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Meta-Analysis
. 2025 Jan 9;1(1):CD006919.
doi: 10.1002/14651858.CD006919.pub5.

Gonadotropin-releasing hormone agonist protocols for pituitary suppression in assisted reproduction

Charalampos S Siristatidis  1 , Li Ning Yong  2   3 , Abha Maheshwari  4 , Smriti Ray Chaudhuri Bhatta  5
Affiliations
Meta-Analysis

Gonadotropin-releasing hormone agonist protocols for pituitary suppression in assisted reproduction

Charalampos S Siristatidis et al. Cochrane Database Syst Rev. .

Abstract

Background: Gonadotropin-releasing hormone agonists (GnRHa) are commonly used in assisted reproduction technology (ART) cycles to prevent a luteinising hormone (LH) surge during controlled ovarian hyperstimulation (COH) prior to planned oocyte retrieval, thus optimising the chances of live birth. We compared the benefits and risks of the different GnRHa protocols used.

Objectives: To evaluate the effectiveness and safety of different GnRHa protocols used as adjuncts to COH in women undergoing ART.

Search methods: We searched the following databases in December 2022: the Cochrane Gynaecology and Fertility Group's Specialised Register, CENTRAL, MEDLINE, Embase, and registries of ongoing trials. We also searched the reference lists of relevant articles and contacted experts in the field for any additional trials.

Selection criteria: We included randomised controlled trials (RCTs) comparing any two protocols of GnRHa, or variations of the protocol in terms of different doses or duration, used in in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) cycles in subfertile women.

Data collection and analysis: We used standard methodological procedures recommended by Cochrane. Our primary outcome measures were number of live births or ongoing pregnancies and incidence of ovarian hyperstimulation syndrome (OHSS) per woman/couple randomised. Our secondary outcome measures included number of clinical pregnancies, pregnancy losses, number of oocytes retrieved, amount of gonadotropins used, and cost and acceptability of the treatment protocols.

Main results: We included 40 RCTs (4148 women). The trials evaluated 10 different comparisons between protocols. The evidence is current to December 2022. Only half of the studies reported the primary outcome of live birth or ongoing pregnancy rates. We restricted the primary analysis of live birth and ongoing pregnancy to trials with low risk of selection and reporting bias. Nineteen studies compared long and short protocols. The primary analysis restricted to trials with low risk of bias included five studies reporting on live birth or ongoing pregnancy rates. Results showed little or no difference when the long protocol was compared with a short protocol (odds ratio (OR) 1.45, 95% confidence interval (CI) 0.83 to 2.52; I² = 0%; 5 studies, 381 women; low-certainty evidence). For the same comparison, there was evidence that the long protocol may improve clinical pregnancy rates when compared to the short protocol (OR 1.56, 95% CI 1.01 to 2.40; I² = 23%; 8 studies, 552 women; low-certainty evidence). No study in this comparison reported on OHSS. We are uncertain if there is a difference between groups in terms of live birth and ongoing pregnancy rates when the following GnRHa protocols were compared: long versus ultrashort (OR 1.78, 95% CI 0.72 to 4.36; 1 study, 150 women; very low-certainty evidence); long luteal versus long follicular phase (OR 1.89, 95% CI 0.87 to 4.10; 1 study, 223 women; very low-certainty evidence); GnRHa reduced-dose versus GnRHa same-dose continued in the long protocol (OR 1.59, 95% CI 0.66 to 3.87; 1 study, 96 women; very low-certainty evidence); GnRHa administration for two versus three weeks before stimulation (OR 0.88, 95% CI 0.37 to 2.05; 1 study, 85 women; very low-certainty evidence); GnRHa continued versus discontinued after human chorionic gonadotropin (HCG) administration in the long protocol (OR 0.89, 95% CI 0.49 to 1.64; 1 study, 181 women; very low-certainty evidence); and 500 µg dose versus 80 µg dose in the short protocol (OR 0.31, 95% CI 0.10 to 0.98; 1 study, 200 women; very low-certainty evidence). Clinical pregnancy rates may improve with a 100 µg dose compared to a 25 µg dose in the short protocol (OR 2.30, 95% CI 1.06 to 5.00; 2 studies, 133 women; low-certainty evidence). Only four of the 40 included studies reported adverse events. We are uncertain of any difference in OHSS rate in the GnRHa reduced-dose versus GnRHa same-dose regimen in the long protocol (OR 0.47, 95% CI 0.04 to 5.35; 1 study, 96 women; very low-certainty evidence) or when administration of GnRHa lasted for two versus three weeks before stimulation (OR 0.93, 95% CI 0.06 to 15.37; 1 study, 85 women; very low-certainty evidence). Regarding miscarriage rates, we are uncertain of any difference when the GnRHa long protocol was administered for two versus three weeks before stimulation (OR 0.93, 95% CI 0.18 to 4.87; 1 study, 85 women; very low-certainty evidence) and when a 500 µg dose was compared with an 80 µg dose in the short protocol (OR 3.15, 95% CI 0.32 to 31.05; 1 study, 131 women; very low-certainty evidence). No studies reported on cost-effectiveness or acceptability of the different treatment protocols. The certainty of the evidence ranged from low to very low. The main limitations were failure to report live birth or ongoing pregnancy rates, poor reporting of methods in the primary studies, imprecise findings due to lack of data, and insufficient data regarding adverse events. Only eight of the 40 included studies were conducted within the last 10 years.

Authors' conclusions: When comparing long and short GnRHa protocols, we found little or no difference in live birth and ongoing pregnancy rates, but there was evidence that the long protocol may improve clinical pregnancy rates overall. We were uncertain of any difference in OHSS and miscarriage rates for all comparisons, which were reported by only two studies each. There was insufficient evidence to draw any conclusions regarding other adverse effects or the cost-effectiveness and acceptability of the different treatment protocols.

