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GnRH agonist trigger for the induction of oocyte maturation in GnRH antagonist IVF cycles: a SWOT analysis

Published:January 05, 2016DOI:https://doi.org/10.1016/j.rbmo.2015.12.007

      Abstract

      Gonadotrophin releasing hormone agonist (GnRHa) trigger is effective in the induction of oocyte maturation and prevention of ovarian hyperstimulation syndrome during IVF treatment. This trigger concept, however, results in early corpora lutea demise and consequently luteal phase dysfunction and impaired endometrial receptivity. The aim of this strenghths, weaknesses, opportunities and threats analysis was to summarize the progress made over the past 15 years to optimize ongoing pregnancy rates after GnRHa trigger. The advantages and potential drawbacks of this type of triggering are reviewed. The current approach to the management of GnRHa trigger in autologous cycles is based on the peak serum oestradiol level or follicle number and aims at a fresh embryo transfer or a segmentation approach with elective cryopreservation policy. We recommend intensive luteal support with transdermal oestradiol and intramuscular progesterone alone if peak serum oestradiol is 4000 or more pg/ml after GnRHa trigger or dual trigger with GnRHa and HCG 1000 IU if peak serum oestradiol is less than 4000 pg/mL. On the contrary, we recommend HCG 1500 IU 35 h after GnRHa trigger if there are less than 25 follicles, or freeze all oocytes or embryos if there are over 25 follicles.

