Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Meta-Analysis
. 2016 Apr 29;4(4):CD001750.
doi: 10.1002/14651858.CD001750.pub4.

Gonadotrophin-releasing hormone antagonists for assisted reproductive technology

Hesham G Al-Inany  1 , Mohamed A Youssef, Reuben Olugbenga Ayeleke, Julie Brown, Wai Sun Lam, Frank J Broekmans
Affiliations
Meta-Analysis

Gonadotrophin-releasing hormone antagonists for assisted reproductive technology

Hesham G Al-Inany et al. Cochrane Database Syst Rev. .

Abstract

Background: Gonadotrophin-releasing hormone (GnRH) antagonists can be used to prevent a luteinizing hormone (LH) surge during controlled ovarian hyperstimulation (COH) without the hypo-oestrogenic side-effects, flare-up, or long down-regulation period associated with agonists. The antagonists directly and rapidly inhibit gonadotrophin release within several hours through competitive binding to pituitary GnRH receptors. This property allows their use at any time during the follicular phase. Several different regimens have been described including multiple-dose fixed (0.25 mg daily from day six to seven of stimulation), multiple-dose flexible (0.25 mg daily when leading follicle is 14 to 15 mm), and single-dose (single administration of 3 mg on day 7 to 8 of stimulation) protocols, with or without the addition of an oral contraceptive pill. Further, women receiving antagonists have been shown to have a lower incidence of ovarian hyperstimulation syndrome (OHSS). Assuming comparable clinical outcomes for the antagonist and agonist protocols, these benefits would justify a change from the standard long agonist protocol to antagonist regimens. This is an update of a Cochrane review first published in 2001, and previously updated in 2006 and 2011.

Objectives: To evaluate the effectiveness and safety of gonadotrophin-releasing hormone (GnRH) antagonists compared with the standard long protocol of GnRH agonists for controlled ovarian hyperstimulation in assisted conception cycles.

Search methods: We searched the Cochrane Menstrual Disorders and Subfertility Group Trials Register (searched from inception to May 2015), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, inception to 28 April 2015), Ovid MEDLINE (1966 to 28 April 2015), EMBASE (1980 to 28 April 2015), PsycINFO (1806 to 28 April 2015), CINAHL (to 28 April 2015) and trial registers to 28 April 2015, and handsearched bibliographies of relevant publications and reviews, and abstracts of major scientific meetings, for example the European Society of Human Reproduction and Embryology (ESHRE) and American Society for Reproductive Medicine (ASRM). We contacted the authors of eligible studies for missing or unpublished data. The evidence is current to 28 April 2015.

Selection criteria: Two review authors independently screened the relevant citations for randomised controlled trials (RCTs) comparing different GnRH agonist versus GnRH antagonist protocols in women undergoing in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI).

Data collection and analysis: Two review authors independently assessed trial eligibility and risk of bias, and extracted the data. The primary review outcomes were live birth and ovarian hyperstimulation syndrome (OHSS). Other adverse effects (miscarriage and cycle cancellation) were secondary outcomes. We combined data to calculate pooled odds ratios (ORs) and 95% confidence intervals (CIs). Statistical heterogeneity was assessed using the I(2) statistic. We assessed the overall quality of the evidence for each comparison using GRADE methods.

Main results: We included 73 RCTs, with 12,212 participants, comparing GnRH antagonist to long-course GnRH agonist protocols. The quality of the evidence was moderate: limitations were poor reporting of study methods.Live birthThere was no conclusive evidence of a difference in live birth rate between GnRH antagonist and long course GnRH agonist (OR 1.02, 95% CI 0.85 to 1.23; 12 RCTs, n = 2303, I(2)= 27%, moderate quality evidence). The evidence suggested that if the chance of live birth following GnRH agonist is assumed to be 29%, the chance following GnRH antagonist would be between 25% and 33%.OHSSGnRH antagonist was associated with lower incidence of any grade of OHSS than GnRH agonist (OR 0.61, 95% C 0.51 to 0.72; 36 RCTs, n = 7944, I(2) = 31%, moderate quality evidence). The evidence suggested that if the risk of OHSS following GnRH agonist is assumed to be 11%, the risk following GnRH antagonist would be between 6% and 9%.Other adverse effectsThere was no evidence of a difference in miscarriage rate per woman randomised between GnRH antagonist group and GnRH agonist group (OR 1.04, 95% CI 0.82 to 1.30; 33 RCTs, n = 7022, I(2) = 0%, moderate quality evidence).With respect to cycle cancellation, GnRH antagonist was associated with a lower incidence of cycle cancellation due to high risk of OHSS (OR 0.47, 95% CI 0.32 to 0.69; 19 RCTs, n = 4256, I(2) = 0%). However cycle cancellation due to poor ovarian response was higher in women who received GnRH antagonist than those who were treated with GnRH agonist (OR 1.32, 95% CI 1.06 to 1.65; 25 RCTs, n = 5230, I(2) = 68%; moderate quality evidence).

Authors' conclusions: There is moderate quality evidence that the use of GnRH antagonist compared with long-course GnRH agonist protocols is associated with a substantial reduction in OHSS without reducing the likelihood of achieving live birth.

PubMed Disclaimer

Conflict of interest statement

Previous author Professor Dr Mohamed Aboulghar was an investigator in one of the included trials, the European Middle East Orgalutran trial Euro Middle East 2001.

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
4
4
Forest plot of comparison: 1 GnRH antagonist versus long course GnRH agonist, outcome: 1.1 Live birth rate per woman randomised.
5
5
Funnel plot of comparison: 1 GnRH antagonist versus long course GnRH agonist, outcome: 1.1 Live birth rate per woman randomised.
6
6
Forest plot of comparison: 1 GnRH antagonist versus long course GnRH agonist, outcome: 1.2 Live birth rate per woman randomised ‐ minimal stimulation.
7
7
Forest plot of comparison: 1 GnRH antagonist versus long‐course GnRH agonist, outcome: 1.3 Live birth rate per woman randomised ‐ grouped by trigger.
8
8
Forest plot of comparison: 1 GnRH antagonist versus long course GnRH agonist, outcome: 1.4 Ovarian hyperstimulation per woman randomised ‐ all women.
9
9
Forest plot of comparison: 1 GnRH antagonist versus long course GnRH agonist, outcome: 1.5 Ovarian hyperstimulation per woman randomised ‐ moderate or severe.
1.1
1.1. Analysis
Comparison 1 GnRH antagonist versus long‐course GnRH agonist, Outcome 1 Live birth rate per woman randomised.
1.2
1.2. Analysis
Comparison 1 GnRH antagonist versus long‐course GnRH agonist, Outcome 2 Live birth rate per woman randomised ‐ minimal stimulation.
1.3
1.3. Analysis
Comparison 1 GnRH antagonist versus long‐course GnRH agonist, Outcome 3 Live birth rate per woman randomised ‐ grouped by trigger.
1.4
1.4. Analysis
Comparison 1 GnRH antagonist versus long‐course GnRH agonist, Outcome 4 Ovarian hyperstimulation per woman randomised ‐ all women.
1.5
1.5. Analysis
Comparison 1 GnRH antagonist versus long‐course GnRH agonist, Outcome 5 Ovarian hyperstimulation per woman randomised ‐ moderate or severe.
1.6
1.6. Analysis
Comparison 1 GnRH antagonist versus long‐course GnRH agonist, Outcome 6 Ongoing pregnancy rate per woman randomised ‐ all women.
1.7
1.7. Analysis
Comparison 1 GnRH antagonist versus long‐course GnRH agonist, Outcome 7 Ongoing pregnancy rate per woman randomised ‐ minimal stimulation.
1.8
1.8. Analysis
Comparison 1 GnRH antagonist versus long‐course GnRH agonist, Outcome 8 Ongoing pregnancy rate per women randomised ‐ grouped by trigger.
1.9
1.9. Analysis
Comparison 1 GnRH antagonist versus long‐course GnRH agonist, Outcome 9 Clinical pregnancy rate per woman randomised ‐ all women.
1.10
1.10. Analysis
Comparison 1 GnRH antagonist versus long‐course GnRH agonist, Outcome 10 Clinical pregnancy rate per woman randomised ‐ minimal stimulation.
1.11
1.11. Analysis
Comparison 1 GnRH antagonist versus long‐course GnRH agonist, Outcome 11 Miscarriage rate per woman randomised.
1.12
1.12. Analysis
Comparison 1 GnRH antagonist versus long‐course GnRH agonist, Outcome 12 Miscarriage rate per clinical pregnancy.
1.13
1.13. Analysis
Comparison 1 GnRH antagonist versus long‐course GnRH agonist, Outcome 13 Cycle cancellation rate per woman randomised.
See this image and copyright information in PMC

