abstract which did not describe the randomization

method. Since then, other studies have been published inthe literature comparing the use of Ant vs Ago in patientswith PCOS. The aim of this meta-analysis is to establishwhether there is an advantage in the use of GnRH Antcompared to the standard long Ago protocol in patientswith PCOS in terms of pregnancy, OHSS, and abortionrates.

Material and methods

Search strategy

The bibliographic database Medline, Embase and Co-chrane were searched from April 2009 back to 1999,(when GnRH Ant became commercially available), usingcombinations of the following Keywords: GnRH antago-nist, GnRH agonist, IVF, polycystic ovary syndrome,OHSS. The search was restricted to articles written inEnglish. The reference sections of all the relevant studiesor reviews were manually cross-checked to identify furtherstudies. The main search, as well as screening for titles,abstracts and full-text articles was completed indepen-dently by three different reviewers (F. Man., R.T., and F.Mar.). Any discrepancy was solved by consultation of afourth reviewer, not involved in the initial procedure(B.C.).

Correspondence: Fulvia Mancini, MD, PhD, Reproductive Medicine Service, Department of Obstetrics, Gynaecology and Reproductive Medicine, Institut

Universitari Dexeus, Gran Vıa Carlos III 71-75, 08028 Barcelona, Espana. Tel: þ34.93.2274700. Fax þ34.93.2057966. E-mail: fulman@dexeus.com

Gynecological Endocrinology, March 2011; 27(3): 150–155

ISSN 0951-3590 print/ISSN 1473-0766 online ª 2011 Informa UK, Ltd.

DOI: 10.3109/09513590.2010.526667

Gyn

ecol

End

ocri

nol D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

ichi

gan

Uni

vers

ity o

n 10

/25/

14Fo

r pe

rson

al u

se o

nly.

Tab

leI.

Ch

arac

teri

stic

so

fth

est

ud

ies

incl

ud

edin

the

met

a-an

alys

is.

Ref

eren

ce

Sam

ple

size

Ran

do

miz

atio

n

Mai

nin

clu

sio

n

crit

eria

Age

Ago

nis

tp

roto

col

An

tago

nis

tp

roto

col

Go

nad

otr

op

hin

typ

eT

rue

Allo

cati

on

con

ceal

ed

OC

pre

trea

tmen

t

Ago

nis

t

typ

e/in

itia

tio

n

OC

pre

trea

tmen

t

An

tagon

ist

typ

e/in

itia

tio

n

Hw

ang

etal

.,

20

04

56

Yes

Yes

PC

Oo

nu

ltra

sou

nd

;

LH

/FS

Hra

tio4

2

or

T4

0.8

ng/m

l

53

9yr

sN

oS

tan

dar

dlo

ng

pro

toco

l(b

use

rlin

)

OC

pre

trea

tmen

t

for

3cy

cles

cetr

ore

lix

star

tin

gd

ay

bef

ore

HM

G,

mu

ltip

led

ose

HM

G

Bah

cec

iet

al.,

20

05

14

8Y

esN

oP

rim

ary

infe

rtilit

y;

oligo

men

orr

ho

ea;

clin

ical

hyp

eran

dro

gen

ism

;

reve

rsed

FS

H/L

H;

PC

Oo

nu

ltra

sou

nd

53

8yr

sY

esle

up

rolid

efr

om

day

14

of

pre

ced

ing

cycl

e

Yes

cetr

ore

lix

flex

ible

,fi

xed

do

se

uF

SH

Lai

nas

etal

.,

20

07

78

Yes

No

PC

Oo

nu

ltra

sou

nd

;

oligo

/an

ovu

lati

on

18

–3

9yr

sY

estr

ipto

relin

3d

ays

bef

ore

sto

pp

ing

OC

Yes

cetr

ore

lix

fro

md

ay1

of

stim

ula

tio

n,

fixed

do

se

rFS

H

Ku

rzaw

a

etal

.,2

00

8

70

Yes

No

Ro

tter

dam

crit

eria

;