      Keywords

      Introduction

      The administration of HCG to induce final oocyte maturation has been used for decades and has been considered the gold standard during ovarian stimulation for IVF cycles. Recently, however, it has been suggested that the time has come for a paradigm shift in triggering policies (
      • Humaidan P.
      • Alsbjerg B.
      GnRHa trigger for final oocyte maturation: is HCG trigger history?.
      ,
      • Humaidan P.
      • Polyzos N.P.
      Human chorionic gonadotropin vs. gonadotropin-releasing hormone agonist trigger in assisted reproductive technology–‘the king is dead, long live the king!’.
      ). Although HCG effectively induces oocyte maturation and maintains excellent pregnancy rates during the IVF process, the prolonged half-life of HCG compared with natural LH promotes supra-physiological luteal steroid levels and the development of multiple corpora lutea, resulting in a potential increased risk of ovarian hyperstimulation sndrome (OHSS). Therefore, the use of alternate modalities to induce oocyte maturation to prevent OHSS, such as gonadotrophin releasing hormone agonist (GnRHa) has been the focus of research for years (
      • Engmann L.
      • DiLuigi A.
      • Schmidt D.
      • Nulsen J.
      • Maier D.
      • 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 prospective randomized controlled study.
      ,
      • Humaidan P.
      • Bredkjaer H.E.
      • Bungum L.
      • Bungum M.
      • Grondahl M.L.
      • Westergaard L.
      • Andersen C.Y.
      GnRH agonist (buserelin) or hCG for ovulation induction in GnRH antagonist IVF/ICSI cycles: a prospective randomized study.
      ,
      • Humaidan P.
      • Ejdrup Bredkjaer H.
      • Westergaard L.G.
      • Yding Andersen C.
      1,500 IU human chorionic gonadotropin administered at oocyte retrieval rescues the luteal phase when gonadotropin-releasing hormone agonist is used for ovulation induction: a prospective, randomized, controlled study.
      ,
      • Itskovitz-Eldor J.
      • Kol S.
      • Mannaerts B.
      Use of a single bolus of GnRH agonist triptorelin to trigger ovulation after GnRH antagonist ganirelix treatment in women undergoing ovarian stimulation for assisted reproduction, with special reference to the prevention of ovarian hyperstimulation syndrome: preliminary report: short communication.
      ,
      • Kol S.
      • Itskovitz-Eldor J.
      Gonadotropin-releasing hormone agonist trigger: the way to eliminate ovarian hyperstimulation syndrome–a 20-year experience.
      ,
      • Shapiro B.S.
      • Daneshmand S.T.
      • Garner F.C.
      • Aguirre M.
      • Hudson C.
      Comparison of ‘triggers’ using leuprolide acetate alone or in combination with low-dose human chorionic gonadotropin.
      ,
      • Shapiro B.S.
      • Daneshmand S.T.
      • Restrepo H.
      • Garner F.C.
      • Aguirre M.
      • Hudson C.
      Efficacy of induced luteinizing hormone surge after ‘trigger’ with gonadotropin-releasing hormone agonist.
      ).
      A single dose of GnRHa induces an endogenous LH and FSH surge similar to that of the natural cycle, sufficiently high enough to successfully induce final oocyte maturation. This modality of triggering was initially advocated in the late 1980s and early 1990s (
      • Emperaire J.C.
      Therapeutic induction of ovulation: towards the replacement of hCG with LH.
      ,
      • Gonen Y.
      • Balakier H.
      • Powell W.
      • Casper R.F.
      Use of gonadotropin-releasing hormone agonist to trigger follicular maturation for in vitro fertilization.
      ,
      • Itskovitz J.
      • Boldes R.
      • Levron J.
      • Erlik Y.
      • Kahana L.
      • Brandes J.M.
      Induction of preovulatory luteinizing hormone surge and prevention of ovarian hyperstimulation syndrome by gonadotropin-releasing hormone agonist.
      ,
      • Itskovitz-Eldor J.
      • Levron J.
      • Kol S.
      Use of gonadotropin-releasing hormone agonist to cause ovulation and prevent the ovarian hyperstimulation syndrome.
      ,
      • Lanzone A.
      • Fulghesu A.M.
      • Apa R.
      • Caruso A.
      • Mancuso S.
      LH surge induction by GnRH agonist at the time of ovulation.
      ,
      • Lewit N.
      • Kol S.
      • Manor D.
      • Itskovitz-Eldor J.
      Comparison of gonadotrophin-releasing hormone analogues and human chorionic gonadotrophin for the induction of ovulation and prevention of ovarian hyperstimulation syndrome: a case-control study.
      ,
      • Segal S.
      • Casper R.F.
      Gonadotropin-releasing hormone agonist versus human chorionic gonadotropin for triggering follicular maturation in in vitro fertilization.
      ,
      • van der Meer S.
      • Gerris J.
      • Joostens M.
      • Tas B.
      Triggering of ovulation using a gonadotrophin-releasing hormone agonist does not prevent ovarian hyperstimulation syndrome.
      ). Soon after the introduction of GnRHa to trigger oocyte maturation during IVF treatment, however, its use was hampered by the introduction of GnRHa for pituitary down-regulation during ovarian stimulation. Subsequently, the introduction of the GnRH antagonist for the prevention of premature LH surge in the late 1990s (
      • Albano C.
      • Smitz J.
      • Camus M.
      • Riethmuller-Winzen H.
      • Van Steirteghem A.
      • Devroey P.
      Comparison of different doses of gonadotropin-releasing hormone antagonist Cetrorelix during controlled ovarian hyperstimulation.
      ,
      The Ganirelix Dose-Finding Study Group
      A double-blind, randomized, dose-finding study to assess the efficacy of the gonadotrophin-releasing hormone antagonist ganirelix (Org 37462) to prevent premature luteinizing hormone surges in women undergoing ovarian stimulation with recombinant follicle stimulating hormone (Puregon).
      ) rekindled the interest in the use of GnRHa to induce oocyte maturation (
      • Itskovitz-Eldor J.
      • Kol S.
      • Mannaerts B.
      Use of a single bolus of GnRH agonist triptorelin to trigger ovulation after GnRH antagonist ganirelix treatment in women undergoing ovarian stimulation for assisted reproduction, with special reference to the prevention of ovarian hyperstimulation syndrome: preliminary report: short communication.
      ).
      After publication of the initial clinical experience from GnRHa trigger during GnRH antagonist co-treatment in IVF cycles (
      • Itskovitz-Eldor J.
      • Kol S.
      • Mannaerts B.
      Use of a single bolus of GnRH agonist triptorelin to trigger ovulation after GnRH antagonist ganirelix treatment in women undergoing ovarian stimulation for assisted reproduction, with special reference to the prevention of ovarian hyperstimulation syndrome: preliminary report: short communication.
      ), two randomized controlled trials in normal responder patients were published, showing an unacceptably high early pregnancy loss rate, resulting in low live birth rates (
      • Humaidan P.
      • Bredkjaer H.E.
      • Bungum L.
      • Bungum M.
      • Grondahl M.L.
      • Westergaard L.
      • Andersen C.Y.
      GnRH agonist (buserelin) or hCG for ovulation induction in GnRH antagonist IVF/ICSI cycles: a prospective randomized study.
      ,
      • Kolibianakis E.M.
      • Schultze-Mosgau A.
      • Schroer A.
      • van Steirteghem A.
      • Devroey P.
      • Diedrich K.
      • Griesinger G.
      A lower ongoing pregnancy rate can be expected when GnRH agonist is used for triggering final oocyte maturation instead of HCG in patients undergoing IVF with GnRH antagonists.
      ). Subsequently, several prospective randomized and retrospective trials evaluated various protocols after GnRHa trigger to optimize conception rates and prevent or reduce OHSS as well as optimize the luteal phase endocrine profile (
      • Beckers N.G.
      • Macklon N.S.
      • Eijkemans M.J.
      • Ludwig M.
      • Felberbaum R.E.
      • Diedrich K.
      • Bustion S.
      • Loumaye E.
      • Fauser B.C.
      Nonsupplemented luteal phase characteristics after the administration of recombinant human chorionic gonadotropin, recombinant luteinizing hormone, or gonadotropin-releasing hormone (GnRH) agonist to induce final oocyte maturation in in vitro fertilization patients after ovarian stimulation with recombinant follicle-stimulating hormone and GnRH antagonist cotreatment.
      ,
      • DiLuigi A.J.
      • Engmann L.
      • Schmidt D.W.
      • Maier D.B.
      • Nulsen J.C.
      • Benadiva C.A.
      Gonadotropin-releasing hormone agonist to induce final oocyte maturation prevents the development of ovarian hyperstimulation syndrome in high-risk patients and leads to improved clinical outcomes compared with coasting.
      ,
      • Engmann L.
      • DiLuigi A.
      • Schmidt D.
      • Nulsen J.
      • Maier D.
      • 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 prospective randomized controlled study.
      ,
      • Fauser B.C.
      • de Jong D.
      • Olivennes F.
      • Wramsby H.
      • Tay C.
      • Itskovitz-Eldor J.
      • van Hooren H.G.
      Endocrine profiles after triggering of final oocyte maturation with GnRH agonist after cotreatment with the GnRH antagonist ganirelix during ovarian hyperstimulation for in vitro fertilization.
      ,
      • Griffin D.
      • Benadiva C.
      • Kummer N.
      • Budinetz T.
      • Nulsen J.
      • Engmann L.
      Dual trigger of oocyte maturation with gonadotropin-releasing hormone agonist and low-dose human chorionic gonadotropin to optimize live birth rates in high responders.
      ,
      • Humaidan P.
      Luteal phase rescue in high-risk OHSS patients by GnRHa triggering in combination with low-dose HCG: a pilot study.
      ,
      • Humaidan P.
      • Bungum L.
      • Bungum M.
      • Yding Andersen C.
      Rescue of corpus luteum function with peri-ovulatory HCG supplementation in IVF/ICSI GnRH antagonist cycles in which ovulation was triggered with a GnRH agonist: a pilot study.
      ,
      • Humaidan P.
      • Ejdrup Bredkjaer H.
      • Westergaard L.G.
      • Yding Andersen C.
      1,500 IU human chorionic gonadotropin administered at oocyte retrieval rescues the luteal phase when gonadotropin-releasing hormone agonist is used for ovulation induction: a prospective, randomized, controlled study.
      ,
      • Humaidan P.
      • Polyzos N.P.
      • Alsbjerg B.
      • Erb K.
      • Mikkelsen A.L.
      • Elbaek H.O.
      • Papanikolaou E.G.
      • Andersen C.Y.
      GnRHa trigger and individualized luteal phase hCG support according to ovarian response to stimulation: two prospective randomized controlled multi-centre studies in IVF patients.
      ,
      • Humaidan P.
      • Thomsen L.H.
      • Alsbjerg B.
      GnRHa trigger and modified luteal support with one bolus of hCG should be used with caution in extreme responder patients.
      ,
      • Kol S.
      • Humaidan P.
      • Itskovitz-Eldor J.
      GnRH agonist ovulation trigger and hCG-based, progesterone-free luteal support: a proof of concept study.
      ,
      • Melo M.
      • Busso C.E.
      • Bellver J.
      • Alama P.
      • Garrido N.
      • Meseguer M.
      • Pellicer A.
      • Remohi J.
      GnRH agonist versus recombinant HCG in an oocyte donation programme: a randomized, prospective, controlled, assessor-blind study.
      ,
      • Papanikolaou E.G.
      • Verpoest W.
      • Fatemi H.
      • Tarlatzis B.
      • Devroey P.
      • Tournaye H.
      A novel method of luteal supplementation with recombinant luteinizing hormone when a gonadotropin-releasing hormone agonist is used instead of human chorionic gonadotropin for ovulation triggering: a randomized prospective proof of concept study.
      ,
      • Shapiro B.S.
      • Daneshmand S.T.
      • Garner F.C.
      • Aguirre M.
      • Hudson C.
      Comparison of ‘triggers’ using leuprolide acetate alone or in combination with low-dose human chorionic gonadotropin.
      ,
      • Shapiro B.S.
      • Daneshmand S.T.
      • Restrepo H.
      • Garner F.C.
      • Aguirre M.
      • Hudson C.
      Efficacy of induced luteinizing hormone surge after ‘trigger’ with gonadotropin-releasing hormone agonist.
      ). Most of these studies have moved the science forward to the present state of affairs and ensured that patient safety is considered paramount during ovarian stimulation.
      The use of GnRHa to induce oocyte maturation during IVF, however, is still not widely accepted and not widely used (
      • Worldwide I.
      Survey on vitrification, GnRH trigger and differed embryo transfer.
      ). Several reasons may account for the lack of widespread acceptance, including premature Cochrane reviews and meta-analyses with debatable conclusions (
      • Griesinger G.
      • Diedrich K.
      • Devroey P.
      • Kolibianakis E.M.
      GnRH agonist for triggering final oocyte maturation in the GnRH antagonist ovarian hyperstimulation protocol: a systematic review and meta-analysis.
      ,
      • Youssef M.A.
      • Van der Veen F.
      • Al-Inany H.G.
      • Griesinger G.
      • Mochtar M.H.
      • Aboulfoutouh I.
      • Khattab S.M.
      • van Wely M.
      Gonadotropin-releasing hormone agonist versus HCG for oocyte triggering in antagonist assisted reproductive technology cycles.
      ,
      • Youssef M.A.
      • Van der Veen F.
      • Al-Inany H.G.
      • Mochtar M.H.
      • Griesinger G.
      • Nagi Mohesen M.
      • Aboulfoutouh I.
      • van Wely M.
      Gonadotropin-releasing hormone agonist versus HCG for oocyte triggering in antagonist-assisted reproductive technology.
      ), reports of bad experiences with its use (
      • Griesinger G.
      • Berndt H.
      • Schultz L.
      • Schultze-Mosgau A.
      • Diedrich K.
      • von Otte S.
      Intensified ovarian stimulation in a GnRH antagonist protocol with agonist triggering: a prospective, clinical feasibility study.
      ,
      • Griesinger G.
      • Schultz L.
      • Bauer T.
      • Broessner A.
      • Frambach T.
      • Kissler S.
      Ovarian hyperstimulation syndrome prevention by gonadotropin-releasing hormone agonist triggering of final oocyte maturation in a gonadotropin-releasing hormone antagonist protocol in combination with a ‘freeze-all’ strategy: a prospective multicentric study.
      ;
      • Honnma H.
      • Hashiba Y.
      • Asada Y.
      • Endo T.
      Failure of triggering oocyte maturation with a GnRH agonist in polycystic ovary syndrome: two case reports.
      ), misconceptions as well as a general resistance to change and adopt a new protocol that may involve some learning curve in its successful usage.
      We, therefore, aim to summarize the studies that have been published since the first study using GnRHa during GnRH antagonist co-administration (2000–2015), and review the progress that has been made. Moreover, we aim to explore potential reasons for the lack of widespread acceptance of GnRHa trigger and try to offer practical proposals for its safe use to allow more clinicians and patients to experience the advantages of this approach of triggering. We have used the format often applied in the business world, the SWOT (strengths, weaknesses, opportunities and threats) analysis (Table 1), which has previously been used in reproductive medicine (
      • Fauser B.C.
      • Nargund G.
      • Andersen A.N.
      • Norman R.
      • Tarlatzis B.
      • Boivin J.
      • Ledger W.
      Mild ovarian stimulation for IVF: 10 years later.
      ) and other areas of medicine (
      • Ferrer J.
      • Prats C.
      • Lopez D.
      • Vives-Rego J.
      Mathematical modelling methodologies in predictive food microbiology: a SWOT analysis.
      ,
      • Pastrana T.
      • Centeno C.
      • De Lima L.
      Palliative care in Latin America from the professional perspective: a SWOT analysis.
      ,
      • Willis D.S.
      • Thurston M.
      Working with the disabled patient: exploring student nurses views for curriculum development using a SWOT analysis.
      ).
      Table 1Strengths, weaknesses, opportunities and threats analysis of gonadotrophin releasing hormone agonist trigger.
      Strengths
       Physiological endogenous gonadotrophin surge
       Similar pregnancy rates using ‘modified luteal support’
       Prevention of ovarian hyperstimulation syndrome
       Less luteal phase patient discomfort
       Improved oocyte yield in immature oocyte syndrome and empty follicle syndrome
      Weaknesses
       Abnormal luteal phase
       Lower ‘success rates’ without modified luteal phase support
       Failure to induce oocyte maturation and empty follicle syndrome in certain case scenarios
       More intense luteal supplementation and monitoring
       No consensus on GnRHa trigger type or dose
      Opportunities
       Development of individualized luteal phase regimens
       Improved safety for oocyte donors and patients
       Ideal protocol for specific clinical scenarios
       Improved performance of embryo cryopreservation programmes
      Threats
       Lack of availability of intramuscular progesterone, HCG dosing, or both, in some countries
       Patient characteristics limiting widespread use
       Premature Cochrane reviews and meta-analyses
       Misconceptions and resistance