Update of

References

References to studies included in this review

Albano 2000 {published data only}
    1. Albano C, Felberbaum R, Smitz J, Riethmuller‐Winzen H, Engel J, Diedrich K, et al. Ovarian stimulation with HMG: results of a prospective randomized phase III European study comparing the luteinizing hormone‐releasing hormone (LHRH)‐antagonist cetrorelix and the LHRH‐agonist buserlin. Human Reproduction 2000;15(3):526‐31. - PubMed
    1. Ludwig M, Felberbaum RE, Devroey P, Albano C, Riethmuller‐Winzen H, Schuler A, et al. Significant reduction of the incidence of ovarian hyperstimulation syndrome (OHSS) by using the LHRH antagonist cetrorelix (Cetrotide) in controlled ovarian stimulation for assisted reproduction. Archives of Gynecology and Obstetrics 2000;264(1):29‐32. - PubMed
Al‐Karaki 2011 {published data only}
    1. Al‐Karaki R, Irzouqi R, Khalifa F, Taher M, Sarraf M. Effectiveness of flexible GnRH antagonist protocol versus minidose long GnRH agonist protocol in poor‐responder patients undergoing IVF. Human Reproduction 2011;26(1):i47.
Anderson 2014 {published data only}
    1. Anderson S, Pereira NE, Brasile DR, Orris JJ, Davies EB, Glassner MJ. Comparison of antagonist to agonist in controlled ovarian stimulation (COS) cycles using human‐derived gonadotropin on in vitro fertilization (IVF) outcomes. A prospective randomized controlled study. Fertility and sterility. 2014; Vol. 102 (3; Suppl 1):e224.
Awata 2010 {published data only}
    1. Awata S, Tanaka A, Nagayoshi M. Selection of an optimal controlled ovarian hyperstimulation method in relation to the number of antral follicles in patients less than 40 years old. Fertility and Sterility 2010;94 suppl 1(4):S164 Abstract no. P‐244.
Baart 2007 {published data only}
    1. Baart EB, Martini E, Eijkemans MJ, Opstal D, Beckers NGM, Verhoeff A, et al. Milder ovarian stimulation for in‐vitro fertilization reduces aneuploidy in the human preimplantation embryo: a randomized controlled trial. Human Reproduction 2007;22(4):980‐8. - PubMed
Badrawi 2005 {published data only}
    1. Badrawi A, Al‐Inany H, Hussein M, Zaki S, Ramzy AM. Agonist versus antagonist in ICSI cycles: a randomized trial and cost effectiveness analysis. Middle East Fertility Society Journal 2005;10(1):49‐54.
Bahceci 2005 {published data only}
    1. Bahceci M, Ulug U, Ben‐Shlomo I, Erden HF, Akman MA. Use of a GnRH antagonist in controlled ovarian hyperstimulation for assisted conception in women with polycystic ovary disease: a randomized, prospective, pilot study. Journal of Reproductive Medicine 2005;50(2):84‐90. [MEDLINE: ] - PubMed
Barmat 2005 {published data only}
    1. Barmat LI, Chantilis SJ, Hurst BS, Dickey RP. A randomized prospective trial comparing gonadotropin‐releasing hormone (GnRH) antagonist/recombinant follicle‐stimulating hormone (r FSH) versus GnRH‐agonist/r FSH in women pretreated with oral contraceptives before in vitro fertilization. Fertility and Sterility 2005;83(2):321‐30. [MEDLINE: ] - PubMed
Brelik 2004 {published data only}
    1. Brelik P, Kurzawa R, Baczkowski T, Sienkiewicz R, Glabowski W. Assessment of the predictive value of LH levels in IVF cycles stimulated with GnRH antagonists and agonists. Human Reproduction 2004;19:i62.
Celik 2011 {published data only}
    1. Celik N, Celik O, Aktan E, Ozerol E, Celik E, Bozkurt K, et al. Plasma urocortin levels in women undergoing long agonist and antagonist protocols for IVF. Human Reproduction 2011;26(1):i203.
Check 2004 {published data only}
    1. Check ML, Check JH, Choel JK, Davies E, Kiefer D. Effect of antagonists vs agonists on in vitro fertilization outcome. Clinical and Experimental Obstetrics & Gynecology 2004;31(4):257‐9. [MEDLINE: ] - PubMed
Cheung 2005 {published data only}
    1. Cheung LP, Lam PM, Lok IH, Chiu TT, Yeung SY, Tjer CC, et al. GnRH antagonist versus long GnRH agonist protocol in poor responders undergoing IVF: a randomized controlled trial. Human Reproduction (Oxford, England) 2005;20(3):616‐21. [MEDLINE: ] - PubMed
Choi 2012 {published data only}
    1. Choi MH, Kim HO, Cha SW, Koong MKK, Kim JY, Park CW. IVF comparison of ART outcomes in infertile PCOS women; in vitro maturation (IVM) vs. GnRH agonist vs. GnRH antagonist cycles. Clinical Experimental Reproductive Medicine December 2012;39(4):S210. - PMC - PubMed
    1. Choi MH, Lee SH, Kim HO, Cha SH, Kim JY, Yang KM, et al. Comparison of assisted reproductive technology outcomes in infertile women with polycystic ovary syndrome: In vitro maturation, GnRH agonist, and GnRH antagonist cycles. Clinical & Experimental Reproductive Medicine 2012;39(4):166‐71. - PMC - PubMed
Cota 2012 {published data only}
    1. Cota AM, Oliveira JB, Petersen CG, Mauri AL, Massaro FC, Silva LF, et al. GnRH agonist versus GnRH antagonist in assisted reproduction cycles: oocyte morphology. Reproductive Biology and Endocrinology 2012;10:33. - PMC - PubMed
    1. Lavorato HL, Oliveira JB, Petersen CG, Vagnini L, Mauri AL, Cavagna M, et al. GnRH agonist versus GnRH antagonist in IVF/ICSI cycles with recombinant LH supplementation: DNA fragmentation and apoptosis granulosa cells. European Journal of Obstetrics & Gynecology and Reproductive Biology 2012;165:61‐5. - PubMed
Depalo 2009 {published data only}
    1. Depalo R, Lorusso F, Palmisano M, Bassi E, Totaro I, Vacca M, et al. Follicular growth and oocyte maturation in GnRH agonist and antagonist protocols for in vitro fertilisation and embryo transfer. Gynecological Endocrinology 2009;25(5):328‐34. - PubMed
El Sahwi 2005 {published data only}
    1. Sahwi S. GnRH agonists versus GnRH antagonists in controlled ovarian stimulation in ICSI trials. Book of Abstracts, 8th International Symposium on GnRH Analogues in Cancer and Human Reproduction. Salzburg, Austria. 2005:A65.
Engmann 2008a {published data only}
    1. Engmann L, DiLuigi A, Schmidt D, Nulsen D, Nulsen J, Benadiva C. The use of gonadotropin‐releasing hormone (GnRH) agonist to induce oocyte maturation after cotreatment with GnRH antagonist in high‐risk patients undergoing in vitro fertilization prevents the risk of ovarian hyperstimulation syndrome: a prospsective randomised controlled study. Fertility and Sterility 2008;89(1):84‐91. - PubMed
Euro Middle East 2001 {published data only}
    1. European and Middle East Orgalutran Study Group. Comparable clinical outcome using the GnRH antagonist ganirelix or a long protocol of the GnRH agonist triptorelin for the prevention of premature LH surges in women undergoing ovarian stimulation. Human Reproduction (Oxford, England) 2001;16(4):644‐51. [MEDLINE: ] - PubMed
    1. Sonntag B, Kiesel L, Nieschlag E, Behre HM. Association of inhibin B serum levels with parameters of follicular response in a randomized controlled trial comparing GnRH agonist versus antagonist protocols for ovarian hyperstimulation. Journal of Assisted Reproduction and Genetics 2004;21(7):249‐55. - PMC - PubMed