BM

I5

26

�35

yrs

Yes

trip

tore

lin

fro

md

ay

16

–1

8o

f

pre

ced

ing

cycl

e

Yes

cetr

ore

lix

flex

ible

,fi

xed

do

se

rFS

H

Lai

nas

etal

.,

20

10

22

0Y

esN

oP

CO

on

ult

raso

un

d;

oligo

/an

ovu

lati

on

18

–3

9yr

sY

estr

ipto

relin

3d

ays

bef

ore

sto

pp

ing

OC

Yes

cetr

ore

lix

flex

ible

,

fixed

do

se

rFS

H

PC

O¼

po

lycy

stic

ova

ries

;O

C¼

Ora

lC

on

trac

epti

ve,

OC

pre

trea

tmen

tis

for

21

day

su

nle

sso

ther

wis

esp

ecifi

ed;

HM

G¼

Hu

man

Men

op

ausa

lG

on

ado

tro

ph

in;

u¼

uri

nar

y;r¼

reco

mb

inan

t;m

ult

iple

do

se¼

the

anta

go

nis

tw

asin

itia

ted

at0

.25

mg/d

ay,

then

red

uce

dto

0.1

25

mg/d

ayfo

r4

day

s,th

enin

crea

sed

to0

.25

mg/d

ay;

fixed

do

se¼

0.2

5m

g/d

ay;

flex

ible¼

wh

enth

ele

adin

gfo

llic

lere

ach

es1

4m

m

ind

iam

eter

.

GnRH-antagonist and PCOS 151

Gyn

ecol

End

ocri

nol D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

ichi

gan

Uni

vers

ity o

n 10

/25/

14Fo

r pe

rson

al u

se o

nly.

Eligibility of studies

Trials comparing the efficacy of GnRH Ant protocol vs astandard long Ago protocol in patients affected by PCOSwere considered eligible for the meta-analysis. Criteria forinclusion/exclusion were established prior to the initiationof the literature search. The following criteria werenecessary for inclusion: prospective randomized studies(non-quasi-randomized), full-length articles, report on theuse of Ant compared to Ago in patients with PCOS.Abstracts and letters to the editor were not included sincethese publications cannot be assessed methodologically.

Data extraction

Information from each study was extracted independentlyby two researchers (F. Man and R.T.) using a standarddata form. The general characteristics of the study such asdesign, study size and number of cases, the characteristicsof the PCO patients and the control group (criteria, age,BMI), the characteristics of stimulation protocols (type ofgonadotrophin used, pretreatment with oral contraceptives,initiation of GnRH-Ant) and results (pregnancy rates,OHSS rates, abortion rates) were recorded and doublechecked. Table I summarizes the characteristics of the trialsincluded in the meta-analysis.

Institutional Review Board approval was not soughtsince no experiment on human was carried out.

Statistical analysis

The dichotomous data results for each study wereexpressed as an odds ratio (OR) with 95% confidenceintervals (CI). These results were combined for the meta-analysis which was conducted using the MIX software withMantel–Haenszel weighting method and the fixed effectmodel.

Results

Search results

The search strategy identified 219 potentially relevantstudies. Of these 162 studies were excluded on a title-basis,40 were excluded based on the abstract. The remaining 17studies were read in full by two independent researchers(F.M. and R.T.) to evaluate if they matched the inclusioncriteria. Eleven of these manuscripts were excluded andseven were deemed as potentially appropriate for the meta-analysis [5–11]. The study by Tehraninejad et al. [10],although prospective and randomized, was discarded

Figure 1. Flow-chart for the meta-analysis: identification and selection of the studies.

152 F. Mancini et al.

Gyn

ecol

End

ocri

nol D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

ichi

gan

Uni

vers

ity o

n 10

/25/

14Fo

r pe

rson

al u

se o

nly.

because in the Ant Group patients that showed estradiollevels 43000 pg/ml were given an Ago to trigger ovulation.Since the Ago trigger in Ant protocols is a well documentedway to reduce the incidence of OHSS we believed that thisstudy could constitute a bias. The study by Hosseini et al.[11] although randomized and prospective was also notincluded since the patients in the Ago Group weresignificantly older compared to the Ant Group(29.31+ 4.23 vs 27.75+ 3.40, p¼ 0.037). Although theauthors believe this difference does not have clinicalsignificance, we cannot exclude that it may be responsiblefor the difference reported in terms of abortion (Ago vsAnt: 7.8% vs 17.6%, p¼ 0.219) and pregnancy rates (Agovs Ant: 15.3% vs 40.3%, p¼ 0.003). Therefore, only fivestudies were included in the meta-analysis. Figure 1represents the flow chart of the search results.