      Current state of affairs

      The administration of a single bolus of GnRHa for trigger results in early corpora lutea demise and, therefore, a decrease in the release of factors such as vascular endothelial growth factor (VEGF) and prevention of OHSS development (
      • Cerrillo M.
      • Rodriguez S.
      • Mayoral M.
      • Pacheco A.
      • Martinez-Salazar J.
      • Garcia-Velasco J.A.
      Differential regulation of VEGF after final oocyte maturation with GnRH agonist versus hCG: a rationale for OHSS reduction.
      ,
      • Cerrillo M.
      • Pacheco A.
      • Rodriguez S.
      • Gomez R.
      • Delgado F.
      • Pellicer A.
      • Garcia-Velasco J.A.
      Effect of GnRH agonist and hCG treatment on VEGF, angiopoietin-2, and VE-cadherin: trying to explain the link to ovarian hyperstimulation syndrome.
      ). The first randomized trials after the initial publication on GnRHa trigger were in normal responder patients, using standard luteal support and showing unacceptably low live birth rates of 4–6% (
      • Humaidan P.
      • Bredkjaer H.E.
      • Bungum L.
      • Bungum M.
      • Grondahl M.L.
      • Westergaard L.
      • Andersen C.Y.
      GnRH agonist (buserelin) or hCG for ovulation induction in GnRH antagonist IVF/ICSI cycles: a prospective randomized study.
      ,
      • Kolibianakis E.M.
      • Schultze-Mosgau A.
      • Schroer A.
      • van Steirteghem A.
      • Devroey P.
      • Diedrich K.
      • Griesinger G.
      A lower ongoing pregnancy rate can be expected when GnRH agonist is used for triggering final oocyte maturation instead of HCG in patients undergoing IVF with GnRH antagonists.
      ). Subsequently, a systematic meta-analysis and a Cochrane review concluded that GnRHa should not be used routinely for final oocyte maturation in autologous cycles in view of the low pregnancy and live birth rates (
      • Griesinger G.
      • Diedrich K.
      • Devroey P.
      • Kolibianakis E.M.
      GnRH agonist for triggering final oocyte maturation in the GnRH antagonist ovarian hyperstimulation protocol: a systematic review and meta-analysis.
      ,
      • Youssef M.A.
      • Van der Veen F.
      • Al-Inany H.G.
      • Griesinger G.
      • Mochtar M.H.
      • Aboulfoutouh I.
      • Khattab S.M.
      • van Wely M.
      Gonadotropin-releasing hormone agonist versus HCG for oocyte triggering in antagonist assisted reproductive technology cycles.
      ). With the realization that the luteal phase was suboptimal, several approaches were subsequently suggested to improve pregnancy rates, ranging from intensive luteal phase steroid support (
      • Engmann L.
      • Siano L.
      • Schmidt D.
      • Nulsen J.
      • Maier D.
      • Benadiva C.
      GnRH agonist to induce oocyte maturation during IVF in patients at high risk of OHSS.
      ,
      • Engmann L.
      • DiLuigi A.
      • Schmidt D.
      • Nulsen J.
      • Maier D.
      • 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 prospective randomized controlled study.
      ,
      • Iliodromiti S.
      • Blockeel C.
      • Tremellen K.P.
      • Fleming R.
      • Tournaye H.
      • Humaidan P.
      • Nelson S.M.
      Consistent high clinical pregnancy rates and low ovarian hyperstimulation syndrome rates in high-risk patients after GnRH agonist triggering and modified luteal support: a retrospective multicentre study.
      ,
      • Iliodromiti S.
      • Lan V.T.
      • Tuong H.M.
      • Tuan P.H.
      • Humaidan P.
      • Nelson S.M.
      Impact of GnRH agonist triggering and intensive luteal steroid support on live-birth rates and ovarian hyperstimulation syndrome: a retrospective cohort study.
      ,
      • Imbar T.
      • Kol S.
      • Lossos F.
      • Bdolah Y.
      • Hurwitz A.
      • Haimov-Kochman R.
      Reproductive outcome of fresh or frozen-thawed embryo transfer is similar in high-risk patients for ovarian hyperstimulation syndrome using GnRH agonist for final oocyte maturation and intensive luteal support.
      ), adjuvant low-dose HCG at the time of GnRHa trigger (
      • Griffin D.
      • Benadiva C.
      • Kummer N.
      • Budinetz T.
      • Nulsen J.
      • Engmann L.
      Dual trigger of oocyte maturation with gonadotropin-releasing hormone agonist and low-dose human chorionic gonadotropin to optimize live birth rates in high responders.
      ,
      • Shapiro B.S.
      • Daneshmand S.T.
      • Garner F.C.
      • Aguirre M.
      • Thomas S.
      Gonadotropin-releasing hormone agonist combined with a reduced dose of human chorionic gonadotropin for final oocyte maturation in fresh autologous cycles of in vitro fertilization.
      ,
      • Shapiro B.S.
      • Daneshmand S.T.
      • Garner F.C.
      • Aguirre M.
      • Hudson C.
      Comparison of ‘triggers’ using leuprolide acetate alone or in combination with low-dose human chorionic gonadotropin.
      ,
      • Shapiro B.S.
      • Daneshmand S.T.
      • Restrepo H.
      • Garner F.C.
      • Aguirre M.
      • Hudson C.
      Efficacy of induced luteinizing hormone surge after ‘trigger’ with gonadotropin-releasing hormone agonist.
      ) or at the time of oocyte retrieval (
      • Humaidan P.
      Luteal phase rescue in high-risk OHSS patients by GnRHa triggering in combination with low-dose HCG: a pilot study.
      ,
      • Humaidan P.
      • Ejdrup Bredkjaer H.
      • Westergaard L.G.
      • Yding Andersen C.
      1,500 IU human chorionic gonadotropin administered at oocyte retrieval rescues the luteal phase when gonadotropin-releasing hormone agonist is used for ovulation induction: a prospective, randomized, controlled study.
      ,
      • Humaidan P.
      • Polyzos N.P.
      • Alsbjerg B.
      • Erb K.
      • Mikkelsen A.L.
      • Elbaek H.O.
      • Papanikolaou E.G.
      • Andersen C.Y.
      GnRHa trigger and individualized luteal phase hCG support according to ovarian response to stimulation: two prospective randomized controlled multi-centre studies in IVF patients.
      ,
      • Humaidan P.
      • Thomsen L.H.
      • Alsbjerg B.
      GnRHa trigger and modified luteal support with one bolus of hCG should be used with caution in extreme responder patients.
      ,
      • Iliodromiti S.
      • Blockeel C.
      • Tremellen K.P.
      • Fleming R.
      • Tournaye H.
      • Humaidan P.
      • Nelson S.M.
      Consistent high clinical pregnancy rates and low ovarian hyperstimulation syndrome rates in high-risk patients after GnRH agonist triggering and modified luteal support: a retrospective multicentre study.
      ,
      • Iliodromiti S.
      • Lan V.T.
      • Tuong H.M.
      • Tuan P.H.
      • Humaidan P.
      • Nelson S.M.
      Impact of GnRH agonist triggering and intensive luteal steroid support on live-birth rates and ovarian hyperstimulation syndrome: a retrospective cohort study.
      ) or during the luteal phase (
      • Castillo J.C.
      • Dolz M.
      • Bienvenido E.
      • Abad L.
      • Casan E.M.
      • Bonilla-Musoles F.
      Cycles triggered with GnRH agonist: exploring low-dose HCG for luteal support.
      ,
      • Humaidan P.
      • Polyzos N.P.
      • Alsbjerg B.
      • Erb K.
      • Mikkelsen A.L.
      • Elbaek H.O.
      • Papanikolaou E.G.
      • Andersen C.Y.
      GnRHa trigger and individualized luteal phase hCG support according to ovarian response to stimulation: two prospective randomized controlled multi-centre studies in IVF patients.
      ,
      • Humaidan P.
      • Thomsen L.H.
      • Alsbjerg B.
      GnRHa trigger and modified luteal support with one bolus of hCG should be used with caution in extreme responder patients.
      ) as well as the use of luteal phase recombinant LH administration (
      • Papanikolaou E.G.
      • Verpoest W.
      • Fatemi H.
      • Tarlatzis B.
      • Devroey P.
      • Tournaye H.
      A novel method of luteal supplementation with recombinant luteinizing hormone when a gonadotropin-releasing hormone agonist is used instead of human chorionic gonadotropin for ovulation triggering: a randomized prospective proof of concept study.
      ).
      There are currently several schools of thought regarding the use of GnRHa trigger in autologous IVF cycles: the first approach is based on the peak serum oestradiol level or follicle number, and aims at a fresh embryo transfer either using an intensive luteal phase steroid support or low dose HCG at the time of trigger (dual trigger) or at the time of oocyte retrieval (
      • Engmann L.
      • Benadiva C.
      Ovarian hyperstimulation syndrome prevention strategies: luteal support strategies to optimize pregnancy success in cycles with gonadotropin-releasing hormone agonist ovulatory trigger.
      ,
      • Engmann L.
      • Benadiva C.
      Agonist trigger: what is the best approach? Agonist trigger with aggressive luteal support.
      ,
      • Griffin D.
      • Benadiva C.
      • Kummer N.
      • Budinetz T.
      • Nulsen J.
      • Engmann L.
      Dual trigger of oocyte maturation with gonadotropin-releasing hormone agonist and low-dose human chorionic gonadotropin to optimize live birth rates in high responders.
      ,
      • Humaidan P.
      Agonist trigger: what is the best approach? Agonist trigger and low dose hCG.
      ,
      • Humaidan P.
      • Engmann L.
      • Benadiva C.
      Luteal phase supplementation after gonadotropin-releasing hormone agonist trigger in fresh embryo transfer: the American versus European approaches.
      ). In the second, segmentation approach, stimulation and embryo transfer are disconnected. Therefore, an elective cryopreservation policy followed by embryo transfer in a subsequent frozen thawed cycle has been proposed to circumvent the abnormal luteal phase seen after GnRHa trigger without the need for modification of the luteal phase support (
      • Devroey P.
      • Polyzos N.P.
      • Blockeel C.
      An OHSS-Free Clinic by segmentation of IVF treatment.
      ,
      • Garcia-Velasco J.A.
      Agonist trigger: what is the best approach? Agonist trigger with vitrification of oocytes or embryos.
      ,
      • Griesinger G.
      • Berndt H.
      • Schultz L.
      • Depenbusch M.
      • Schultze-Mosgau A.
      Cumulative live birth rates after GnRH-agonist triggering of final oocyte maturation in patients at risk of OHSS: a prospective, clinical cohort study.
      ,
      • Griesinger G.
      • Berndt H.
      • Schultz L.
      • Schultze-Mosgau A.
      • Diedrich K.
      • von Otte S.
      Intensified ovarian stimulation in a GnRH antagonist protocol with agonist triggering: a prospective, clinical feasibility study.
      ,
      • Griesinger G.
      • Schultz L.
      • Bauer T.
      • Broessner A.
      • Frambach T.
      • Kissler S.
      Ovarian hyperstimulation syndrome prevention by gonadotropin-releasing hormone agonist triggering of final oocyte maturation in a gonadotropin-releasing hormone antagonist protocol in combination with a ‘freeze-all’ strategy: a prospective multicentric study.
      ).
      Interestingly, GnRHa trigger in oocyte donors is less controversial and currently more widely used in view of the excellent pregnancy rates reported in recipients, and the clear advantage of OHSS prevention (
      • Acevedo B.
      • Gomez-Palomares J.L.
      • Ricciarelli E.
      • Hernandez E.R.
      Triggering ovulation with gonadotropin-releasing hormone agonists does not compromise embryo implantation rates.
      ,
      • Bodri D.
      • Guillen J.J.
      • Trullenque M.
      • Schwenn K.
      • Esteve C.
      • Coll O.
      Early ovarian hyperstimulation syndrome is completely prevented by gonadotropin releasing-hormone agonist triggering in high-risk oocyte donor cycles: a prospective, luteal-phase follow-up study.
      ,
      • Bodri D.
      • Sunkara S.K.
      • Coomarasamy A.
      Gonadotropin-releasing hormone agonists versus antagonists for controlled ovarian hyperstimulation in oocyte donors: a systematic review and meta-analysis.
      ,
      • Melo M.
      • Busso C.E.
      • Bellver J.
      • Alama P.
      • Garrido N.
      • Meseguer M.
      • Pellicer A.
      • Remohi J.
      GnRH agonist versus recombinant HCG in an oocyte donation programme: a randomized, prospective, controlled, assessor-blind study.
      ).