Euro Orgalutran 2000 {published data only}
    1. The European Orgalutran Study Group, Borm G, Mannaerts B. Treatment with the gonadotrophin‐releasing hormone antagonist ganirelix in women undergoing ovarian stimulation with recombinant follicle stimulating hormone is effective, safe and convenient: results of a controlled, randomized, multicentre trial. Human Reproduction (Oxford, England) 15;7:1490‐8. - PubMed
Ferrari 2006 {published data only}
    1. Ferrari B, Pezzuto A, Barusi L, Coppola F. Follicular fluid vascular endothelial growth factor concentrations are increased during GnRH antagonist/FSH ovarian stimulation cycles. European Journal of Obstetrics & Gynecology and Reproductive Biology 2006;124(1):70‐6. - PubMed
    1. Ferrari B, Pezzuto A, Barusi L, Coppola F. Gonadotrophin‐releasing hormone antagonists increase follicular fluid insulin‐like growth factor‐I and vascular endothelial growth factor during ovarian stimulation cycles. Gynecological Endocrinology June 2006;22(6):289‐96. [DOI: 10.1080/09513590600777602] - DOI - PubMed
Ferrero 2010 {published data only}
    1. Ferrero S, Abbamonte L H, Privamera MR, Levi S, Venturini PL, Anserini P. Flexible GnRH antagonist protocol versus GnRH agonist long protocol in patients at high risk of ovarian hyperstimulation syndrome: A prospective randomized controlled trial. Fertility and Sterility 2010;94 suppl 1(4):S28 Abstract no. O‐92.
Firouzabadi 2010 {published data only}
    1. Firouzabadi RD, Ahmadi S, Oskouian H, Davar R. Comparing GnRH agonist long protocol and GnRH antagonist protocol in outcome the first cycle of ART. Archives of Gynecology and Obstetrics 2010;281(1):81‐5. [PUBMED: PMID: 19357861 ] - PubMed
Fluker 2001 {published and unpublished data}
    1. Fluker M, Grifo J, Leader A, Levy M, Meldrum D, Muasher SJ, et al. for The North American Ganirelix Study Group. Efficacy and safety of ganirelix acetate versus leuprolide acetate in women undergoing controlled ovarian hyperstimulation. Fertility and Sterility 2001;75(1):38‐45. - PubMed
Franco 2003 {published data only}
    1. Franco Jr JG, Baruffi RLR, Petersen CG, Mauri AL, Felipe V, Contart P. Comparison of ovarian stimulation with recombinant FSH After 2nd phase protocols with GnRH Analogs (I‐estradiol + ganirelix versus II‐nafarelin) [Comparacao da estimulacao ovariana com FSH recombinante apos protocolo de 2A fase com analogos do GNRH (I ‐estradiol + ganirelix versus II‐nafarelin)]. Jornal Brasileiro de Reproducao Assistida 2003;7(1):26‐32.
Friedler 2003 {published data only}
    1. Friedler S, Gilboa S, Schachter M, Raziel R, Strassburger D, Kasterstein E, et al. Luteal phase characteristics following GnRH antagonist or agonist treatment: a randomized comparative study. Human Reproduction (Oxford, England) 2003;18 Suppl 1:26.
Gizzo 2014 {published data only}
    1. Gizzo S, Andrisani A, Esposito F, Noventa M, Gangi S, Angioni S, et al. Which luteal phase support is better for each IVF stimulation protocol to achieve the highest pregnancy rate? A superiority randomized clinical trial. Gynecological Endocrinology 2014;30(12):902‐8. [DOI: 10.3109/09513590.2014.964638] - DOI - PubMed
Haydardedeoglu 2012 {published data only}
    1. Haydardedeoglu B, Kilicdag EB, Parlakgumus AH, Zeyneloglu HB. IVF/ICSI outcomes of the OCP plus GnRH agonist protocol versus the OCP plus GnRH antagonist fixed protocol in women with PCOS: a randomized trial. Archives of Gynecology and Obstetrics September 2012;286(3):763‐769. - PubMed
Heijnen 2007 {published data only}
    1. Heijnen EM, Eijkemans MJ, Klerk C, Polinder S, Beckers NG, Klinkert ER, et al. A mild treatment strategy for in‐vitro fertilisation: a randomised non‐inferiority trial. The Lancet 2007;369:743‐9. - PubMed
Hershko Klement 2015 {published data only}
    1. Hershko Klement A, Berkovitz A, Wiser A, Gonen O, Amichay K, Cohen I, et al. GnRH‐antagonist programming versus GnRH agonist protocol: a randomized trial. European Journal of Obstetrics Gynecology and Reproductive Biology 2015;185:170‐3. - PubMed
    1. Hershko Klement A, Berkovitz A, Wiser A, Gonen O, Amichay K, Shulman A. Follicular estrogen for GnRH‐antagonist protocol programming: a prospective randomized clinical trial. Fertility and Sterility. 2013; Vol. 1:S523.
Hohmann 2003 {published data only}
    1. Hohmann FP, Macklon NS, Fauser BC. A randomized comparison of two ovarian stimulation protocols with gonadotropin‐releasing hormone (GnRH) antagonist cotreatment for in vitro fertilization commencing recombinant follicle‐stimulating hormone on cycle day 2 or 5 with the standard long GnRH agonist protocol. The Journal of Clinical Endocrinology and Metabolism 2003;88(1):166‐73. - PubMed
Hoseini 2014 {published data only}
    1. Hoseini FS, Mugahi SM, Akbari‐Asbagh F, Eftekhari‐Yazdi P, Aflatoonian B, Aghaee‐Bakhtiari SH, et al. A randomized controlled trial of gonadotropin‐releasing hormone antagonist in Iranian infertile couples: oocyte gene expression. Journal of Pharmaceutical Sciences 2014;22:67. - PMC - PubMed
Hosseini 2010 {published data only}
    1. Hosseini MA, Aleyasin A, Saeedi H, Mahdavi A. Comparison of gonadotropin‐releasing hormone agonists and antagonists in assisted reproduction cycles of polycystic ovarian syndrome patients. Journal of Obstetrics & Gynaecology Research 2010;36(3):605‐10. - PubMed
Hsieh 2008 {published data only}
    1. Hsieh YY, Chang CC, Tsai HD. Comparisons of different dosages of gonadotropin‐releasing hormone (GnRH) antagonist, short‐acting form and single, half‐dose, long‐acting form of GnRH agonist during controlled ovarian hyperstimulation and in vitro fertilization. Taiwan Journal of Obstetrics and Gynecology 2008;47:66‐74. - PubMed
Huirne 2006 {published data only}
    1. Huirne JA, Loenen AC, Donnez J, Pirard C, Homburg R, Schats R, et al. Effect of an oral contraceptive pill on follicular development in IVF/ICSI patients receiving a GnRH antagonist: a randomized study. Reproductive Biomedicine Online 2006;13(2):235‐45. - PubMed
Hwang 2004 {published data only}
    1. Hwang JL, Seow K, Lin Y, Huang L, Hsieh B, Tsai Y, 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. Human Reproduction 2004;19(9):1993‐2000. - PubMed
Inza 2004 {published data only}
    1. Inza R, Thillo G, Lombardi E, Bisioli C, Diradourian M, Kenny A. Reproductive performance in second IVF cycles treated with the use of either GnRH antagonists (‐antag) vs GnRH agonists (‐ag) after failure with long protocols with GnRH agonists: a prospective randomized trial. Fertility and Sterility 2004;82 Suppl:233‐4.
Karimzadeh 2010 {published data only}