Trial registration: ClinicalTrials.gov NCT02681536 NCT02940535.

PubMed Disclaimer

Conflict of interest statement

Charalampos S Siristatidis: nothing to declare concerning this review. I run my private practice office. In my new Unit (2nd Dept of Obstet‐Gynecol, University of Athens, Greece) I have no funding from companies. The only funding that I use comes from E‐learning programs through the National and Kapodistrian University of Athens.

Li Ning Yong: nothing to declare.

Abha Maheshwari: declares receipt of travel support from Ferring Pharmaceuticals, Gedeon Richter, and Merck, and consultancy/independent contractor fees from Ferring Pharmaceuticals and Cook Medical.

Smriti Ray Chaudhuri Bhatta: nothing to declare.

Figures

1
1
Study flow diagram.
2
2
Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
3
3
Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
4
4
Funnel plot of comparison 1: long versus short protocol; outcome 1.2: clinical pregnancies.
5
5
Forest plot of comparison 1: long versus short protocol; outcome 1.1: live birth/ongoing pregnancies.
6
6
Forest plot of comparison 1: long versus short protocol; outcome 1.2: clinical pregnancies.
1.1
1.1. Analysis
Comparison 1: Long versus short protocol, Outcome 1: Live birth/ongoing pregnancies primary analysis
1.2
1.2. Analysis
Comparison 1: Long versus short protocol, Outcome 2: Live birth/ongoing pregnancies all studies
1.3
1.3. Analysis
Comparison 1: Long versus short protocol, Outcome 3: Clinical pregnancies primary analysis
1.4
1.4. Analysis
Comparison 1: Long versus short protocol, Outcome 4: Clinical pregnancies all studies
1.5
1.5. Analysis
Comparison 1: Long versus short protocol, Outcome 5: Number of oocytes
1.6
1.6. Analysis
Comparison 1: Long versus short protocol, Outcome 6: Amount of gonadotropins administered
1.7
1.7. Analysis
Comparison 1: Long versus short protocol, Outcome 7: Cycle cancellation
2.1
2.1. Analysis
Comparison 2: Long protocol versus ultrashort protocol, Outcome 1: Live birth and ongoing pregnancies
2.2
2.2. Analysis
Comparison 2: Long protocol versus ultrashort protocol, Outcome 2: Clinical pregnancies
2.3
2.3. Analysis
Comparison 2: Long protocol versus ultrashort protocol, Outcome 3: Number of oocytes
2.4
2.4. Analysis
Comparison 2: Long protocol versus ultrashort protocol, Outcome 4: Amount of gonadotropins administered
2.5
2.5. Analysis
Comparison 2: Long protocol versus ultrashort protocol, Outcome 5: Cycle cancellation
3.1
3.1. Analysis
Comparison 3: Short versus ultrashort protocol, Outcome 1: Clinical pregnancies
3.2
3.2. Analysis
Comparison 3: Short versus ultrashort protocol, Outcome 2: Number of oocytes
3.3
3.3. Analysis
Comparison 3: Short versus ultrashort protocol, Outcome 3: Amount of gonadotropins administered
3.4
3.4. Analysis
Comparison 3: Short versus ultrashort protocol, Outcome 4: Cycle cancellation
4.1
4.1. Analysis
Comparison 4: Long protocol: luteal versus follicular phase, Outcome 1: Live birth and ongoing pregnancies
4.2
4.2. Analysis
Comparison 4: Long protocol: luteal versus follicular phase, Outcome 2: Clinical pregnancies
4.3
4.3. Analysis
Comparison 4: Long protocol: luteal versus follicular phase, Outcome 3: Number of oocytes
4.4
4.4. Analysis
Comparison 4: Long protocol: luteal versus follicular phase, Outcome 4: Amount of gonadotropins administered
4.5
4.5. Analysis
Comparison 4: Long protocol: luteal versus follicular phase, Outcome 5: Cycle cancellation
5.1
5.1. Analysis
Comparison 5: Long protocol: continuing GnRHa versus stopping GnRHa ('long stop'), Outcome 1: Ongoing pregnancy rate primary analysis
5.2
5.2. Analysis
Comparison 5: Long protocol: continuing GnRHa versus stopping GnRHa ('long stop'), Outcome 2: Ongoing pregnancy rate all studies
5.3
5.3. Analysis
Comparison 5: Long protocol: continuing GnRHa versus stopping GnRHa ('long stop'), Outcome 3: Clinical pregnancies
5.4
5.4. Analysis
Comparison 5: Long protocol: continuing GnRHa versus stopping GnRHa ('long stop'), Outcome 4: Number of oocytes
5.5
5.5. Analysis
Comparison 5: Long protocol: continuing GnRHa versus stopping GnRHa ('long stop'), Outcome 5: Amount of gonadotropins administered
5.6
5.6. Analysis
Comparison 5: Long protocol: continuing GnRHa versus stopping GnRHa ('long stop'), Outcome 6: Cycle cancellation
6.1
6.1. Analysis
Comparison 6: Long protocol: continued same‐dose GnRHa versus reduced‐dose GnRHa, Outcome 1: Ongoing pregnancy rate
6.2
6.2. Analysis
Comparison 6: Long protocol: continued same‐dose GnRHa versus reduced‐dose GnRHa, Outcome 2: OHSS
6.3
6.3. Analysis
Comparison 6: Long protocol: continued same‐dose GnRHa versus reduced‐dose GnRHa, Outcome 3: Clinical pregnancies
6.4
6.4. Analysis
Comparison 6: Long protocol: continued same‐dose GnRHa versus reduced‐dose GnRHa, Outcome 4: Number of oocytes
6.5
6.5. Analysis
Comparison 6: Long protocol: continued same‐dose GnRHa versus reduced‐dose GnRHa, Outcome 5: Amount of gonadotropins administered
6.6
6.6. Analysis
Comparison 6: Long protocol: continued same‐dose GnRHa versus reduced‐dose GnRHa, Outcome 6: Cycle cancellation
7.1
7.1. Analysis
Comparison 7: Long protocol: discontinuing versus continuing GnRHa after HCG administration, Outcome 1: Live birth and ongoing pregnancies
7.2
7.2. Analysis
Comparison 7: Long protocol: discontinuing versus continuing GnRHa after HCG administration, Outcome 2: Clinical pregnancies
7.3
7.3. Analysis
Comparison 7: Long protocol: discontinuing versus continuing GnRHa after HCG administration, Outcome 3: Number of oocytes
7.4
7.4. Analysis
Comparison 7: Long protocol: discontinuing versus continuing GnRHa after HCG administration, Outcome 4: Amount of gonadotropins administered
7.5
7.5. Analysis
Comparison 7: Long protocol: discontinuing versus continuing GnRHa after HCG administration, Outcome 5: Cycle cancellation
8.1
8.1. Analysis
Comparison 8: Long protocol: GnRHa for 2 weeks versus 3 weeks before stimulation, Outcome 1: Live birth and ongoing pregnancies
8.2
8.2. Analysis
Comparison 8: Long protocol: GnRHa for 2 weeks versus 3 weeks before stimulation, Outcome 2: Clinical pregnancies
8.3
8.3. Analysis
Comparison 8: Long protocol: GnRHa for 2 weeks versus 3 weeks before stimulation, Outcome 3: Number of oocytes
8.4
8.4. Analysis
Comparison 8: Long protocol: GnRHa for 2 weeks versus 3 weeks before stimulation, Outcome 4: Amount of gonadotropins administered
8.5
8.5. Analysis
Comparison 8: Long protocol: GnRHa for 2 weeks versus 3 weeks before stimulation, Outcome 5: Adverse outcomes: OHSS and pregnancy loss
9.1
9.1. Analysis
Comparison 9: Short protocol: continuing GnRHa versus stopping GnRha ('short stop'), Outcome 1: Clinical pregnancies
9.2
9.2. Analysis
Comparison 9: Short protocol: continuing GnRHa versus stopping GnRha ('short stop'), Outcome 2: Number of oocytes
9.3
9.3. Analysis
Comparison 9: Short protocol: continuing GnRHa versus stopping GnRha ('short stop'), Outcome 3: Amount of gonadotropins administered
9.4
9.4. Analysis
Comparison 9: Short protocol: continuing GnRHa versus stopping GnRha ('short stop'), Outcome 4: Cycle cancellation
10.1
10.1. Analysis
Comparison 10: Short protocol variations: comparison of different doses of GnRHa, Outcome 1: Live birth 500 µg versus 80 µg
10.2
10.2. Analysis
Comparison 10: Short protocol variations: comparison of different doses of GnRHa, Outcome 2: Clinical pregnancy 500 µg vs 80 µg
10.3
10.3. Analysis
Comparison 10: Short protocol variations: comparison of different doses of GnRHa, Outcome 3: Clinical pregnancy 100 µg vs 50 µg
10.4
10.4. Analysis
Comparison 10: Short protocol variations: comparison of different doses of GnRHa, Outcome 4: Clinical pregnancy 100 µg vs 25 µg
10.5
10.5. Analysis
Comparison 10: Short protocol variations: comparison of different doses of GnRHa, Outcome 5: Clinical pregnancy 50 µg vs 25 µg
10.6
10.6. Analysis
Comparison 10: Short protocol variations: comparison of different doses of GnRHa, Outcome 6: Number of oocytes 500 µg vs 80 µg
10.7
10.7. Analysis
Comparison 10: Short protocol variations: comparison of different doses of GnRHa, Outcome 7: Number of oocytes 100 µg vs 50 µg
10.8
10.8. Analysis
Comparison 10: Short protocol variations: comparison of different doses of GnRHa, Outcome 8: Number of oocytes 100 µg vs 25 µg
10.9
10.9. Analysis
Comparison 10: Short protocol variations: comparison of different doses of GnRHa, Outcome 9: Number of oocytes 50 µg vs 25 µg
10.10
10.10. Analysis
Comparison 10: Short protocol variations: comparison of different doses of GnRHa, Outcome 10: Amount of gonadotropins administered
10.11
10.11. Analysis
Comparison 10: Short protocol variations: comparison of different doses of GnRHa, Outcome 11: Cycle cancellation
10.12
10.12. Analysis
Comparison 10: Short protocol variations: comparison of different doses of GnRHa, Outcome 12: Other outcomes: pregnancy loss
See this image and copyright information in PMC