Meta-analysis results

We analyzed 269 Ant and 303 Ago cycles. Unfortunately,only pregnancy rates and the incidence of OHSS could beanalyzed, since the duration of stimulation, the gonado-trophin consumption, and the number of cumulus-oocytescomplexes were not reported in all five manuscripts andsome of the authors did not provide the required data. Forthis reason, the abortion rate was analyzed only on three[5,6,8] of the five manuscripts.

Pregnancy rates did not differ between the two groups:137/269 in the Ant Group versus 172/303 in the Ago Group(OR: 0.80 CI: [0.57–1.11]) (Figure 2). On the contrary,the incidence of OHSS per Ant (13/269) was significantly

lower compared to the Ago (35/303) (OR: 0.47 CI: [0.24–0.92]) (Figure 3). No difference was found between thetwo groups in the abortion rate: 10/77 in the Ant Groupversus 9/88 in the Ago Group (OR: 1.29 CI: [0.49–3.36])(Figure 4).

Discussion

Because the inhibitory effect of GnRH Ant on LH is morepronounced than that on FSH, a low therapeutic dose alsominimizes the suppression of endogenous FSH. Hence, theGnRH Ant protocol appears to be highly physiological andallows more flexibility during treatment [12]. Ovarianstimulation with GnRH Ant is therefore associated with acertain number of advantages such as short duration oftreatment and reduced total quantity of gonadotrophinsused per cycle [13]. In women affected by PCOS, whodisplay higher elevated levels of LH these advantages couldmake the difference between developing or not OHSS, thusmaking the Ant stimulation protocol the elective choice forthese patients.

Even though the subjects in the studies by Bahceci et al.[5] and by Hwang et al. [8] were recruited prior to thepublication of the Rotterdam criteria on PCOS diagnosis[14], all five studies were homogeneous in terms of PCOSinclusion criteria (polycystic ovaries at ultrasound, oligo-amenorrea, and hyperandrogenemia), patients age (meanage: 29–32 years) and use of a long Ago protocol. Anotherimportant homogenous factor that all studies shared waspatients’ BMI (mean BMI¼ 26), it is well ascertained thatobesity should be considered as a confounding factor given

Figure 3. OHSS rates comparative studies on GnRH antagonist vs GnRH agonist stimulation protocol in patients with PCOS. The

standardized differences of the OR with 95% confidence intervals (CI) are shown (fixed effect model; no significant heterogeneity, p¼ 0.07).

Figure 2. Pregnancy rates from comparative studies on GnRH antagonist vs GnRH agonist stimulation protocol in patients with PCOS. The

standardized differences of the OR with 95% confidence intervals (CI) are shown (fixed effect model; no significant heterogeneity, p¼ 0.83).

GnRH-antagonist and PCOS 153

Gyn

ecol

End

ocri

nol D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

ichi

gan

Uni

vers

ity o

n 10

/25/

14Fo

r pe

rson

al u

se o

nly.

its prevalence in PCOS patients and the response togonadotropin induction is inversely related to BMI. Therandomization was true in all studies; however allocationwas concealed only in one [8]. The type of gonadotrophinused was different: HMG in the study by Hwang et al. [8];Bahceci et al. used uFSH [5]; in both studies by Lainaset al. [7,9] and in the one by Kurzawa et al. [6] patientswere stimulated with rFSH. Four studies pretreatedpatients with oral contraceptives [5–7,9], but one did not[8], and the Ant administration started alternatively on day1 [7], on day 6 [8], or when one or two follicles reached thediameter of 14 mm [5,6,9]. Fertilization methods includedboth IVF and intracytoplasmatic sperm injection (ICSI),embryo transfers were performed 2 or 3 days after oocyteretrieval and the number of embryos transferred wasbetween 2 and 4 in all studies, also an important factor,since it can be related to the severity of OHSS. Lutealphase support was given according to each centre practice.The incidence of multiple pregnancies was not reported inall cases. Therefore, it is very difficult to infer accurateconclusions. Nevertheless, the limited evidence present inliterature suggests that in PCOS patients there is nodifference between a long Ago and an Ant protocol interms of pregnancy rates. The meta-analysis by Kolibiana-kis et al. [13] on general population demonstrated that theprobability of live-birth does not differ between the twoprotocols. However, Al-Inany et al. [15] reported that theuse of Ant shows a lower probability of clinical pregnancyper treatment cycle compared to the long Ago protocol.These conflicting reports could be one of the main reasonsfor the slow uptake of GnRH-Ant by clinicians.