    1. Karimzadeh MA, Ahmadi S, Oskouian H, Rahmani E. Comparison of mild stimulation and conventional stimulation in ART outcome. Archives of Gynecology and Obstetrics 2010;281(4):741‐6. - PubMed
Khalaf 2010 {published data only}
    1. Khalaf M, Mittre H, Levallet J, Hanoux V, Denoual C, Herlicoviez M, et al. GnRH agonist and GnRH antagonist protocols in ovarian stimulation: differential regulation pathway of aromatase expression in human granulosa cells. Reproductive Biomedicine Online 2010;21(1):56‐65. - PubMed
Kim 2004 {published data only}
    1. Kim C‐H, Lee Y‐J, Hong S‐H, Nah H‐Y, Kim S‐H, Chae H‐D, et al. Efficacy of a GnRH antagonist during early and late controlled ovarian hyperstimulation period in women with polycystic ovary syndrome undergoing IVF‐ET. Human Reproduction (Oxford, England) 2004;19:i104‐5.
Kim 2011 {published data only}
    1. Kim C‐H, Jeon G‐H, Cheon Y‐P, Jeon I, Kim S‐H, Chae H‐D, et al. Comparison of GnRH antagonist protocol with or without oral contraceptive pill pretreatment and GnRH agonist low‐dose long protocol in low responders undergoing IVF/intracytoplasmic sperm injection. Fertility and Sterility 2009;92(5):1758‐60. - PubMed
    1. Kim C‐H, You R‐M, Kang H‐K, Ahn J‐W, Jeon I, Lee J‐W, et al. GnRH antagonist multiple dose protocol with oral contraceptive pill pre‐treatment in poor responders undergoing IVF/ICSI. Clinical and Experimental Reproductive Medicine 2011;38(4):228‐33. - PMC - PubMed
    1. Kim CH, Lee HA, Lee JW, Lee YJ, Nah HY, Hong SH, et al. The efficacy of oral contraceptive pretreatment in controlled ovarian hyperstimulation using a GnRH antagonist for low responders [poster]. Abstracts of the 21st Annual Meeting of the ESHRE. Copenhagen, Denmark, 2005. Human Reproduction. 2005; Vol. 20 Suppl 1:i105‐6.
Kim 2012 {published data only}
    1. Kim C‐H, Moon J‐W, Kang H‐J, Ahn J‐W, Kim S‐H, Chae H‐D, et al. Effectiveness of GnRH antagonist multiple dose protocol applied during early and late follicular phase compared with GnRH agonist long protocol in non‐obese and obese patients with polycystic ovary syndrome undergoing IVF/ICSI. Clinical and Experimental Reproductive Medicine 2012;39(1):22‐7. - PMC - PubMed
Kurzawa 2008 {published data only}
    1. 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. Journal for Assisted Reproduction and Genetics 2008;25(8):365‐74. - PMC - PubMed
Kyono 2005 {published data only}
    1. Kyono K, Fuchinoue K, Nakajo Y, Yagi A, Sasaki K. A prospective randomized study of three ovulation induction protocols for IVF: GnRH agonist versus antagonist with and without low dose hCG. Fertility and Sterility 2004;82 Suppl:31.
    1. Kyono K, Nakajo Y, Sasaki S, Kumagai S, Suzuki S. A prospective randomized study of three different controlled ovarian hyperstimulation (COH) protocols. Fertility and Sterility 2005;84 Suppl 1:299.
Lainas 2007 {published data only}
    1. Lainas TG, Petsas GK, Zorovilis IZ, Lliadis GS, Lainas GT, Gazlaris HE, et al. Initiation of GnRH antagonist on day 1 of stimulation as compared to the long agonist protocol in PCOS patients: a randomised controlled trial: effect on hormonal levels and follicular development. Human Reproduction 2007;22(6):1540‐6. - PubMed
Lainas 2010 {published data only}
    1. Basly M, Achour R, Ben Jemaa S, Chnitir M, Messaoudi L, Chibani M, et al. Flexible Gnrh antagonist protocol versus Gnrh agonist long protocol in patients with polycystic ovary syndrome treated for IVF: a prospective randomised controlled trial (RCT). Internet Journal of Gynecology & Obstetrics 2012;16(3):1.
    1. Lainas TG, Sfontouris IA, Zorzovilis IZ, Petsas GK, Lainas GT, Alexopoulou E, et al. Flexible GnRH antagonist protocol versus GnRH agonist long protocol in patients with polycystic ovary syndrome treated for IVF: a prospective randomised controlled trial (RCT). Human Reproduction 2010;25(3):683‐9. - PubMed
Lavorato 2012 {unpublished data only}
    1. Lavorato HL, Oliveira JB, Petersen CG, Vagnini L, Maur AL, Cavagna M, et al. GnRH agonist versus GnRH antagonist in IVF/ICSI cycles with recombinant LH supplementation: DNA fragmentation and apoptosis in granulosa cells. European Journal of Obstetrics & Gynecology and Reproductive Biology 2012;165(1):61‐5. - PubMed
Lee 2005 {published data only}
    1. Lee TH, Wu MH, Chen HF, Chen MJ, Ho HN, Yang YS. Ovarian response and follicular development for single‐dose and multiple‐dose protocols for gonadotropin‐releasing hormone antagonist administration. Fertility and Sterility 2005;83(6):1700‐7. - PubMed
Lin 2006 {published data only}
    1. Lin YH, Hwang JL, Seow KM, Huang LW, Hsieh BC, Tzeng CR. Comparison of outcome of clomiphene citrate/human menopausal gonadotropin/cetrorelix protocol and buserelin long protocol ‐ a randomized study. Gynecological Endocrinology 2006;22(6):297‐302. - PubMed
Loutradis 2004 {published data only}
    1. Loutradis D, Stefanidis K, Drakakis P, Milingos S, Antsaklis A, Michalas S. A modified gonadotropin‐releasing hormone (GnRH) antagonist protocol failed to increase clinical pregnancy rates in comparison with the long GnRH protocol. Fertility and Sterility 2004;82(5):1446‐8. [MEDLINE: ] - PubMed
Marci 2005 {published data only}
    1. Marci R, Caserta D, Dolo V, Tatone C, Pavan A, Moscarini M. GnRH antagonist in IVF poor‐responder patients: results of a randomized trial. Reproductive Biomedicine Online 2005;11(2):189‐93. - PubMed
    1. Marci R, Caserta D, Farina M, Dessole S, Germond M, Tatone C, et al. The use of GnRH antagonist in ovarian stimulation for IVF cycles can achieve good pregnancy rates in poor responder patients. Human Reproduction (Oxford, England) 2002;17:115‐6.
Martinez 2008 {published data only}
    1. Martínez F, Clua E, Parera N, Rodríguez I, Boada M, Coroleu B. Prospective, randomized, comparative study of leuprorelin + human menopausal gonadotropins versus ganirelix + recombinant follicle‐stimulating hormone in oocyte donors and pregnancy rates among the corresponding recipients. Gynecological Endocrinology 2008;24(4):188‐93. - PubMed
Mohamed 2006 {published data only}
    1. Mohamed KA, Davies WAR, Lashen H. Effect of gonadotropin‐releasing hormone agonist and antagonist on steroidogenesis of low responders undergoing in vitro fertilization. Gynecological Endocrinology 2006;22(2):57‐62. - PubMed
Moraloglu 2008 {published data only}
    1. Moraloglu O, Kilic S, Karayalçin R, Yuksel B, Tasdemir N, Ugur M. Comparison of GnRH agonists and antagonists in normo‐responder IVF/ICSI in Turkish female patients. Advances in Therapy 2008;25(3):266‐73. - PubMed
Moshin 2007 {published data only}
    1. Moshin V, Croitor M, Hotineanu A. GnRH antagonist versus long GnRH agonists protocol in PCOS patients undergoing IVF treatment. Abstracts of the 23rd Annual Meeting of the ESHRE, Lyon, France 2007;22 Suppl 1:i121.