Update of

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Ye 2001 {published data only}
    1. Ye H, Huang G, Pei L. A prospective, randomized controlled study comparing the effects of gonadotropin-releasing hormone agonist long and short protocols for in vitro fertilization. Zhonghua Fu Chan Ke Za Zhi 2001;36(4):222-5. [PMID: ] - PubMed
Zhang 2009 {published data only}
    1. Zhang J, Li Y, Liu J, Liu De, Liu N, Chen X. Effect of 7-day gonadotropin-releasing hormone agonist protocol on IGF-II and IGFBP-4 levels in the follicular fluid. Zhong Nan Da Xue Xue Bao Yi Xue Ban 2009;34(3):190-4. [PMID: ] - PubMed

References to studies excluded from this review

Abd Rabo 2012 {published data only}
    1. Abd Rabbo MH, Elmaghraby HA, Mashali NA, Abdel Moneim ME. Effect of aromatase inhibitor (letrozole) with long agonist protocol on the results of ICSI/ET in females with minimal and mild endometriosis. Alexandria Journal of Medicine 2012;48(4):303-7. [DOI: 10.1016/j.ajme.2012.04.001] - DOI
Aflatoonian 2012 {published data only}
    1. Aflatoonian A, Yousefnejad F, Eftekhar M, Mohammadian F. Efficacy of low-dose hCG in late follicular phase in controlled ovarian stimulation using GnRH agonist protocol. Archives of Gynecology and Obstetrics 2012;286(3):771-5. [PMID: ] - PubMed
Albuquerque 2013 {published data only}
    1. Albuquerque LE, Tso LO, Saconato H, Albuquerque MC, Macedo CR. Depot versus daily administration of gonadotrophin-releasing hormone agonist protocols for pituitary down regulation in assisted reproduction cycles. Cochrane Database of Systematic Reviews 2013, Issue 1. Art. No: CD002808. [DOI: 10.1002/14651858.CD002808.pub3] - DOI - PMC - PubMed
Antoine 1990 {published data only}
    1. Antoine JM, Firmin C, Alvarez S, Cornet D, Tibi C, Mandelbaum J, et al. Ovarian stimulation for in vitro fertilization using LHRH agonists: comparison of plasma and intra-follicular hormone profiles using "short" and "long" protocols [Stimulation ovarienne pour fecondation in vitro utilisant les agonistes de la LHRH: comparison des profils hormonaux plasmatiques et intra-folliculaires des protocoles courts et longs]. Journal de Gynecologie, Obstetrique et Biologie de la Reproduction 1990;19(8):1035-40. [PMID: ] - PubMed
Awaad 2022 {published data only}
    1. Awwad JT, Faour S, Moubarak E, Khalife D, Salame A, Ghunaim SS, et al. A three-dose- GnRH agonist triggering protocol to improve live births in hyper-responders undergoing fresh embryo transfer and intensive luteal support: a prospective randomised controlled clinical trial. Fertility and Sterility 2022;118(4):e57-58. [DOI: 10.1016/j.fertnstert.2022.08.181] - DOI
Azem 2010 {published data only}
    1. Azem F, Bloch M, Kuvalsky D, Wagman I, Bibi G, Amit A. Comparison of short and long GnRH agonist protocols using recombinant FSH for IVF/ICSI: a controlled prospective study. Fertility and Sterility 2010;94(4 Suppl):S163.
Beckers 2000 {published data only}
    1. Beckers NG, Laven JS, Eijkemans MJ, Fauser BC. Follicular and luteal phase characteristics following early cessation of gonadotrophin-releasing hormone agonist during ovarian stimulation for in-vitro fertilization. Human Reproduction (Oxford, England) 2000;15(1):43-9. [PMID: ] - PubMed
Bloch 2011 {published data only}
    1. Bloch M, Azem F, Aharonov I, Ben Avi I, Yagil Y, Schreiber S, et al. GnRH-agonist induced depressive and anxiety symptoms during in vitro fertilization-embryo transfer cycles. Fertility and Sterility 2011;95(1):307-9. [PMID: ] - PubMed
Braendle 1989 {published data only}
    1. Braendle W, Lindner C, Lichtenberg V, Goepel E, Bettendorf G. Endocrine profiles and luteal function during GnRH-analogue/HMG therapy. Human Reproduction (Oxford, England) 1989;4(8 Suppl):121-6. [PMID: ] - PubMed
Buvat 1993 {published data only}
    1. Buvat J, Marcolin G, Guittard C, Herbaut M, Louvet A, Renouard O. Requiem for the short protocol? [Requiem pour le protocol]. Contraception, Fertilite, Sexualite 1993;21:436.
Cambiaghi 2011 {published data only}
    1. Cambiaghi AS, Leao RBF, Castellotti DS, Nascimento P. Triptorelin every other day can prevent premature LH surge: a strategy to reduce the daily gonadotrophin-releasing hormone agonists injections. Fertility and Sterility 2011;96(3 Suppl):S175.
Cao 2020 {published data only}
    1. Cao X, Chang H-Y, Xu J-Y, Zheng Y, Xiang Y-G, Xiao B, et al. The effectiveness of different down-regulating protocols on in vitro fertilization-embryo transfer in endometriosis: a meta-analysis. Reproductive Biology and Endocrinology : RB&E 2020;18(16):[12 p.]. [DOI: ] - PMC - PubMed
Check 1992 {published data only}
    1. Check JH, Nowroozi K, Chase JS. Comparison of short versus long-term leuprolide acetate-human menopausal gonadotrophin hyperstimulation in in-vitro fertilization patients. Human Reproduction (Oxford, England) 1992;7(1):31-4. [PMID: ] - PubMed
Chen 2018 {published data only}