      Strengths

      More physiological endogenous gonadotrophin surge

      The endogenous gonadotrophin surge released after the administration of a single bolus of GnRHa is considered more physiological than HCG trigger as LH as well as FSH are released, inducing a surge similar to that of the natural mid-cycle surge of gonadotrophins. Although the specific function of the mid-cycle FSH surge has not been completely elucidated, and its role may not be completely essential, some studies have shown that it may have an effect on the resumption of oocyte meiosis and oocyte maturation, expansion and dispersion of the oocyte cumulus complex, and establishment of adequate complements of LH receptors on granulosa cells (
      • Eppig J.J.
      FSH stimulates hyaluronic acid synthesis by oocyte-cumulus cell complexes from mouse preovulatory follicles.
      ,
      • Yanagishita M.
      • Hascall V.C.
      • Rodbard D.
      Biosynthesis of proteoglycans by rat granuloma cells cultured in vitro: modulation by gonadotropins, steroid hormones, prostaglandins, and a cyclic nucleotide.
      ,
      • Yding Andersen C.
      Effect of FSH and its different isoforms on maturation of oocytes from pre-ovulatory follicles.
      ,
      • Zelinski-Wooten M.B.
      • Hutchison J.S.
      • Hess D.L.
      • Wolf D.P.
      • Stouffer R.L.
      Follicle stimulating hormone alone supports follicle growth and oocyte development in gonadotrophin-releasing hormone antagonist-treated monkeys.
      ).
      In fact, previous studies have shown a higher proportion of mature oocytes after GnRHa trigger compared with HCG (
      • Humaidan P.
      • Bredkjaer H.E.
      • Bungum L.
      • Bungum M.
      • Grondahl M.L.
      • Westergaard L.
      • Andersen C.Y.
      GnRH agonist (buserelin) or hCG for ovulation induction in GnRH antagonist IVF/ICSI cycles: a prospective randomized study.
      ,
      • Humaidan P.
      • Kol S.
      • Papanikolaou E.G.
      • Copenhagen Gn R.H.A.T.W.G.
      GnRH agonist for triggering of final oocyte maturation: time for a change of practice?.
      ,
      • Oktay K.
      • Turkcuoglu I.
      • Rodriguez-Wallberg K.A.
      GnRH agonist trigger for women with breast cancer undergoing fertility preservation by aromatase inhibitor/FSH stimulation.
      ,
      • Reddy J.
      • Turan V.
      • Bedoschi G.
      • Moy F.
      • Oktay K.
      Triggering final oocyte maturation with gonadotropin-releasing hormone agonist (GnRHa) versus human chorionic gonadotropin (hCG) in breast cancer patients undergoing fertility preservation: an extended experience.
      ), although other studies have not confirmed this (
      • Acevedo B.
      • Gomez-Palomares J.L.
      • Ricciarelli E.
      • Hernandez E.R.
      Triggering ovulation with gonadotropin-releasing hormone agonists does not compromise embryo implantation rates.
      ,
      • Bodri D.
      • Sunkara S.K.
      • Coomarasamy A.
      Gonadotropin-releasing hormone agonists versus antagonists for controlled ovarian hyperstimulation in oocyte donors: a systematic review and meta-analysis.
      ,
      • Engmann L.
      • DiLuigi A.
      • Schmidt D.
      • Nulsen J.
      • Maier D.
      • 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 prospective randomized controlled study.
      ,
      • Melo M.
      • Busso C.E.
      • Bellver J.
      • Alama P.
      • Garrido N.
      • Meseguer M.
      • Pellicer A.
      • Remohi J.
      GnRH agonist versus recombinant HCG in an oocyte donation programme: a randomized, prospective, controlled, assessor-blind study.
      ). The use of a dual trigger, however, i.e. the combination of a standard dose HCG with a bolus of GnRHa, has been shown to improve the number, proportion of mature oocytes, or both, in normal responders (
      • Lin M.H.
      • Wu F.S.
      • Lee R.K.
      • Li S.H.
      • Lin S.Y.
      • Hwu Y.M.
      Dual trigger with combination of gonadotropin-releasing hormone agonist and human chorionic gonadotropin significantly improves the live-birth rate for normal responders in GnRH-antagonist cycles.
      ), and specifically in cases of immature oocyte syndrome (
      • Castillo J.C.
      • Garcia-Velasco J.
      • Humaidan P.
      Empty follicle syndrome after GnRHa triggering versus hCG triggering in COS.
      ,
      • Griffin D.
      • Benadiva C.
      • Kummer N.
      • Budinetz T.
      • Nulsen J.
      • Engmann L.
      Dual trigger of oocyte maturation with gonadotropin-releasing hormone agonist and low-dose human chorionic gonadotropin to optimize live birth rates in high responders.
      ), which could be potentially attributed to the combined LH and FSH surge induced by the GnRHa trigger.