Olivennes 2000 {published data only}
    1. Olivennes F, Belaisch‐Allart, Emperare J, Dechaud H, S Alvarez S, Moreau L. 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). Fertility and Sterility 2000;73(2):314‐20. - PubMed
Papanikolaou 2012 {published data only}
    1. Papanikolaou EG, Pados G, Grimbizis G, Bili E, Kyriazi L, Polyzos NP, et al. GnRH‐agonist versus GnRH‐antagonist IVF cycles: is the reproductive outcome affected by the incidence of progesterone elevation on the day of HCG triggering? A randomized prospective study. Human Reproduction 2012;27(6):1822‐8. - PubMed
Prapas 2013 {published data only}
    1. Prapas Y, Petousis S, Dagklis T, Panagiotidis Y, Papatheodorou A, Assunta I, et al. GnRH antagonist versus long GnRH agonist protocol in poor IVF responders: a randomized clinical trial. European Journal of Obstetrics, Gynecology, & Reproductive Biology 2013;166(1):43‐6. - PubMed
Qiao 2012 {published data only}
    1. Qiao J, Lu G, Zhang HW, Chen H, Ma C, Olofsson JI, et al. A randomized controlled trial of the GnRH antagonist ganirelix in Chinese normal responders: high efficacy and pregnancy rates. Gynecological Endocrinology 2012;28(10):800‐4. - PubMed
Rabati 2012 {published data only}
    1. Rabati BK, Zeidi SN. Investigation of pregnancy outcome and ovarian hyper stimulation syndrome prevention in agonist and antagonist gonadotropin‐releasing hormone protocol. Journal of Research in Medical Sciences 2012;17(11):1063‐6. - PMC - PubMed
Revelli 2014 {published data only}
    1. Revelli A, Chiadò A, Dalmasso P, Stabile V, Evangelista F, Basso G, et al. “Mild” vs. “long” protocol for controlled ovarian hyperstimulation in patients with expected poor ovarian responsiveness undergoing in vitro fertilization (IVF): a large prospective randomized trial. Journal of Assisted Reproduction and Genetics July 2014;31(7):809‐15. [DOI: 10.1007/s10815-014-0227-y] - DOI - PMC - PubMed
Rinaldi 2014 {published data only}
    1. Rinaldi L, Lisi F, Selman H. Mild/minimal stimulation protocol for ovarian stimulation of patients at high risk of developing ovarian hyperstimulation syndrome. Journal of Endocrinological Investigation 2014;37:65‐70. - PubMed
Rombauts 2006 {published data only}
    1. Rombauts L, Healy D, Norman RJ. A comparative randomized trial to assess the impact of oral contraceptive pretreatment on follicular growth and hormone profiles in GnRH antagonist‐treated patients. Human Reproduction (Oxford, England) 2006;21(1):95‐103. - PubMed
Sauer 2004 {published data only}
    1. Sauer MV, Thornton MH, Schoolcraft W, Frishman GN. Comparative efficacy and safety of cetrorelix with or without mid‐cycle recombinant LH and leuprolide acetate for inhibition of premature LH surges in assisted reproduction. Reproductive Biomedicine Online 2004;9(5):487‐93. - PubMed
Sbracia 2009 {published data only}
    1. Sbracia M, Colabianchi J, Giallonardo A, Giannini P, Piscitelli C, Morgia F, et al. Cetrorelix protocol versus gonadotropin‐releasing hormone analog suppression long protocol for superovulation in intracytoplasmic sperm injection patients older than 40. Fertility and Sterility 2009;91(5):1842‐7. - PubMed
Serafini 2008 {published data only}
    1. Serafini P, Yadid I, Alegretti J, Panzan M, Cosloversusky M, Motta E. A prospective, randomized trial of three ovulation induction protocols for IVF including a novel approach with low‐dose HCG and GnRH antagonist in the mid‐late follicular phase. Human Reproduction (Oxford, England) 2003;18:1.
    1. Serafini P, Yadid I, Motta ELA, Alegretti JR, Fioavanti J, Coslovsky M. Ovarian stimulation with daily late follicular phase administration of low dose human chorionic gonadotropin for in vitro fertilization: a prospective randomized trial. Fertility and Sterility 2006;86(4):830‐8. - PubMed
Stenbaek 2015 {published data only}
    1. Stenbaek DS, Toftager M, Hjordt LV, Jensen PS, Holst KK, Bryndorf T, et al. Mental distress and personality in women undergoing GnRH agonist versus GnRH antagonist protocols for assisted reproductive technology. Human Reproduction 2015;30(1):103‐10. - PubMed
Sunkara 2014 {published data only}
    1. Sunkara S, Coomarasamy A, Faris R, Braude P, Khalaf Y. Effectiveness of the GnRH agonist long, GnRH agonist short and GnRH antagonist regimens in poor responders undergoing IVF treatment: a three arm randomised controlled trial. Human Reproduction. 2013; Vol. 28:i348.
    1. Sunkara SK, Coomarasamy A, Faris R, Braude P, Khalaf Y. Long gonadotropin‐releasing hormone agonist versus short agonist versus antagonist regimens in poor responders undergoing in vitro fertilization: A randomized controlled trial. Fertility and Sterility 2014;101(1):147‐53. - PubMed
Tazegul 2008 {published data only}
    1. Tazegül A, Görkemli H, Ozdemir S, Aktan TM. Comparison of multiple dose GnRH antagonist and minidose long agonist protocols in poor responders undergoing in vitro fertilization: a randomized controlled trial. Archives of Gynecology and Obstetrics 2008;278(5):467‐72. - PubMed
Tehraninejad 2010 {published data only}
    1. 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. Archives of Gynecology and Obstetrics 2010;282(3):319‐25. - PubMed
Tehraninejad 2011 {published data only}
    1. Nezamabadi AG, Tehraninejad ES, Rashidi B. GnRH Antagonist versus Agonist in Normoresponders Undergoing ICSI: A Randomized Clinical Trial in Iran. International Journal of Fertility and Sterility 2013;7(1):106. - PMC - PubMed
    1. Tehraninejad E, Nezamabadi AG, Rashidi B, Sohrabi M, Bagheri M, Haghollahi F, et al. GnRH antagonist versus agonist in normoresponders undergoing ICSI: a randomized clinical trial in Iran. Iranian Journal of Reproductive Medicine 2011;9(3):171‐6. [IRCT138902283950N1]] - PMC - PubMed
Toltager 2015 {published data only}
    1. Toltager M, Bogstad J, Lossl, K, et al. Pregnancy rates and risk of ovarian hyperstimulation syndrome (OHSS) in a fixed GnRH‐antagonist versus GnRH‐agonist protocol: randomised controlled trial including 1099 first IVF/ICSI CYCLES. Abstract of the 31st annual meeting of ESHRE I Lisbon, Portigal. 2015:i94.
Xavier 2005 {published data only}
    1. Xavier P, Gamboa C, Calejo L, Silva J, Stevenson D, Nunes A, et al. A randomised study of GnRH antagonist (cetrorelix) versus agonist (busereline) for controlled ovarian stimulation: effect on safety and efficacy. Eurpean Journal of Obstetrics, Gynecology, and Reproductive Biology 2005;120(2):185‐9. [MEDLINE: ] - PubMed
Ye 2009 {published data only}
    1. Ye H, Huang G, Zeng P, Pei L. IVF/ICSI outcomes between cycles with luteal estradiol (E2) pre‐treatment before GnRH antagonist protocol and standard long GnRH agonist protocol: a prospective and randomized study. Journal of Assisted Reproduction and Genetics 2009;2(3):105‐11. - PMC - PubMed