According to our meta-analysis, it seems more likely thatthe use of the Ant may reduce the incidence of OHSS. Thisdata, however, should be taken with caution for tworeasons. The difference in favor of the Ant derives mostlyfrom one paper [7] which showed an extremely highincidence of OHSS in the Ago Group (20/52 patients). Thesame group on a subsequent study still reports asignificantly lower incidence of OHSS in the Ant Group;nevertheless, the number of OHSS in the Ago is not asstriking as in their first publication. This may be due to thelarger studied population or to the different classificationthe authors used to define OHSS. Moreover, the OHSSclassification and its severity were not described in allmanuscripts, therefore we may have merged in our analysismild with severe OHSS and this could bias the results.

In conclusion this meta-analysis did not find a statisti-cally significant difference between the use of a GnRH Antprotocol versus the standard long protocol in the incidenceof pregnancy and of abortion in patients with PCOSundergoing IVF. Although the data should be taken withcaution, the Ant protocol also seems to reduce significantlythe incidence of OHSS, but further randomized controlledtrials are necessary to allow more solid conclusions to be

drawn. This said, it will be difficult to compare futurestudies with older ones since, as it is the case with themanuscript by Tehraninejad et al. [10], authors are nowapplying updated recommended measures to preventOHSS, both in long and short protocols [16].

In our meta-analysis, we could not study the total doses ofgonadotrophins used, nor the duration of stimulation or thenumber of cumulus-oocyte complexes, however previousstudies all agree that the Ant protocol is more patient friendly[3,12]. This, added to the equal pregnancy and abortion ratescompared to the Ago, suggests that the Ant protocol could bethe most suited for PCOS patients. Still, since the Ant can bestarted alternatively on the first day of stimulation, on day 6,or according to the follicles diameter, to date no comparativestudies have been made in PCOS to determine if there is aprotocol that works best for this population.

Acknowledgements

The authors like to thank the following persons forproviding additional information for this work: R. Kurzawaand P. Ciepiela (Szczecin, Poland); M. Bahceci and U.Ulug (Istanbul, Turkey). This work was performed underthe auspices of ‘‘Catedra d’Investigacio en Obstetricia iGinecologıa’’ of the Department of Obstetrics and Gynae-cology, Institut Universitari Dexeus, Universitat Autonomade Barcelona.

Declaration of interest: The authors report no conflictsof interest. The authors alone are responsible for thecontent and writing of the paper.

References

1. Tummon I, Gavrilova-Jordan L, Allemand MC, Session D.

Polycystic ovaries and ovarian hyperstimulation syndrome: a

systematic review. Acta Obstet Gynecol Scand 2005;84:

611–616.

2. The ganirelix dose-finding study group. A double-blind,

randomized, dose-finding study to assess the efficacy of

the gonadotrophin-releasing hormone antagonist ganirelix

(Org 37462) to prevent premature luteinizing hormone surges

in women undergoing ovarian stimulation with recombinant

follicle stimulating hormone (Puregon). Hum Reprod

1998;13:3023–3031.

3. Griesinger G, Diedrich K, Tarlatzis BC, Kolibianakis EM.

GnRH-antagonists in ovarian stimulation for IVF in patients

with poor response to gonadotrophins, polycystic ovary

syndrome, and risk of ovarian hyperstimulation: a meta-

analysis. Reprod Biomed Online 2006;13:628–638.

4. Bellver J, Melo MA, Bosch E, Serra V, Remohı J, Pellicer A.

Obesity and poor reproductive outcome: the potential role of

the endometrium. Fertil Steril 2007;88:446–451.