    1. Chen Y, Zhao J, Zhang H. Comparative effectiveness of three ovarian hyperstimulation protocol in in vitro fertilization (IVF) cycles for women with polycystic ovary syndrome. Medical Science Monitor 2018;24:9424-8. [DOI: 10.12659/MSM.913757] - DOI - PMC - PubMed
Cheon 2008 {published data only}
    1. Cheon KW, Song SJ, Choi BC, Lee SC, Lee HB, Yu SY, et al. Comparison of clinical efficacy between a single administration of long-acting gonadotrophin-releasing hormone agonist (GnRHa) and daily administrations of short-acting GnRHa in in vitro fertilization-embryo transfer cycles. Journal of Korean Medical Science 2008;23(4):662-6. [PMID: ] - PMC - PubMed
CN‐02329751 {published data only}
    1. A comparative of triptorelin and buserelin in the outcome of IVF. https://trialsearch.who.int/Trial2.aspx?TrialID=IRCT20210529051424N1.
Corson 1992 {published data only}
    1. Corson SL, Batzer FR, Gocial B, Eisenberg E, Huppert LC, Nelson JR. Leuprolide acetate-prepared in vitro fertilization-gamete intrafallopian transfer cycles: efficacy versus controls and cost analysis. Fertility and Sterility 1992;57(3):601-5. [PMID: ] - PubMed
Dakhly 2016 {published data only}
    1. Dakhly DM, Bayoumi YA, Gad Allah SH. Which is the best IVF/ICSI protocol to be used in poor responders receiving growth hormone as an adjuvant treatment? A prospective randomized trial. Gynecological Endocrinology 2016;32(2):116-9. [DOI: 10.3109/09513590.2015.1092136] - DOI - PubMed
Dessolle 2011 {published data only}
    1. Dessolle L, Ferrier D, Colombel A, Fréour T, Jean M, Barrière P. Prolonging GnRH-agonist to achieve ovarian suppression does not compromise the results of a long protocol. European Journal of Obstetrics, Gynecology, and Reproductive Biology 2011;159(1):111-4. [PMID: ] - PubMed
Devroey 1994 {published data only}
    1. Devroey P, Mannaerts B, Smitz J, Coelingh Bennink H, Van Steirteghem A. Clinical outcome of a pilot efficacy study on recombinant human follicle-stimulating hormone (Org 32489) combined with various gonadotrophin-releasing hormone agonist regimens. Human Reproduction (Oxford, England) 1994;9(6):1064-9. [PMID: ] - PubMed
Dor 1992 {published data only}
    1. Dor J, Shulman A, Pariente C, Levran D, Bider D, Menashe Y, et al. The effect of gonadotropin-releasing hormone agonist on the ovarian response and in vitro fertilization results in polycystic ovarian syndrome: a prospective study. Fertility and Sterility 1992;57(2):366-71. [PMID: ] - PubMed
Eftekhar 2013 {published data only}
    1. Eftekhar M, Rahmani E, Mohammadian F. Comparison of pregnancy outcome in half-dose Triptorelin and short-acting Decapeptyl in long protocol in ART cycles: a randomized clinical trial. Iranian Journal of Reproductive Medicine 2013;11(2):133-8. [PMID: ] - PMC - PubMed
Elgendy 1998 {published data only}
    1. Elgendy M, Afnan M, Holder R, Lashen H, Afifi Y, Lenton W, et al. Reducing the dose of gonadotrophin-releasing hormone agonist on starting ovarian stimulation: effect on ovarian response and in-vitro fertilization outcome. Human Reproduction (Oxford, England) 1998;13(9):2382-5. [PMID: ] - PubMed
Faber 1998 {published data only}
    1. Faber BM, Mayer J, Cox B, Jones D, Toner JP, Oehninger S, Muasher SJ. Cessation of gonadotropin-releasing hormone agonist therapy combined with high-dose gonadotropin stimulation yields favourable pregnancy results in low responders. Fertility and Sterility 1998;69(5):826-30. [PMID: ] - PubMed
Ferraretti 1996 {published data only}
    1. Ferraretti AP, Magli C, Feliciani E, Montanaro N, Gianaroli L. Relationship of timing of agonist administration in the cycle phase to the ovarian response to gonadotropins in the long down-regulation protocols for assisted reproductive technologies. Fertility and Sterility 1996;65(1):114-21. [PMID: ] - PubMed
Fujii 1997 {published data only}
    1. Fujii S, Sagara M, Kudo H, Kagiya A, Sato S, Saito Y. A prospective randomized comparison between long and discontinuous-long protocols of gonadotropin-releasing hormone agonist for in vitro fertilization. Fertility and Sterility 1997;67(6):1166-8. [PMID: ] - PubMed
Garcia 1990 {published data only}
    1. Garcia JE, Padilla SL, Bayati J, Baramki TA. Follicular phase gonadotropin-releasing hormone agonist and human gonadotropins: a better alternative for ovulation induction in in vitro fertilization. Fertility and Sterility 1990;53(2):302-5. [PMID: ] - PubMed
Gersak 1994 {published data only}
    1. Gersak K, Meden-Vrtovec H, Tomazevic T. The effects of gonadotrophin-releasing hormone agonist on follicular development in patients with polycystic ovary syndrome in an in-vitro fertilization and embryo transfer programme. Human Reproduction (Oxford, England) 1994;9(9):1596-9. [PMID: ] - PubMed
Gianaroli 1994 {published data only}
    1. Gianaroli L, Ferraretti AP, Feliciani E, Tabanelli C, Magli C, Fortini D. Prospective randomized study of D-Trp6-LHRH versus buserelin in long desensitization protocols for medically assisted conception cycles. Human Reproduction (Oxford, England) 1994;9(2):220-5. [PMID: ] - PubMed
Gizzo 2014 {published data only}