References to studies excluded from this review

Ashrafi 2004 {published data only}
    1. Ashrafi M, Mohammadzadeh A, Ezabadi Z, Baghestani AR. A comparative study of GnRH‐ant and GnRH‐ag protocols on IVF‐ICSI in PCOD patients. Book of Abstracts, 18th World Congress on Fertility and Sterility (IFFS 2004), Montreal Canada. 2004.
Bonduelle 2010 {published data only}
    1. Bonduelle M, Oberyé J, Mannaerts B, Devroey P. Large prospective, pregnancy and infant follow‐up trial assures the health of 1000 fetuses conceived after treatment with the GnRH antagonist ganirelix during controlled ovarian stimulation. Human Reproduction 2010;25(6):1433‐40. - PubMed
Cattani 2000 {published data only}
    1. Cattani R, Cela V, Cristello F, Matteucci C, Valentino V, Artini P. Efficacy and safety of gonadotrophin releasing hormone (GnRH) antagonist administration in infertile women during controlled ovarian hyperstimulation. Gynecological Endocrinology. 2000; Vol. 14, issue Suppl 2:212.
Causio 2004 {published data only}
    1. Causio F, Sarcina E, Leonetti T. GnRH agonist versus GnRH antagonist in an IVF program: luteal phase hormonal characteristics. Human Reproduction 2004;19:i103.
Crosignani 2007 {published data only}
    1. Crosignani PG, Somigliana E. Effect of GnRH antagonists in FSH mildly stimulated intrauterine insemination cycles: a multi centre randomized trial. Human Reproduction 2007;22(2):500‐5. - PubMed
D'Amato 2004 {published data only}
    1. D'Amato G, Caroppo E, Pasquadibisceglie A, Carone D, Vitti A, Vizziello GM. A novel protocol of ovulation induction with delayed gonadotropin‐releasing hormone antagonist administration combined with high‐dose recombinant follicle‐stimulating hormone and clomiphene citrate for poor responders and women over 35 years. Fertility and Sterility 2004;81(6):1572‐7. - PubMed
Davar 2012 {published data only}
    1. Davar R, Rahsepar M, Rahmani E. A comparative study of luteal estradiol pre‐treatment in GnRH antagonist protocols and in micro dose flare protocols for poor responding patients. Fertlity and Sterility 2012;6(1):107. - PubMed
De Klerk 2007 {published data only}
    1. Klerk C, Macklon NS, Heijnen EMEW, Eijkemans MJC, Fauser BCJM, Passchier J, Hunfeld JAM. The psychological impact of IVF failure after two or more cycles of IVF with a mild versus standard treatment strategy. Human Reproduction 2007;22(9):2554‐8. - PubMed
Dudley 2010 {published data only}
    1. Dudley PS, Thyer AC, Davis LB, Klein NA, Criniti AR, Soules MR. A new IVF stimulation protocol improves live birth rate in women with diminished ovarian reserve (DOR). Fertility and Sterility September 2010;94(4):S85‐S86. [DOI: 10.1016/j.fertnstert.2010.07.329] - DOI
Eijkemans 2006 {published data only}
    1. Eijkemans MJ, Heijnen EM, Klerk C, Habbema JD, Fauser BC. Comparison of different treatment strategies in IVF with cumulative live birth over a given period of time as the primary end‐point: methodological considerations on a randomized controlled non‐inferiority trial. Human Reproduction (Oxford, England) 2006;21(2):344‐52. [MEDLINE: ] - PubMed
Engmann 2008b {published data only}
    1. Engmann L, DiLuigi A, Schmidt D, Benadiva C, Maier D, Nulsen J. The effect of luteal phase vaginal estradiol supplementation on the success of in vitro fertilization treatment: a prospective randomized study. Fertility and Sterility 2008;89(3):554‐61. - PubMed
Evangelio 2011 {published data only}
    1. Evangelio PM, Buendicho IE, Yeste AMM, Gustem RB, Egea IB, Hernandez NC. Randomized prospective study on the effect of the addition of business cycles exogenous LH IVF/ICSI GnRH antagonist predictors in patients with low response [Estudio prospectivo aleatorizado sobre el efecto de la adicion de actividad LH exogena en ciclos FIV/ICSI con antagonistas de GnRH en pacientes con factores predictivos de baja respuesta]. Revista Iberoamericana de Fertilidad 2011;28(3):219‐27.
Fabregues 2012 {published data only}
    1. Fabregues F, Iraola A, Casals G, Peralta S, Creus M, Balasch J. Evaluation of GnRH agonists and antagonists in tertiary prevention of OHSS. Clinical, neurohormonal and vasoactive effects in the luteal phase in high risk patients. Human Reproduction 2012;27(2):ii26‐ii28.
Ficicioglu 2010 {published data only}
    1. Ficicioglu C, Kumbak B, Akcin O. Comparison of follicular fluid and serum cytokine concentrations in women undergoing assisted reproductive treatment with GnRH agonist long and antagonist protocols. Gynecological Endocrinology 2010;26(3):181‐6. - PubMed
Freitas 2004 {published data only}
    1. Freitas GC, Cavagna M, Dzik A, Soares JB, Szterenfeld C, Izzo VM. Gonadotropin‐releasing hormone (GnRH)‐agonist versus GnRH‐antagonist in ovarian stimulation for assisted reproductive techniques: results of a prospective randomized trial. Fertility and Sterility 2004;82 Suppl:231‐2.
Ghosh 2003 {published data only}
    1. Ghosh M, Shirazee HH, Vijay PK, Chakravarty BN. Comparative evaluation of CC/FSH with single dose antagonist versus conventional long protocol gonadotrophin stimulation for IVF in women with several attempts of failed IUI for unexplained infertility. Human Reproduction (Oxford, England) 2003;18 Suppl 1:114‐5. [P‐333]
Gordts 2011 {published data only}
    1. Gordts S, Puttemans P, Campo R, Valkenburg M, Gordts S. A prospective randomized study comparing a GnRH‐antagonist versus a GnRH‐agonist short protocol for ovarian stimulation in patients referred for IVF. Fertility and Sterility September 2011;96(3):S176. - PMC - PubMed
Guivarc’h‐Levêque 2010 {published data only}
    1. Guivarc’h‐Levêque A, Arvis P, Bouchet JL, Broux PL, Moy L, Priou G, et al. Efficiency of antagonist IVF cycle programming by estrogens [Efficacité de la programmation des cycles FIV en antagonistes par les estrogenes]. Gynécologie Obstétrique & Fertilité 2010;38:18‐22. - PubMed
Ibrahim 2011 {published data only}
    1. Ibrahim ZM, Mohamed Youssef HY, Elbialy MM, Farrag MM. Micro‐dose flare‐up gonadotrophin‐releasing hormone (GnRH) agonist vs. flexible gonadotrophin‐releasing hormone (GnRH) antagonist protocol in patient with poor ovarian reserve. Middle East Fertility Society Journal 2011;16:272‐277. [DOI: 10.1016/j.mefs.2011.06.003] - DOI
Jindal 2013 {published data only}
    1. Jindal A, Singh R. A prospective randomised controlled study comparing a low‐cost antagonist protocol using oral ovulation inducing agents in IVF‐ICSI cycles with a standard agonist long protocol. Fertility and Sterility October 2013;100(3):S273.
Karimzadeh 2011 {published data only}
    1. Karimzadeh MA, Mashayekhy M, Mohammadian F, Moghaddam FM. Comparison of mild and microdose GnRH agonist flare protocols on IVF outcome in poor responders. Archives of Gynecology and Obstetrics 2011;283:1159‐64. [DOI: 10.1007/s00404-010-1828-z] - DOI - PubMed
Kdous 2009 {published data only}
    1. Kdous M, Chaker A, Bouyahia M, Zhioua F, Zhioua A. Increased risk of early pregnancy loss and lower live birth rate with GnRH antagonists vs. long GNRH agonist protocol in PCOS women undergoing controlled ovarian hyperstimulation. La Tunisie Medicale 2009;87(12):834‐42. - PubMed
Kim 2010 {published data only}
    1. Kim YJ, Ku SY, Jee BC, Suh CS, Kim SH, Choi YM, et al. A comparative study on the outcomes of in vitro fertilization between women with polycystic ovary syndrome and those with sonographic polycystic ovary‐only in GnRH antagonist cycles. Archives of Gynecology and Obstetrics 2010;282(2):199‐205. [PUBMED: 20182736 [PubMed ‐ as supplied by publisher]] - PubMed