Figure 4. Abortion rates from comparative studies on GnRH antagonist vs GnRH agonist stimulation protocol in patients with PCOS. The

standardized differences of the OR with 95% confidence intervals (CI) are shown (fixed effect model; no significant heterogeneity, p¼0.22).

154 F. Mancini et al.

Gyn

ecol

End

ocri

nol D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

ichi

gan

Uni

vers

ity o

n 10

/25/

14Fo

r pe

rson

al u

se o

nly.

5. Bahceci M, Ulug U, Ben-Shlomo I, Erden HF, Akman MA.

Use of a GnRH antagonist in controlled ovarian hyperstimula-

tion for assisted conception in women with polycystic ovary

disease: a randomized, prospective, pilot study. J Reprod Med

2005;50:84–90.

6. Kurzawa R, Ciepiela P, Baczkowski T, Safranow K, Brelik P.

Comparison of embryological and clinical outcome in GnRH

antagonist vs. GnRH agonist protocols for in vitro fertilization

in PCOS non-obese patients. A prospective randomized study.

J Assist Reprod Genet 2008;25:365–374.

7. Lainas TG, Petsas GK, Zorzovilis IZ, Iliadis GS, Lainas GT,

Cazlaris HE, Kolibianakis EM. Initiation of GnRH antagonist

on Day 1 of stimulation as compared to the long agonist

protocol in PCOS patients. A randomized controlled trial:

effect on hormonal levels and follicular development. Hum

Reprod 2007;22:1540–1546.

8. Hwang JL, Seow KM, Lin YH, Huang LW, Hsieh BC, Tsai

YL, Wu GJ, Huang SC, Chen CY, Chen PH, et al. Ovarian

stimulation by concomitant administration of cetrorelix acetate

and HMG following Diane-35 pre-treatment for patients with

polycystic ovary syndrome: a prospective randomized study.

Hum Reprod 2004;19:1993–2000.

9. Lainas TG, Sfontouris IA, Zorzovilis IZ, Petsas GK, Lainas

GT, Alexopoulou E, Kolibianakis EM. Flexible GnRH

antagonist protocol versus GnRH agonist long protocol in

patients with polycystic ovary syndrome treated for IVF: a

prospective randomised controlled trial (RCT). Hum Reprod

2010;25:683–689.

10. Tehraninejad ES, Nasiri R, Rashidi B, Haghollahi F, Ataie M.

Comparison of GnRH antagonist with long GnRH agonist

protocol after OCP pretreatment in PCOs patients. Arch

Gynecol Obstet 2010;282:319–325.

11. Hosseini MA, Aleyasin A, Saeedi H, Mahdavi A. Comparison

of gonadotropin-releasing hormone agonists and antagonists

in assisted reproduction cycle. J Obstet Gynecol Res 2010;36:

605–610.

12. Elkind-Hirsch KE, Webster BW, Brown CP, Vernon MW.

Concurrent ganirelix and follitropin beta therapy is an

effective and safe regimen for ovulation induction in women

with polycystic ovary syndrome. Fertil Steril 2003;79:

603–607.

13. Kolibianakis EM, Collins J, Tarlatzis BC, Devroey P, Diedrich K,

Griesinger G. Among patients treated for IVF with gonadotro-

phins and GnRH analogues, is the probability of live birth

dependent on the type of analogue used? A systematic review and

meta-analysis. Hum Reprod Update 2006;12:651–671.

14. Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus

Workshop Group. Revised 2003 consensus on diagnostic

criteria and long-term health risks related to polycystic ovary

syndrome. Fertil Steril 2004;81:19–25.

15. Al-Inany HG, Abou-Setta AM, Aboulghar M. Gonadotro-

phin-releasing hormone antagonists for assisted conception:

a Cochrane review. Reprod Biomed Online 2007;14:640–649.

16. Humaidan P, Quartarolo J, Papanikolaou EG. Preventing

ovarian hyperstimulation syndrome: guidance for the clinician.

Fertil Steril 2010;94:389–400.

GnRH-antagonist and PCOS 155

Gyn

ecol

End

ocri

nol D

ownl

oade

d fr

om in

form

ahea

lthca

re.c

om b

y M

ichi

gan

Uni

vers

ity o

n 10

/25/

14Fo

r pe

rson

al u

se o

nly.