    1. Gizzo S, Andrisani A, Esposito F, Noventa M, Di 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;30:1-7. [PMID: ] - PubMed
Harrison 1994 {published data only}
    1. Harrison RF, Kondaveeti U, Barry-Kinsella C, Gordon A, Drudy L, Cottell E, et al. Should gonadotropin-releasing hormone down-regulation therapy be routine in in vitro fertilization? Fertility and Sterility 1994;62(3):568-73. [PMID: ] - PubMed
Huang 2012 {published data only}
    1. Huang R, Fang C, Xu S, Yi Y, Liang X. Premature progesterone rise negatively correlated with live birth rate in IVF cycles with GnRH agonist: an analysis of 2,566 cycles. Fertility and Sterility 2012;98(3):664-70.e2. [PMID: ] - PubMed
IRCT2016022326711N1 {unpublished data only}
    1. IRCT2016022326711N1. Comparison of long protocol and agonist-antagonist protocol in the infertile normal responder patients undergoing ICSI cycles. en.irct.ir/trial/22056 (first received 11 April 2016).
Jinno 1996 {published data only}
    1. Jinno M, Yoshimura Y, Ubukata Y, Nakamura Y. A novel method of ovarian stimulation for in vitro fertilization: bromocriptine-rebound method. Fertility and Sterility 1996;66(2):271-4. [PMID: ] - PubMed
Jinno 2009 {published data only}
    1. Jinno M, Watanabe A, Hirohama J, Eguchi N, Hatakeyama N. Diminished but significant mid-cycle LH surge can be induced in the long protocol of GNRH agonist and HMG regimen, resulting in a great increase in the rate of ongoing pregnancy. Fertility and Sterility 2009;92(3 Suppl):S235.
Ku 2005 {published data only}
    1. Ku SY, Choi YS, Jee BC, Suh CS, Choi YM, Kim JG, et al. A preliminary study on reduced dose (33 or 25 g) gonadotropin-releasing hormone agonist long protocol for multi follicular ovaria stimulation in patients with high basal serum follicular-stimulating hormone levels undergoing in vitro fertilization-embryo transfer. Gynecological Endocrinology 2005;21:227-31. - PubMed
Kubik 1990 {published data only}
    1. Kubik CJ, Guzick DS, Berga SL, Zeleznik AJ. Randomized, prospective trial of leuprolide acetate and conventional superovulation in first cycle of in vitro fertilization and gamete intrafallopian transfer. Fertility and Sterility 1990;54(5):836-41. [PMID: ] - PubMed
Kuć 2011 {published data only}
    1. Kuć P, Kuczyńska A, Topczewska M, Tadejko P, Kuczyński W. The dynamics of endometrial growth and the triple layer appearance in three different controlled ovarian hyperstimulation protocols and their influence on IVF outcomes. Gynecological Endocrinology 2011;27(11):867-73. [PMID: ] - PubMed
Li 2012 {published data only}
    1. Li Y, Yang D, Zhang Q. Clinical outcome of one-third-dose depot triptorelin is the same as half-dose depot triptorelin in the long protocol of controlled ovarian stimulation. Journal of Human Reproductive Sciences 2012;5(1):14-9. [PMID: ] - PMC - PubMed
Liu 2012 {published data only}
    1. Liu N, Ma Y, Li R, Jin H, Li M, Huang X, et al. Comparison of follicular fluid amphiregulin and EGF concentrations in patients undergoing IVF with different stimulation protocols. Endocrine 2012;42(3):708-16. [PMID: ] - PubMed
Lorusso 2004 {published data only}
    1. Lorusso F, Depalo R, Selvaggi L. Relationship between gonadotropin releasing hormone agonist dosage and in vitro fertilization outcome. Gynecological Endocrinology 2004;18(2):69-73. [PMID: ] - PubMed
Loutradis 1998 {published data only}
    1. Loutradis D, Drakakis P, Kallianidis K, Bletsa R, Milingos S, Makris N, et al. The effect of the duration of GnRH-agonist down regulation before ovarian stimulation on the biological and clinical outcome after intracytoplasmic sperm injection. European Journal of Obstetrics, Gynecology, and Reproductive Biology 1998;80(2):251-5. [PMID: ] - PubMed
Lukaszuk 2015 {published data only}
    1. Lukaszuk K, Liss J, Kunicki M, Kuczynski W, Pastuszek E, Jakiel G, et al. Estradiol valerate pretreatment in short protocol GnRH-agonist cycles versus combined pretreatment with oral contraceptive pills in long protocol GnRH-agonist cycles: a randomised controlled trial. BioMed Research International 2015 Apr 2 [Epub ahead of print];2015:6. [DOI: 10.1155/2015/628056] - DOI - PMC - PubMed
Maged 2018 {published data only}
    1. Maged AM, Rashwan H, Mahmoud M, El-Mazny A, Farouk M, Belal DS, et al. Effect of prolonged GnRH agonist downregulation on ICSI outcome in patients with endometriomas of less than 5 cm: a randomized controlled trial. Reproductive Sciences (Thousand Oaks, Calif.) 2018;25(10):1509-1514. [DOI: 10.1177/1933719118756753] - DOI - PubMed
Marcus 1993 {published data only}
    1. Marcus SF, Brinsden PR, Macnamee M, Rainsbury PA, Elder KT, Edwards RG. Comparative trial between an ultra-short and long protocol of luteinizing hormone-releasing hormone agonist for ovarian stimulation in in-vitro fertilization. Human Reproduction (Oxford, England) 1993;8(2):238-43. [PMID: ] - PubMed
Maroulis 1991 {published data only}