Lee 2008 {published data only}
    1. Lee JR, Kim SH, Kim SM, Jee BC, Ku SY, Suh CS, et al. Follicular fluid anti‐Müllerian hormone and inhibin B concentrations: comparison between gonadotropin‐releasing hormone (GnRH) agonist and GnRH antagonist cycles. Fertility and Sterility 2008;89(4):860‐7. - PubMed
Lin 1999 {published data only}
    1. Lin Y, Kahn JA, Hillensjo T. Is there a difference in the function of granulosa‐luteal cells in patients undergoing in‐vitro fertilization either with gonadotrophin‐releasing hormone agonist or gonadotrophin‐releasing hormone antagonist?. Human Reproduction (Oxford, England) 1999;14(4):885‐8. [MEDLINE: ] - PubMed
Londra 2003 {published data only}
    1. Londra L, Inza R, Lombardi E, Marconi G, Young E, Kenny A. GnRh antagonist versus GnRh agonist in good prognosis IVF patients. Human Reproduction 2003;18 Suppl 1:114.
Maldonado 2011 {published data only}
    1. Maldonado LG, Setti AS, Franco JG, Braga DPAF, Figueira RCS, Iaconelli A, et al. Pituitary suppression with GnRH agonist on alternate days: can costs, effectiveness and comfort be brought together?. Human Reproduction 2011;26(1):i151.
Maldonado 2013 {published data only}
    1. Maldonado LGL, Franco JG, Setti AS, Iaconelli A, Borges E. Cost‐effectiveness comparison between pituitary down‐regulation with a gonadotropin‐releasing hormone agonist short regimen on alternate days and an antagonist protocol for assisted fertilization treatments. Fertility and Sterility May 2013;99(6):1615‐1622. [DOI: 10.1016/j.fertnstert.2013.01.095] - DOI - PubMed
Malhotra 2013 {published data only}
    1. Malhotra N, Singh N. Microdose GnRH agonist flare‐up versus flexible GnRH antagonist protocol in poor responders undergoing in‐vitro fertilization (IVF) cycles: a randomized controlled trial. Fertility and Sterility 2013;100(3):S106. [DOI: 10.1016/j.fertnstert.2013.07.1695] - DOI
Mohsen 2013 {published data only}
    1. Mohsen IA, Din RE. Minimal stimulation protocol using letrozole versus microdose flare up GnRH agonist protocol in women with poor ovarian response undergoing ICSI. Gynecological Endocrinology 2013;29(2):105‐8. - PubMed
Orvieto 2007 {published data only}
    1. Orvieto R, Volodarsky M, Hod E, Homburg R, Rabinson J, Zohav E, et al. Controlled ovarian hyperstimulation using multi‐dose gonadotropin‐releasing hormone (GnRH) antagonist results in less systemic inflammation than the GnRH‐agonist long protocol. Gynecological Endocrinology 2007;23(8):494‐6. - PubMed
Orvieto 2008 {published data only}
    1. Orvieto R, Meltzer S, Rabinson J. GnRH agonist versus GnRH antagonist in ovarian stimulation: the role of endometrial receptivity. Fertility and Sterility 2008;90(4):1294‐6. - PubMed
Ozdogan 2012 {published data only}
    1. Ozdogan S, Ozdegirmenci O, Dilbaz S, Demir B, Cinar O, Dilbaz B, et al. A randomized prospective study of a gonadotropin‐releasing hormone antagonist versus agonist microdose flare‐up protocol in poor responder patients. Human Reproduction 2012;27(2):ii302. [CENTRAL: CN‐01026190]
Pabuccu 2005 {published data only}
    1. Pabuccu R, Onalan G, Selam B, Ceyhan T, Akar M, Onalan R. Comparison of GnRH agonist and antagonist protocols among patients with mild‐moderate endometriosis and endometrioma: a novel clinical approach. Fertility and Sterility 2005;84 Suppl 1:197‐8.
Perino 2002 {published data only}
    1. Perino M, Abate A, Brigandi A, Magnoli D, Abate F. Comparison between the GnRH antagonist ganirelix and the GnRH agonist buserelin: a prospective randomized controlled study. Human Reproduction (Oxford, England) 2002;17:33. [O‐096]
Pinto 2009 {published data only}
    1. Pinto F, Oliveira C, Cardoso MF, Teixeira‐da‐Silva J, Silva J, Sousa M, et al. Impact of GnRH ovarian stimulation protocols on intra‐cytoplasmic sperm injection outcomes. Reproductive Biology and Endocrinology 2009;7(5):1‐10. [DOI: 10.1007/s00404-010-1429-x] - DOI - PMC - PubMed
Polinder 2008 {published data only}
    1. Polinder S, Heijnen EM, Macklon NS, Habbema JD, Fauser BJ, Eijkemans MJ. Cost‐effectiveness of a mild compared with a standard strategy for IVF: a randomized comparison using cumulative term live birth as the primary endpoint. Human Reproduction 2008;23(2):316‐23. - PubMed
Prapas 2005 {published data only}
    1. Prapas N, Prapas Y, Panagiotidis Y, Prapa S, Vanderzwalmen P, Schoysman R, et al. GnRH agonist versus GnRH antagonist in oocyte donation cycles: a prospective randomized study. Human Reproduction (Oxford, England) 2005;20(6):1516‐20. [MEDLINE: ] - PubMed
Saini 2010 {published data only}
    1. Saini P, Saini A. New protocol of ovulation induction with GnRH antagonist compared with GnRH analogue long protocol in IVFET/ICSI cycles. Abstracts of the 26th Annual Meeting of ESHRE, Rome, Italy, 27 June – 30 June, 2010 June 2010;26:i317.
Shamma 2003 {published data only}
    1. Shamma F, Grossman M, Abuzeid M, al Hosn L, Ayers J, Fakih M. Comparison of daily ganirelix administration to a long protocol agonist for controlled ovarian hyperstimulation in oocyte donors: the results of a prospective randomized controlled trial. Fertility and Sterility 2003;80 Suppl 3:37‐8.
Tanaka 2014b {published data only}
    1. Tanaka A, Nagayoshi M, Tanaka I. Selection of an optimal controlled ovarian hyperstimulation method in relation to the number of antral follicles in patients less than 40 years old. Fertility and Sterility September 2014;102(3):e223. [DOI: 10.1016/j.fertnstert.2014.07.756] - DOI
Tiras 2013 {published data only}
    1. Tiras B, Leylek OA, Halicigil C, Saltik A, Kavci N. Does single dose GNRH agonist administration after oocyte pick‐up in antagonist cycles improve endometrial receptivity and pregnancy rates?. Fertility and Sterility October 2013;100(3):S59‐S60.
Verpoest 2013 {published data only}
    1. Verpoest W, Vloeberghs V, Staessen C, Devos A, Rycke M, Bonduelle M, et al. The effect of the type of ovarian stimulation protocol on PGD results: a prospective randomised trial. Human Reproduction 2013;28(1):i44.
Vlaisavljevic 2003 {published data only}
    1. Vlaisavljevic V, Reljic M, Lovrec VG, Kovacic B. Comparable effectiveness using flexible single‐dose GnRH antagonist (cetrorelix) and single‐dose long GnRH agonist (goserelin) protocol for IVF cycles‐‐a prospective, randomized study. Reproductive Biomedicine Online 2003;7(3):301‐8. [MEDLINE: ] - PubMed
Wang 2008 {published data only}
    1. Wang B, Sun HX, Hu YL, Chen H, Zhang NY. Application of GnRH‐antagonist to IVF‐ET for patients with poor ovarian response [GnRH拮抗剂用于卵巢反应不良患者的体外受精胚胎移植]. National Journal of Andrology May 2008;14(5):423‐6. - PubMed
Willman 2005 {published data only}
    1. Willman SP, Kliman HJ. Comparison of the luteal phase after pituitary suppression with GnRH‐agonist versus GnRH antagonist in controlled ovarian stimulation. Fertility and Sterility 2005;84 Suppl:308.
Zikopoulos 2005 {published data only}
    1. Zikopoulos K, Kaponis A, Adonakis G, Sotiriadis A, Kalantaridou S, Georgiou I, et al. A prospective randomized study comparing gonadotropin‐releasing hormone agonists or gonadotropin‐releasing hormone antagonists in couples with unexplained infertility and/or mild oligozoospermia. Fertility and Sterility 2005;83(5):1354‐62. [MEDLINE: ] - PubMed