      Similar pregnancy rates using ‘modified’ luteal support

      Modified luteal support consisting of intensive steroidal support or adjuvant low-dose HCG (Table 2) has been advocated to circumvent the abnormal corpora luteal function induced by the administration of a bolus of GnRHa. The use of intensive steroidal support in the form of intramuscular progesterone and transdermal oestradiol and luteal phase serum oestradiol and progesterone monitoring to maintain levels of 200 pg/ml and 20 ng/ml, respectively, have been shown to have similar pregnancy rates compared with HCG trigger (
      • Engmann L.
      • Siano L.
      • Schmidt D.
      • Nulsen J.
      • Maier D.
      • Benadiva C.
      GnRH agonist to induce oocyte maturation during IVF in patients at high risk of OHSS.
      ,
      • Engmann L.
      • DiLuigi A.
      • Schmidt D.
      • Nulsen J.
      • Maier D.
      • 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 prospective randomized controlled study.
      ,
      • Iliodromiti S.
      • Blockeel C.
      • Tremellen K.P.
      • Fleming R.
      • Tournaye H.
      • Humaidan P.
      • Nelson S.M.
      Consistent high clinical pregnancy rates and low ovarian hyperstimulation syndrome rates in high-risk patients after GnRH agonist triggering and modified luteal support: a retrospective multicentre study.
      ,
      • Iliodromiti S.
      • Lan V.T.
      • Tuong H.M.
      • Tuan P.H.
      • Humaidan P.
      • Nelson S.M.
      Impact of GnRH agonist triggering and intensive luteal steroid support on live-birth rates and ovarian hyperstimulation syndrome: a retrospective cohort study.
      ,
      • Imbar T.
      • Kol S.
      • Lossos F.
      • Bdolah Y.
      • Hurwitz A.
      • Haimov-Kochman R.
      Reproductive outcome of fresh or frozen-thawed embryo transfer is similar in high-risk patients for ovarian hyperstimulation syndrome using GnRH agonist for final oocyte maturation and intensive luteal support.
      ).
      Table 2Luteal phase support protocols after gonadotrophin releasing hormone agonist trigger.
      ProtocolIndication
      Intensive luteal supportPeak serum oestradiol ≥4000 pg/ml
      Dual trigger with GnRHa and HCG 1000 IUPeak serum oestradiol <4000 pg/ml
      GnRHa trigger and HCG 1500 IU 35 h later<25 follicles
      Freeze all oocytes or embryos≥25 follicles
      GnRHa, gonadotrophin releasing hormone agonist.
      Moreover, several clinical trials have also shown excellent pregnancy rates with the use of low-dose HCG 1500 IU at the time of oocyte retrieval after GnRHa trigger in both normal and high responders (
      • Humaidan P.
      Luteal phase rescue in high-risk OHSS patients by GnRHa triggering in combination with low-dose HCG: a pilot study.
      ,
      • Humaidan P.
      • Bungum L.
      • Bungum M.
      • Yding Andersen C.
      Rescue of corpus luteum function with peri-ovulatory HCG supplementation in IVF/ICSI GnRH antagonist cycles in which ovulation was triggered with a GnRH agonist: a pilot study.
      ,
      • Humaidan P.
      • Ejdrup Bredkjaer H.
      • Westergaard L.G.
      • Yding Andersen C.
      1,500 IU human chorionic gonadotropin administered at oocyte retrieval rescues the luteal phase when gonadotropin-releasing hormone agonist is used for ovulation induction: a prospective, randomized, controlled study.
      ,
      • Humaidan P.
      • Polyzos N.P.
      • Alsbjerg B.
      • Erb K.
      • Mikkelsen A.L.
      • Elbaek H.O.
      • Papanikolaou E.G.
      • Andersen C.Y.
      GnRHa trigger and individualized luteal phase hCG support according to ovarian response to stimulation: two prospective randomized controlled multi-centre studies in IVF patients.
      ,
      • Humaidan P.
      • Thomsen L.H.
      • Alsbjerg B.
      GnRHa trigger and modified luteal support with one bolus of hCG should be used with caution in extreme responder patients.
      ,
      • Iliodromiti S.
      • Blockeel C.
      • Tremellen K.P.
      • Fleming R.
      • Tournaye H.
      • Humaidan P.
      • Nelson S.M.
      Consistent high clinical pregnancy rates and low ovarian hyperstimulation syndrome rates in high-risk patients after GnRH agonist triggering and modified luteal support: a retrospective multicentre study.
      ,
      • Iliodromiti S.
      • Lan V.T.
      • Tuong H.M.
      • Tuan P.H.
      • Humaidan P.
      • Nelson S.M.
      Impact of GnRH agonist triggering and intensive luteal steroid support on live-birth rates and ovarian hyperstimulation syndrome: a retrospective cohort study.
      ,
      • Radesic B.
      • Tremellen K.
      Oocyte maturation employing a GnRH agonist in combination with low-dose hCG luteal rescue minimizes the severity of ovarian hyperstimulation syndrome while maintaining excellent pregnancy rates.
      ).
      Finally, the use of dual trigger with low-dose HCG 1000 IU and GnRHa with intensive luteal phase steroid support results in optimal pregnancy rates in high responders with peak serum oestradiol less than 4000 pg/ml (
      • Griffin D.
      • Benadiva C.
      • Kummer N.
      • Budinetz T.
      • Nulsen J.
      • Engmann L.
      Dual trigger of oocyte maturation with gonadotropin-releasing hormone agonist and low-dose human chorionic gonadotropin to optimize live birth rates in high responders.
      ,
      • Shapiro B.S.
      • Daneshmand S.T.
      • Garner F.C.
      • Aguirre M.
      • Thomas S.
      Gonadotropin-releasing hormone agonist combined with a reduced dose of human chorionic gonadotropin for final oocyte maturation in fresh autologous cycles of in vitro fertilization.
      ,
      • Shapiro B.S.
      • Daneshmand S.T.
      • Garner F.C.
      • Aguirre M.
      • Hudson C.
      Comparison of ‘triggers’ using leuprolide acetate alone or in combination with low-dose human chorionic gonadotropin.
      ,
      • Shapiro B.S.
      • Daneshmand S.T.
      • Restrepo H.
      • Garner F.C.
      • Aguirre M.
      • Hudson C.
      Efficacy of induced luteinizing hormone surge after ‘trigger’ with gonadotropin-releasing hormone agonist.
      ). Adjuvant low-dose HCG, however, should be used with caution and should take the number of follicles at the time of trigger into account to reduce the risk of OHSS (
      • Bodri D.
      Low-dose hCG supplementation after GnRH agonist triggering: don't be too quick on the trigger.
      ,
      • Seyhan A.
      • Ata B.
      • Polat M.
      • Son W.Y.
      • Yarali H.
      • Dahan M.H.
      Severe early ovarian hyperstimulation syndrome following GnRH agonist trigger with the addition of 1500 IU hCG.
      ).