    1. Maroulis GB, Emery M, Verkauf BS, Saphier A, Bernhisel M, Yeko TR. Prospective randomized study of human menotropin versus a follicular and a luteal phase gonadotropin-releasing hormone analog-human menotropin stimulation protocols for in vitro fertilization. Fertility and Sterility 1991;55(6):1157-64. [PMID: ] - PubMed
McKenna 1989 {published data only}
    1. McKenna KM, Foster P, McBain J, Martin M, Johnston WI. Combined treatment with gonadotrophin releasing hormone agonist and gonadotrophins in poor responders to hyperstimulation for in vitro fertilization (IVF): clinical and endocrine results. Australian and New Zealand Journal of Obstetrics and Gynaecology 1989;29(4):428-32. [PMID: ] - PubMed
Mochtar 2011 {published data only}
    1. Mochtar MH, Custers IM, Koks CA, Bernardus RE, Verhoeve HR, Mol BW, et al. Timing oocyte collection in GnRH agonists down-regulated IVF and ICSI cycles: a randomized clinical trial. Human Reproduction (Oxford, England) 2011;26(5):1091-6. [PMID: ] - PubMed
NCT00436319 {published data only}
    1. NCT00436319. Effect of the duration of GnRH-analogue downregulation on pregnancy rates in IVF. clinicaltrials.gov/ct2/show/NCT00436319 (first received 19 February 2007).
NCT02342197 {published data only}
    1. NCT02342197. Comparative study between minidose long protocol and microdose flare protocol in controlled ovarian hyperstimulation for poor responders in ICSI cycles. clinicaltrials.gov/ct2/show/NCT02342197 (first received 19 January 2015).
NCT05103228 {unpublished data only}
    1. NCT05103228. Cumulative pregnancy rate with lower and higher gonadotropin dose during IVF among poor responders. clinicaltrials.gov/study/NCT05103228 (first received 21 October 2021).
Neuspiller 1998 {published data only}
    1. Neuspiller F, Levy M, Remohí J, Ruiz A, Simón C, Pellicer A. The use of long- and short-acting forms of gonadotrophin-releasing hormone analogues in women undergoing oocyte donation. Human Reproduction (Oxford, England) 1998;13(5):1148-51. [PMID: ] - PubMed
Norman 1991 {published data only}
    1. Norman RJ, Warnes GM, Wang X, Kirby CA, Matthews CD. Differential effects of gonadotrophin-releasing hormone agonists administered as desensitizing or flare protocols on hormonal function in the luteal phase of hyperstimulated cycles. Human Reproduction (Oxford, England) 1991;6(2):206-13. [PMID: ] - PubMed
Padilla 1991 {published data only}
    1. Padilla SL, Smith RD, Garcia JE. The Lupron screening test: tailoring the use of leuprolide acetate in ovarian stimulation for in vitro fertilization. Fertility and Sterility 1991;56(1):79-83. [PMID: ] - PubMed
Pantos 1994 {published data only}
    1. Pantos K, Meimeth-Damianaki T, Vaxevanoglou T, Kapetanakis E. Prospective study of a modified gonadotropin-releasing hormone agonist long protocol in an in vitro fertilization program. Fertility and Sterility 1994;61(4):709-13. [PMID: ] - PubMed
Polyzos 2015 {published data only}
    1. Polyzos NP, Corona R, Van De Vijver A, Blockeel C, Drakopoulos P, Vloeberghs V, et al. Corifollitropin alfa followed by hpHMG in GnRH agonist protocols. Two prospective feasibility studies in poor ovarian responders. Gynecological Endocrinology 2015;31(11):885-90. [DOI: 10.3109/09513590.2015.1065481] - DOI - PubMed
Remorgida 1989 {published data only}
    1. Remorgida V, Anserini P, Croce S, Costa M, Ferraiolo A, Centonze A, et al. The duration of pituitary suppression by means of intranasal gonadotropin hormone-releasing hormone analogue administration does not influence the ovarian response to gonadotropin stimulation and success rate in a gamete intrafallopian transfer (GIFT) program. Journal of In Vitro Fertilization and Embryo Transfer 1989;6(2):76-80. [PMID: ] - PubMed
Rezaeian 2016 {published data only}
    1. Rezaeian P, Esmaeilzadeh S, Tajali Z, Nadi Heidari F, Golsorkhtabaramiri M. Short, semi-short or long GnRH agonist treatment regimens in women ICSI candidate: which is proper in preventing premature LH surge? Middle East Fertility Society Journal 2016;21(3):161-7. [DOI: ]
Rodrigues 2014 {published data only}
    1. Rodrigues RS, Setti AS, Braga D, Valente FM, Iaconelli A, Borges E. Pituitary suppression with a GnRHa short protocol in an alternate day schedule associated with rhCG microdoses. JBRA Assisted Reproduction 2014;18(3):76-9. [DOI: 10.5935/1518-0557.20140011] - DOI - PMC - PubMed
Ron‐El 1992 {published data only}
    1. Ron-El R, Herman A, Golan A, Soffer Y, Nachum H, Caspi E. Ultrashort gonadotropin-releasing hormone agonist (GnRH-a) protocol in comparison with the long-acting GnRH-a protocol and menotropin alone. Fertility and Sterility 1992;58(6):1164-8. [PMID: ] - PubMed
Sarhan 2012 {published data only}
    1. Sarhan A, Elsamanoudy A, Harira M. Hormonal responses and clinical outcome are the same with three doses of gonadotropin-releasing hormone agonist used in short stimulation protocol. Human Reproduction 2012;27 Suppl 2:ii302-37. - PubMed
Sathanandan 1989 {published data only}
    1. Sathanandan M, Warnes GM, Kirby CA, Petrucco OM, Matthews CD. Adjuvant leuprolide in normal, abnormal, and poor responders to controlled ovarian hyperstimulation for in vitro fertilization/gamete intrafallopian transfer. Fertility and Sterility 1989;51(6):998-1006. [PMID: ] - PubMed