References to studies awaiting assessment

Toftager 2016 {published data only}
    1. Toftager M, Bogstad J, Bryndorf T, Løssl K, Roskær J, Holland T, et al. Risk of severe ovarian hyperstimulation syndrome in GnRH antagonist versus GnRH agonist protocol: RCT including 1050 first IVF/ICSI cycles. Human Reproduction 2016;0(0. Advance Access published April 8. Accessed 26 April 2016):1–12. - PubMed

Additional references

Al‐Inany 2005
    1. Al‐Inany H, Aboulghar MA, Mansour RT, Serour GI. Optimizing GnRH antagonist administration: meta‐analysis of fixed versus flexible protocol. Reproductive biomedicine online 2005;10(5):567‐70. [PUBMED: 15949209] - PubMed
Albano 1996
    1. Albano C, Smitz J, Camus M, Riethmuller‐Winzen H, Siebert‐Weiger M, Diedrich K, et al. Hormonal profile during the follicular phase in cycles stimulated with a combination of human menopausal gonadotrophin and gonadotrophin‐releasing hormone antagonist (cetrorelix). Human Reproduction (Oxford, England) 1996;11(10):2114‐8. - PubMed
Bosch 2003
    1. Bosch E, Valencia I, Escudero E, Crespo J, Simon C, Remohi J, et al. Premature luteinization during gonadotropin‐releasing hormone antagonist cycles and its relationship with in vitro fertilization outcome. Fertility and Sterility 2003;80(6):1444‐9. - PubMed
Brinsden 1995
    1. Brinsden PR, Wada I, Tan SL, et al. Diagnosis, prevention and management of ovarian hyperstimulation syndrome. Br J Obstet Gynaecol 1995;102:767–772. - PubMed
Daya 2000
    1. Daya S. Gonadotropin releasing hormone agonist protocols for pituitary desensitization in in vitro fertilization and gamete intrafallopian transfer cycles. Cochrane Database of Systematic Reviews 2000, Issue 1. [DOI: 10.1002/14651858.CD001299] - DOI - PMC - PubMed
Deeks 2011
    1. Deeks JJ, Higgins JPT, Altman DG (editors). Chapter 9: Analysing data and undertaking meta‐analyses. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from www.cochrane‐handbook.org.
Delvigne 2002
    1. Delvigne A, Rozenberg S. Epidemiology and prevention of ovarian hyperstimulation syndrome (OHSS): a review. Human Reproduction Update 2002;8:559‐77. - PubMed
Duijkers 1998
    1. Duijkers IJM, Klipping C, Willemsen WNP, Krone D, Schneider E, Niebch G, et al. Single and multiple dose pharmacokinetics and pharmacodynamics of the gonadotrophin‐releasing hormone antagonist cetrorelix in healthy female volunteers. Human Reproduction 1998;13(9):2392‐8. - PubMed
Egger 1997
    1. Egger M, Smith GD, Schneider M, Minder C. Bias in meta‐analysis detected by a simple, graphical test. BMJ 1997;315:629‐34. - PMC - PubMed
Felberbaum 1995
    1. Felberbaum RE, Reissmann T, Kuper W, Bauer O, al Hasani S, Diedrich C, et al. Preserved pituitary response under ovarian stimulation with hMG and GnRH‐antagonists (cetrorelix) in women with tubal infertility. European Journal of Obstetrics, Gynecology, and Reproductive Biology 1995;61(2):151‐5. - PubMed
Ferriman 1961
    1. Ferriman D, Gallwey JD. Clinical assessment of body hair growth in women. Journal of Clinical Endocrinology 1961;21:1440–1447. - PubMed
Golan 1989
    1. Golan A. Ron‐El R, Herman A, Soffer Y, Weinraub Z, Caspi E. Ovarian hyperstimulation syndrome: an update review. Obstet. Gynecol. Surv 1989;44:430‐40. - PubMed
GRADEpro GDT 2015 [Computer program]
    1. McMaster University (developed by Evidence Prime, Inc.). Available from www.gradepro.org. GRADEpro Guideline Develoopment Tool. McMaster University (developed by Evidence Prime, Inc.). Available from www.gradepro.org, 2015.
Griesinger 2008
    1. Griesinger G, Venetis CA, Marx T, Diedrich K, Tarlatzis BC, Kolibianakis EM. Oral contraceptive pill pretreatment in ovarian stimulation with GnRH antagonists for IVF: a systematic review and meta‐analysis. Fertility and Sterility 2008;90(4):1055. - PubMed
Higgins 2003
    1. Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta‐analyses. BMJ 2003;327:557‐60. - PMC - PubMed
Higgins 2011a
    1. Higgins JPT, Deeks JJ (editors). Chapter 7: Selecting studies and collecting data. In: Higgins JPT, Green S (editors), Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from www.cochrane‐handbook.org.
Higgins 2011b
    1. Higgins JPT, Altman DG, Sterne JAC (editors). Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from www.cochrane‐handbook.org.
Hughes 1992
    1. Hughes EG, Fedorkow DM, Daya S, Sagle MA, Koppel P, Collins JA. The routine use of gonadotropin‐releasing hormone agonists prior to in vitro fertilization and gamete intrafallopian transfer: a meta‐analysis of randomized trials. Fertility and Sterility 1992;58:888‐96. - PubMed
Huirne 2007
    1. Huirne JA, Homburg R, Lambalk CB. Are GnRH antagonists comparable to agonists for use in IVF?. Human Reproduction 2007;11:2805‐13. - PubMed
Kolibianakis 2003
    1. Kolibianakis EM, Albano C, Camus M, Tournaye H, Steirteghem AC, Devroey P. Initiation of gonadotropin‐releasing hormone antagonist on day 1 as compared to day 6 of stimulation: effect on hormonal levels and follicular development in in vitro fertilization cycles.. Journal of Clinical Endocrinology & Metabolism 2003;88:5632‐7. - PubMed
Kolibianakis 2004
    1. Kolibianakis EM, Zikopoulos K, Smitz J, Camus M, Tournaye H, Steirteghemand AC, et al. Elevated progesterone at initiation of stimulation is associated with a lower ongoing pregnancy rate after IVF using GnRH antagonists. Human Reproduction 2004;19(7):1525‐9. - PubMed
Kolibianakis 2006
    1. Kolibianakis EM, Collins J, Tarlatzis BC, Devroey P, Diedrich K, Griesinger G. Among patients treated for IVF with gonadotrophins and GnRH analogues, is the probability of live birth dependent on the type of analogue used? A systematic review and meta‐analysis. Human reproduction update 2006;12(6):651‐71. [PUBMED: 16920869] - PubMed
Lefebvre 2011
    1. Lefebvre C, Manheimer E, Glanville J. Chapter 6: Searching for studies. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from www.cochrane‐handbook.org.
Mathur 2007
    1. Mathur R, Kailasam C, Jenkins J. Review of the evidence base strategies to prevent ovarian hyperstimulation syndrome. Human Fertility 2007;10:75‐85. - PubMed
Moher 1999
    1. Moher D, Jones A, Cook DJ, Jadad AR, Moher M, Tugwell P, et al. Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta‐analyses?. The Lancet 1999;352(9128):609‐18. - PubMed
Moher 2009
    1. Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred reporting items for systematic reviews and meta‐analyses: The PRISMA Statement. PLoS Medicine 2009;6(7):e1000097. [DOI: 10.1371/journal.pmed.1000097] - DOI - PMC - PubMed
Mozes 1965
    1. Mozes M, Bogokowsky H, Antebi E, Lunenfeld B, Rabau E, Serr DM, et al. Thromboembolic phenomena after ovarian stimulation with human gonadotrophins. Lancet 1965;2:1213‐5. - PubMed
Navot 1992
    1. Navot D, Bergh PA, Laufer N. Ovarian hyperstimulation syndrome in novel reproductive technologies: prevention and treatment. Fertility and Sterility 1992;58:249‐61. - PubMed
Olivennes 1994
    1. Olivennes F, Fanchin R, Bouchard P, Ziegler D, Taieb J, Selva J. The single or dual administration of the gonadotrophin‐releasing hormone antagonist cetrorelix in an in‐vitro fertilisation‐embryo transfer program. Fertility and Sterility 1994;62(3):468‐76. - PubMed
Olivennes 1998
    1. Olivennes F, Alvarez S, Bouchard P, Fanchin R, Salat‐Baroux J, Frydman R. The use of GnRH antagonist (cetrorelix) in a single dose protocol in IVF‐embryo transfer: a dose finding study of 3 versus 2mg. Human Reproduction (Oxford,England) 1998;13(9):2411‐4. - PubMed
RevMan 2014 [Computer program]
    1. The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.
Rizk 1999
    1. Rizk B, Aboulghar MA. Classification, pathophysiology and management of ovarian hyperstimulation syndrome. Brinsden P (ed) In‐Vitro Fertilization and Assisted Reproduction. New York, London: The Parthenon Publishing Group, 1999:131‐55.
Rotterdam 2004
    1. Rotterdam ESHRE/ASRM‐Sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long‐term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004;19(1):41‐7. - PubMed
Schulz 2010
    1. Schulz KF, Altman DG, Moher D, for the CONSORT Group. CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials. Annals of Internal Medicine 2010;152:Epub 24 March. - PubMed
Seow 2010
    1. Seow KM, Lin YH, Hsieh BC, Huang LW, Huang SC, Chen CY, et al. Characteristics of progesterone changes in women with subtle progesterone rise in recombinant follicle‐stimulating hormone and gonadotropin‐releasing hormone antagonist cycle. Gynecologic and Obstetric Investigation 2010;70:64–8. - PubMed
Shoham 2002
    1. Shoham Z. The clinical therapeutic window for luteinizing hormone in controlled ovarian stimulation. Fertility and Sterility 2002;77:1170‐7. - PubMed
Tremellen 2010
    1. Tremellen KP, Lane M. Avoidance of weekend oocyte retrievals during GnRH antagonist treatment by simple advancement or delay of hCG administration does not adversely affect IVF live birth outcomes. Humanan Reproduction 2010;25(5):1219‐24. - PubMed
Youssef 2012
    1. Youssef M, Aboulfoutouh L, Veen F, Wely M. Could mild/minimal ovarian stimulation‐IVF displace conventional IVF in poor responder women undergoing IVF/ICSI treatment cycles: systematic review & meta‐analysis. Human Reproduction 2012;27.

References to other published versions of this review

Al‐Inany 2006
    1. Al‐Inany H, Aboulghar M. Gonadotrophin‐releasing hormone antagonists for assisted reproductive technology. Cochrane Database of Systematic Reviews 2006, Issue 3. [DOI: 10.1002/14651858.CD001750] - DOI - PubMed
Al‐Inany 2009
    1. Al‐Inany HG, Abou‐Setta AM, Aboulghar MA. Gonadotrophin‐releasing hormone antagonists for assisted conception. Cochrane Database of Systematic Reviews 2009, Issue 1. [DOI: 10.1002/14651858.CD001750.pub2] - DOI - PubMed
Al‐Inany 2011
    1. Al‐Inany HG, Youssef MAFM, Aboulghar M, Broekmans FJ, Sterrenburg MD, Smit JG, et al. Gonadotrophin‐releasing hormone antagonists for assisted reproductive technology. Cochrane Database of Systematic Reviews 2011, Issue 5. [DOI: 10.1002/14651858] - DOI - PubMed

MeSH terms

Substances