      Prevention of OHSS

      Without question, one of the major benefits of GnRHa trigger is the prevention of OHSS. The administration of GnRHa induces a short LH surge duration of only 24–36 h (
      • Itskovitz J.
      • Boldes R.
      • Levron J.
      • Erlik Y.
      • Kahana L.
      • Brandes J.M.
      Induction of preovulatory luteinizing hormone surge and prevention of ovarian hyperstimulation syndrome by gonadotropin-releasing hormone agonist.
      ) resulting in defective corpora lutea formation. Hence, the defective corpus luteum formation or early corpus luteum demise results in the decrease in release of vasoactive peptides such as VEGF (
      • Cerrillo M.
      • Rodriguez S.
      • Mayoral M.
      • Pacheco A.
      • Martinez-Salazar J.
      • Garcia-Velasco J.A.
      Differential regulation of VEGF after final oocyte maturation with GnRH agonist versus hCG: a rationale for OHSS reduction.
      ,
      • Cerrillo M.
      • Pacheco A.
      • Rodriguez S.
      • Gomez R.
      • Delgado F.
      • Pellicer A.
      • Garcia-Velasco J.A.
      Effect of GnRH agonist and hCG treatment on VEGF, angiopoietin-2, and VE-cadherin: trying to explain the link to ovarian hyperstimulation syndrome.
      ), which per se prevent OHSS development (
      • Bodri D.
      • Sunkara S.K.
      • Coomarasamy A.
      Gonadotropin-releasing hormone agonists versus antagonists for controlled ovarian hyperstimulation in oocyte donors: a systematic review and meta-analysis.
      ,
      • Engmann L.
      • DiLuigi A.
      • Schmidt D.
      • Nulsen J.
      • Maier D.
      • 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 prospective randomized controlled study.
      ,
      • Humaidan P.
      • Kol S.
      • Papanikolaou E.G.
      • Copenhagen Gn R.H.A.T.W.G.
      GnRH agonist for triggering of final oocyte maturation: time for a change of practice?.
      ). In fact, the mid-luteal ovarian volume is significantly reduced after GnRHa trigger compared with HCG trigger (
      • Babayof R.
      • Margalioth E.J.
      • Huleihel M.
      • Amash A.
      • Zylber-Haran E.
      • Gal M.
      • Brooks B.
      • Mimoni T.
      • Eldar-Geva T.
      Serum inhibin A, VEGF and TNFalpha levels after triggering oocyte maturation with GnRH agonist compared with HCG in women with polycystic ovaries undergoing IVF treatment: a prospective randomized trial.
      ,
      • Engmann L.
      • DiLuigi A.
      • Schmidt D.
      • Nulsen J.
      • Maier D.
      • 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 prospective randomized controlled study.
      ,
      • Garcia-Velasco J.A.
      • Motta L.
      • Lopez A.
      • Mayoral M.
      • Cerrillo M.
      • Pacheco A.
      Low-dose human chorionic gonadotropin versus estradiol/progesterone luteal phase support in gonadotropin-releasing hormone agonist-triggered assisted reproductive technique cycles: understanding a new approach.
      ). Similarly, less fluid is found in the cul de sac in the mid-luteal phase after GnRHa trigger (
      • Garcia-Velasco J.A.
      • Motta L.
      • Lopez A.
      • Mayoral M.
      • Cerrillo M.
      • Pacheco A.
      Low-dose human chorionic gonadotropin versus estradiol/progesterone luteal phase support in gonadotropin-releasing hormone agonist-triggered assisted reproductive technique cycles: understanding a new approach.
      ).
      Several randomized and retrospective studies in autologous high responders and oocyte donors previously reported the total elimination of OHSS after GnRHa trigger (
      • Babayof R.
      • Margalioth E.J.
      • Huleihel M.
      • Amash A.
      • Zylber-Haran E.
      • Gal M.
      • Brooks B.
      • Mimoni T.
      • Eldar-Geva T.
      Serum inhibin A, VEGF and TNFalpha levels after triggering oocyte maturation with GnRH agonist compared with HCG in women with polycystic ovaries undergoing IVF treatment: a prospective randomized trial.
      ,
      • Bodri D.
      • Sunkara S.K.
      • Coomarasamy A.
      Gonadotropin-releasing hormone agonists versus antagonists for controlled ovarian hyperstimulation in oocyte donors: a systematic review and meta-analysis.
      ,
      • DiLuigi A.J.
      • Engmann L.
      • Schmidt D.W.
      • Maier D.B.
      • Nulsen J.C.
      • Benadiva C.A.
      Gonadotropin-releasing hormone agonist to induce final oocyte maturation prevents the development of ovarian hyperstimulation syndrome in high-risk patients and leads to improved clinical outcomes compared with coasting.
      ,
      • Engmann L.
      • DiLuigi A.
      • Schmidt D.
      • Nulsen J.
      • Maier D.
      • 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 prospective randomized controlled study.
      ,
      • Humaidan P.
      • Kol S.
      • Papanikolaou E.G.
      • Copenhagen Gn R.H.A.T.W.G.
      GnRH agonist for triggering of final oocyte maturation: time for a change of practice?.
      ,
      • Kol S.
      • Muchtar M.
      Recombinant gonadotrophin-based, ovarian hyperstimulation syndrome-free stimulation of the high responder: suggested protocol for further research.
      ). In a randomized study involving high responders, such as women with polycystic ovary syndrome, no patient developed moderate or severe OHSS compared with 31% after HCG trigger and fresh transfer (
      • Engmann L.
      • DiLuigi A.
      • Schmidt D.
      • Nulsen J.
      • Maier D.
      • 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 prospective randomized controlled study.
      ). Similar findings were reported by
      • Babayof R.
      • Margalioth E.J.
      • Huleihel M.
      • Amash A.
      • Zylber-Haran E.
      • Gal M.
      • Brooks B.
      • Mimoni T.
      • Eldar-Geva T.
      Serum inhibin A, VEGF and TNFalpha levels after triggering oocyte maturation with GnRH agonist compared with HCG in women with polycystic ovaries undergoing IVF treatment: a prospective randomized trial.
      in women with polycystic ovary syndrome.
      • Kol S.
      • Muchtar M.
      Recombinant gonadotrophin-based, ovarian hyperstimulation syndrome-free stimulation of the high responder: suggested protocol for further research.
      reported no OHSS development in six women with mean serum oestradiol levels of 6322 pg/ml and 20 oocytes retrieved. Moreover, no cases of OHSS were reported in a study consisting of 61 high responders with mean peak serum oestradiol levels above 4824 pg/ml who had an average of 26 oocytes retrieved (
      • DiLuigi A.J.
      • Engmann L.
      • Schmidt D.W.
      • Maier D.B.
      • Nulsen J.C.
      • Benadiva C.A.
      Gonadotropin-releasing hormone agonist to induce final oocyte maturation prevents the development of ovarian hyperstimulation syndrome in high-risk patients and leads to improved clinical outcomes compared with coasting.
      ).
      In recent years, however, cases of OHSS occurring after GnRHa trigger and a ‘freeze all’ policy have been reported (
      • Fatemi H.M.
      • Popovic-Todorovic B.
      • Humaidan P.
      • Kol S.
      • Banker M.
      • Devroey P.
      • Garcia-Velasco J.A.
      Severe ovarian hyperstimulation syndrome after gonadotropin-releasing hormone (GnRH) agonist trigger and ‘freeze-all’ approach in GnRH antagonist protocol.
      ,
      • Gurbuz A.S.
      • Gode F.
      • Ozcimen N.
      • Isik A.Z.
      Gonadotrophin-releasing hormone agonist trigger and freeze-all strategy does not prevent severe ovarian hyperstimulation syndrome: a report of three cases.
      ,
      • Ling L.P.
      • Phoon J.W.
      • Lau M.S.
      • Chan J.K.
      • Viardot-Foucault V.
      • Tan T.Y.
      • Nadarajah S.
      • Tan H.H.
      GnRH agonist trigger and ovarian hyperstimulation syndrome: relook at ‘freeze-all strategy’.
      ), raising concerns that GnRHa trigger may not totally eliminate OHSS in all patient categories as either GnRH, FSH or LH receptor mutations in these patients might explain the occurrence of OHSS. Moreover, specific patient characteristics, which have not yet been elucidated, may play an important role. It is, therefore, important that, although GnRHa may be effective in reducing the risk of OHSS, caution is exercised and efforts made to use mild ovarian simulation protocols, especially in high-risk patients.