Smitz 1992a {published data only}
    1. Smitz J, Van Den Abbeel E, Bollen N, Camus M, Devroy P, Tournaye H, et al. The effect of gonadotrophin-releasing hormone (GnRH) agonist in the follicular phase on in-vitro fertilization outcome in normo-ovulatory women. Human Reproduction (Oxford, England) 1992;7(8):1098-102. [PMID: ] - PubMed
Smitz 1992b {published data only}
    1. Smitz J, Erard P, Camus M, Devroy P, Tournaye H, Wisanto A, et al. Pituitary gonadotrophin secretory capacity during the luteal phase in superovulation using GnRH-agonists and HMG in a desensitization or flare-up protocol. Human Reproduction (Oxford, England) 1992;7(9):1225-9. [PMID: ] - PubMed
Stenbaek 2013 {published data only}
    1. Stenbaek DS, Toftager M, Hjordt LV, Jensen PS, Holst K, Holland T, et al. A comparison of changes in mental distress in women undergoing short versus long in vitro fertilization protocol: a clinical prospective randomized trial. Human Reproduction 2013;28(Suppl):i261-82.
Suganuma 1996 {published data only}
    1. Suganuma N, Tsukahara SI, Kitagawa T, Furuhashi M, Asada Y, Kondo I. A controlled ovarian hyperstimulation regimen involving intermittent gonadotropin administration with a "short" protocol of gonadotropin releasing hormone agonist for in vitro fertilization. Journal of Assisted Reproduction and Genetics 1996;13(1):43-8. [PMID: ] - PubMed
Tanaka 2014 {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 2014;102(3):e223.
Tarlatzis 1993 {published data only}
    1. Tarlatzis BC, Pados G, Bontis J, Lagos S, Grimbizis G, Spanos E, et al. Ovarian stimulation with buserelin/HMG/HCG: prospective randomized study of short versus long protocol. Human Reproduction (Oxford, England) 1993;8(6):807-12. [PMID: ] - PubMed
Tarlatzis 1994 {published data only}
    1. Tarlatzis BC, Grimbizis G, Pournaropoulos F, Bontis J, Lagos S, Pados G, et al. Evaluation of two gonadotropin-releasing hormone (GnRH) analogues (leuprolide and buserelin) in short and long protocols for assisted reproduction techniques. Journal of Assisted Reproduction and Genetics 1994;11(2):85-91. [PMID: ] - PubMed
Tehraninejad 2010 {published data only}
    1. Tehraninejad ES, Nekoo EA, Ezabadi Z, Rashidi BH, Amirchaghmaghi E, Matroud EP. Half-dose, long-acting gonadotropin-releasing hormone agonist (Diphereline) is comparable with daily injections of short-acting gonadotropin-releasing hormone agonist (Suprefact) in IVF/ICSI cycles. Archives of Medical Science 2010;6(6):945-9. [PMID: ] - PMC - PubMed
Tehraninejad 2021 {published data only}
    1. Tehraninejad ES, Nekoo ZA, Nekoo EA, Kalantari V, Tarafdari A. Comparison of assisted reproductive technology cycle outcomes among daily buserelin, daily, and every other day triptorelin in infertile patients referring to Imam Khomeini Hospital complex: a randomized controlled trial. International Journal of Women's Health and Reproduction Sciences 2021;9(1):49-54.
Umemmuo 2020 {published data only}
    1. Umemmuo MU, Efetie ER, Agboghoroma CO, Momoh JA, Ikechebelu JI. Comparison of clinical efficacy of long- versus short-acting gonadotrophin-releasing hormone agonists for pituitary down regulation in in vitro fertilisation cycles. Nigerian Postgraduate Medical Journal 2020;27(3):171-176. [DOI: 10.4103/npmj.npmj_65_20] - DOI - PubMed
Van de‐Helder 1990b {published data only}
    1. Van de-Helder AB, Helmerhorst FM, Blankhart A, Brand R, Waegemaekers C, Naaktgeboren N. Comparison of ovarian stimulation regimens for in vitro fertilization (IVE) with and without a gonadotropin-releasing hormone (GnRH) agonist: results of a randomized study. Journal of In Vitro Fertilization and Embryo Transfer 1990;7(6):358-62. [PMID: ] - PubMed
Wu 2012 {published data only}
    1. Wu Z, Li R, Ma Y, Deng B, Zhang X, Meng Y, et al. Effect of HCG-day serum progesterone and oestradiol concentrations on pregnancy outcomes in GnRH agonist cycles. Reproductive Biomedicine Online 2012;24(5):511-20. [PMID: ] - PubMed
Xu 2020 {published data only}
    1. Xu B, Geerts D, Hu S, Yue J, Li Z, Zhu G, et al. The depot GnRH agonist protocol improves the live birth rate per fresh embryo transfer cycle, but not the cumulative live birth rate in normal responders: a randomized controlled trial and molecular mechanism study. Human Reproduction 2020;35(6):1306-18. [DOI: ] - PubMed
Yang 1991 {published data only}
    1. Yang YS, Ho HN, Lien YR, Hwang JL, Melinda S, Lin HR, et al. The use of a long-acting gonadotropin-releasing hormone analog (D-Trp-6-LHRH) for improvement of ovarian stimulation in assisted conception programs. Journal of the Formosan Medical Association 1991;90(11):1081-5. [PMID: ] - PubMed
Ying 2019 {published data only}
    1. Ying Y, Tanchu Y, Zhang H, Liu C, Zhao J. Prolonged pituitary down-regulation with full-dose of gonadotropin-releasing hormone agonist in different menstrual cycles: a retrospective cohort study. PeerJ 2019;7:e6837. [DOI: 10.7717/peerj.6837.] - DOI - PMC - PubMed

References to studies awaiting assessment

Kabodmehri 2021 {published data only}
    1. Kabodmehri R, Mehrafza M. Effect of a reduced dose of long-acting gonadotropin releasing hormone (GnRH) agonist versus short-acting GnRH agonist on pregnancy outcome in patients undergoing ICSI/ET cycles. Oxford University Press 2021;36:430. [DOI: 10.1093/humrep/deab130.643] - DOI

References to ongoing studies

NCT02681536 {published data only}
    1. NCT02681536. Miniflare versus long protocol in poor responders [Miniflare versus long protocol in poor responders]. https://clinicaltrials.gov/ct2/show/NCT02681536 (first posted 12 February 2016).
NCT02940535 {unpublished data only}
    1. NCT02940535. Low dose GnRHa early luteal phase down regulation versus GnRHa ultra-short protocol for poor ovarian response [Low dose GnRHa early luteal phase down regulation versus GnRHa ultra-short protocol for poor ovarian response: a randomized control trial]. https://clinicaltrials.gov/ct2/show/NCT02940535 (first posted 21 October 2016).
NCT05567731 {unpublished data only}
    1. NCT05567731. Effect of long, short, and ultrashort GnRH agonist treatment protocols in intracytoplasmic sperm injection candidates on ovarian reserve. clinicaltrials.gov/study/NCT05567731 (first received 2 October 2022).

Additional references

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References to other published versions of this review

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