      Less patient discomfort

      Multiple follicular development and a significant increase in ovarian volume and fluid retention after HCG trigger may predispose the patent to significant abdominal discomfort, bloating and pain in the luteal phase. On the contrary, GnRHa trigger results in reduced ovarian volumes (
      • Engmann L.
      • DiLuigi A.
      • Schmidt D.
      • Nulsen J.
      • Maier D.
      • 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 prospective randomized controlled study.
      ), less fluid in the cul de sac (
      • Garcia-Velasco J.A.
      • Motta L.
      • Lopez A.
      • Mayoral M.
      • Cerrillo M.
      • Pacheco A.
      Low-dose human chorionic gonadotropin versus estradiol/progesterone luteal phase support in gonadotropin-releasing hormone agonist-triggered assisted reproductive technique cycles: understanding a new approach.
      ) and onset of early menses (
      • Bodri D.
      • Guillen J.J.
      • Galindo A.
      • Mataro D.
      • Pujol A.
      • Coll O.
      Triggering with human chorionic gonadotropin or a gonadotropin-releasing hormone agonist in gonadotropin-releasing hormone antagonist-treated oocyte donor cycles: findings of a large retrospective cohort study.
      ), which result in less abdominal discomfort and bloating after GnRHa trigger and hence an improved quality of life. In a study consisting of 39 oocyte donors, no patients complained of abdominal discomfort 1 week after GnRHa trigger compared with 42% after HCG trigger (
      • Cerrillo M.
      • Rodriguez S.
      • Mayoral M.
      • Pacheco A.
      • Martinez-Salazar J.
      • Garcia-Velasco J.A.
      Differential regulation of VEGF after final oocyte maturation with GnRH agonist versus hCG: a rationale for OHSS reduction.
      ). This, therefore, makes GnRHa trigger the protocol of choice for oocyte donors and women undergoing an elective cryopreservation cycle.

      Improved oocyte yield in immature oocyte syndrome and empty follicle syndrome

      Immature oocyte syndrome is characterized by the retrieval of more than 25% immature oocytes (
      • Bar-Ami S.
      • Zlotkin E.
      • Brandes J.M.
      • Itskovitz-Eldor J.
      Failure of meiotic competence in human oocytes.
      ), and the exact incidence and cause is currently unknown. The dual surge of FSH and LH seen after GnRHa trigger may be beneficial in improving oocyte maturation because the FSH surge may have a role in the induction of oocyte maturation and has been shown to induce ovulation independent of the LH surge in animals (
      • Zelinski-Wooten M.B.
      • Hutchison J.S.
      • Hess D.L.
      • Wolf D.P.
      • Stouffer R.L.
      A bolus of recombinant human follicle stimulating hormone at midcycle induces periovulatory events following multiple follicular development in macaques.
      ).
      GnRHa trigger has been used alone for successful induction of oocyte maturation in a patient with a previous history of empty follicle syndrome (EFS) (
      • Lok F.
      • Pritchard J.
      • Lashen H.
      Successful treatment of empty follicle syndrome by triggering endogenous LH surge using GnRH agonist in an antagonist down-regulated IVF cycle.
      ). Moreover,
      • Castillo J.C.
      • Moreno J.
      • Dolz M.
      • Bonilla-Musoles F.
      Successful pregnancy following dual triggering concept (rhCG þ GnRH agonist) in a patient showing repetitive inmature oocytes and empty follicle syndrome: case report.
      described a case of a successful pregnancy after the use of a dual trigger of GnRHa and standard dose of HCG in a patient who previously had repetitive immature oocytes and EFS (
      • Castillo J.C.
      • Moreno J.
      • Dolz M.
      • Bonilla-Musoles F.
      Successful pregnancy following dual triggering concept (rhCG þ GnRH agonist) in a patient showing repetitive inmature oocytes and empty follicle syndrome: case report.
      ). Finally,
      • Griffin D.
      • Feinn R.
      • Engmann L.
      • Nulsen J.
      • Budinetz T.
      • Benadiva C.
      Dual trigger with gonadotropin-releasing hormone agonist and standard dose human chorionic gonadotropin to improve oocyte maturity rates.
      evaluated 27 patients who had immature oocytes in a previous cycle triggered with HCG, and showed a higher proportion of mature oocytes and higher fertilization rates after a dual trigger of GnRHa and a standard dose of HCG (
      • Griffin D.
      • Feinn R.
      • Engmann L.
      • Nulsen J.
      • Budinetz T.
      • Benadiva C.
      Dual trigger with gonadotropin-releasing hormone agonist and standard dose human chorionic gonadotropin to improve oocyte maturity rates.
      ).

      Weaknesses

      Abnormal luteal phase

      The cause of the abnormal luteal phase after GnRHa trigger is currently not completely understood. It has, however, been shown that administration of GnRHa to induce oocyte maturation results in a defective corpus luteum formation, early demise of the corpus luteum, or both. This is because the administration of GnRHa induces a rise of LH lasting only 24–36 h (
      • Itskovitz J.
      • Boldes R.
      • Levron J.
      • Erlik Y.
      • Kahana L.
      • Brandes J.M.
      Induction of preovulatory luteinizing hormone surge and prevention of ovarian hyperstimulation syndrome by gonadotropin-releasing hormone agonist.
      ), with subsequent pituitary desensitization and withdrawal of LH support for the development and function of the corpora lutea. Although an LH surge of around 18–24 h duration will induce oocyte maturation, it will not be of sufficient duration to induce adequate corpora luteum formation (
      • Chandrasekher Y.A.
      • Brenner R.M.
      • Molskness T.A.
      • Yu Q.
      • Stouffer R.L.
      Titrating luteinizing hormone surge requirements for ovulatory changes in primate follicles. II. Progesterone receptor expression in luteinizing granulosa cells.
      ,
      • Zelinski-Wooten M.B.
      • Lanzendorf S.E.
      • Wolf D.P.
      • Chandrasekher Y.A.
      • Stouffer R.L.
      Titrating luteinizing hormone surge requirements for ovulatory changes in primate follicles. I. Oocyte maturation and corpus luteum function.
      ,
      • Zelinski-Wooten M.B.
      • Hutchison J.S.
      • Chandrasekher Y.A.
      • Wolf D.P.
      • Stouffer R.L.
      Administration of human luteinizing hormone (hLH) to macaques after follicular development: further titration of LH surge requirements for ovulatory changes in primate follicles.
      ).
      Evidence of defective corpus luteum formation and function has been demonstrated by previous studies showing a significantly reduced mid-luteal phase ovarian volume (
      • Engmann L.
      • DiLuigi A.
      • Schmidt D.
      • Nulsen J.
      • Maier D.
      • 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 prospective randomized controlled study.
      ,
      • Garcia-Velasco J.A.
      • Motta L.
      • Lopez A.
      • Mayoral M.
      • Cerrillo M.
      • Pacheco A.
      Low-dose human chorionic gonadotropin versus estradiol/progesterone luteal phase support in gonadotropin-releasing hormone agonist-triggered assisted reproductive technique cycles: understanding a new approach.
      ), low levels of serum markers of corpus luteum function in the non-supplemented (
      • Beckers N.G.
      • Macklon N.S.
      • Eijkemans M.J.
      • Ludwig M.
      • Felberbaum R.E.
      • Diedrich K.
      • Bustion S.
      • Loumaye E.
      • Fauser B.C.
      Nonsupplemented luteal phase characteristics after the administration of recombinant human chorionic gonadotropin, recombinant luteinizing hormone, or gonadotropin-releasing hormone (GnRH) agonist to induce final oocyte maturation in in vitro fertilization patients after ovarian stimulation with recombinant follicle-stimulating hormone and GnRH antagonist cotreatment.
      ) as well as the supplemented luteal phase (
      • Engmann L.
      • DiLuigi A.
      • Schmidt D.
      • Nulsen J.
      • Maier D.
      • 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 prospective randomized controlled study.
      ,
      • Fauser B.C.
      • de Jong D.
      • Olivennes F.
      • Wramsby H.
      • Tay C.
      • Itskovitz-Eldor J.
      • van Hooren H.G.
      Endocrine profiles after triggering of final oocyte maturation with GnRH agonist after cotreatment with the GnRH antagonist ganirelix during ovarian hyperstimulation for in vitro fertilization.
      ,
      • Nevo O.
      • Eldar-Geva T.
      • Kol S.
      • Itskovitz-Eldor J.
      Lower levels of inhibin A and pro-alphaC during the luteal phase after triggering oocyte maturation with a gonadotropin-releasing hormone agonist versus human chorionic gonadotropin.
      ) and shorter duration of the luteal phase (
      • Acevedo B.
      • Gomez-Palomares J.L.
      • Ricciarelli E.
      • Hernandez E.R.
      Triggering ovulation with gonadotropin-releasing hormone agonists does not compromise embryo implantation rates.
      ,
      • Beckers N.G.
      • Macklon N.S.
      • Eijkemans M.J.
      • Ludwig M.
      • Felberbaum R.E.
      • Diedrich K.
      • Bustion S.
      • Loumaye E.
      • Fauser B.C.
      Nonsupplemented luteal phase characteristics after the administration of recombinant human chorionic gonadotropin, recombinant luteinizing hormone, or gonadotropin-releasing hormone (GnRH) agonist to induce final oocyte maturation in in vitro fertilization patients after ovarian stimulation with recombinant follicle-stimulating hormone and GnRH antagonist cotreatment.
      ,
      • Garcia-Velasco J.A.
      • Motta L.
      • Lopez A.
      • Mayoral M.
      • Cerrillo M.
      • Pacheco A.
      Low-dose human chorionic gonadotropin versus estradiol/progesterone luteal phase support in gonadotropin-releasing hormone agonist-triggered assisted reproductive technique cycles: understanding a new approach.
      ,
      • Hernandez E.R.
      • Gomez-Palomares J.L.
      • Ricciarelli E.
      No room for cancellation, coasting, or ovarian hyperstimulation syndrome in oocyte donation cycles.
      ). The consequences of an abnormal luteal phase include impaired endometrial receptivity and implantation rates.

      Lower ‘success’ rates

      Early studies reported lower pregnancy rates after GnRHa trigger when a standard luteal phase support, only, was used after fresh transfer (
      • Humaidan P.
      • Bredkjaer H.E.
      • Bungum L.
      • Bungum M.
      • Grondahl M.L.
      • Westergaard L.
      • Andersen C.Y.
      GnRH agonist (buserelin) or hCG for ovulation induction in GnRH antagonist IVF/ICSI cycles: a prospective randomized study.
      ,
      • Kolibianakis E.M.
      • Schultze-Mosgau A.
      • Schroer A.
      • van Steirteghem A.
      • Devroey P.
      • Diedrich K.
      • Griesinger G.
      A lower ongoing pregnancy rate can be expected when GnRH agonist is used for triggering final oocyte maturation instead of HCG in patients undergoing IVF with GnRH antagonists.
      ). An adverse effect of GnRHa on oocyte or embryo quality and implantation potential was previously suggested as the reason for the lower pregnancy rates; however, several studies have actually shown excellent oocyte maturation rates (
      • Acevedo B.
      • Gomez-Palomares J.L.
      • Ricciarelli E.
      • Hernandez E.R.
      Triggering ovulation with gonadotropin-releasing hormone agonists does not compromise embryo implantation rates.
      ,
      • Engmann L.
      • DiLuigi A.
      • Schmidt D.
      • Nulsen J.
      • Maier D.
      • 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 prospective randomized controlled study.
      ,
      • Melo M.
      • Busso C.E.
      • Bellver J.
      • Alama P.
      • Garrido N.
      • Meseguer M.
      • Pellicer A.
      • Remohi J.
      GnRH agonist versus recombinant HCG in an oocyte donation programme: a randomized, prospective, controlled, assessor-blind study.
      ) and good-quality embryos (
      • Acevedo B.
      • Gomez-Palomares J.L.
      • Ricciarelli E.
      • Hernandez E.R.
      Triggering ovulation with gonadotropin-releasing hormone agonists does not compromise embryo implantation rates.
      ,
      • Hernandez E.R.
      • Gomez-Palomares J.L.
      • Ricciarelli E.
      No room for cancellation, coasting, or ovarian hyperstimulation syndrome in oocyte donation cycles.
      ) as well as optimal numbers of supernumerary embryos available for cryopreservation (
      • Engmann L.
      • DiLuigi A.
      • Schmidt D.
      • Nulsen J.
      • Maier D.
      • 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 prospective randomized controlled study.
      ). Moreover, excellent pregnancy rates have been reported in oocyte recipients who received embryos from GnRHa triggered oocyte donor cycles (
      • Acevedo B.
      • Gomez-Palomares J.L.
      • Ricciarelli E.
      • Hernandez E.R.
      Triggering ovulation with gonadotropin-releasing hormone agonists does not compromise embryo implantation rates.
      ,
      • Bodri D.
      • Sunkara S.K.
      • Coomarasamy A.
      Gonadotropin-releasing hormone agonists versus antagonists for controlled ovarian hyperstimulation in oocyte donors: a systematic review and meta-analysis.
      ,
      • Melo M.
      • Busso C.E.
      • Bellver J.
      • Alama P.
      • Garrido N.
      • Meseguer M.
      • Pellicer A.
      • Remohi J.
      GnRH agonist versus recombinant HCG in an oocyte donation programme: a randomized, prospective, controlled, assessor-blind study.
      ) and in women who underwent frozen embryo transfer where the oocytes originated from fresh GnRHa triggered cycles (
      • Eldar-Geva T.
      • Zylber-Haran E.
      • Babayof R.
      • Halevy-Shalem T.
      • Ben-Chetrit A.
      • Tsafrir A.
      • Varshaver I.
      • Brooks B.
      • Margalioth E.J.
      Similar outcome for cryopreserved embryo transfer following GnRH-antagonist/GnRH-agonist, GnRH-antagonist/HCG or long protocol ovarian stimulation.
      ,
      • Griesinger G.
      • Berndt H.
      • Schultz L.
      • Schultze-Mosgau A.
      • Diedrich K.
      • von Otte S.
      Intensified ovarian stimulation in a GnRH antagonist protocol with agonist triggering: a prospective, clinical feasibility study.
      ,
      • Griesinger G.
      • Schultz L.
      • Bauer T.
      • Broessner A.
      • Frambach T.
      • Kissler S.
      Ovarian hyperstimulation syndrome prevention by gonadotropin-releasing hormone agonist triggering of final oocyte maturation in a gonadotropin-releasing hormone antagonist protocol in combination with a ‘freeze-all’ strategy: a prospective multicentric study.
      ,
      • Herrero L.
      • Pareja S.
      • Losada C.
      • Cobo A.C.
      • Pellicer A.
      • Garcia-Velasco J.A.
      Avoiding the use of human chorionic gonadotropin combined with oocyte vitrification and GnRH agonist triggering versus coasting: a new strategy to avoid ovarian hyperstimulation syndrome.
      ). These pieces of evidence have clearly excluded any possible adverse effect of GnRHa on oocyte and embryo quality.
      The reasons for the reported lower pregnancy rates after GnRHa trigger have now been clearly attributed to low circulating early luteal LH levels, impairing corpus luteum function, endometrial receptivity and implantation (
      • Beckers N.G.
      • Macklon N.S.
      • Eijkemans M.J.
      • Ludwig M.
      • Felberbaum R.E.
      • Diedrich K.
      • Bustion S.
      • Loumaye E.
      • Fauser B.C.
      Nonsupplemented luteal phase characteristics after the administration of recombinant human chorionic gonadotropin, recombinant luteinizing hormone, or gonadotropin-releasing hormone (GnRH) agonist to induce final oocyte maturation in in vitro fertilization patients after ovarian stimulation with recombinant follicle-stimulating hormone and GnRH antagonist cotreatment.
      ,
      • Chandrasekher Y.A.
      • Brenner R.M.
      • Molskness T.A.
      • Yu Q.
      • Stouffer R.L.
      Titrating luteinizing hormone surge requirements for ovulatory changes in primate follicles. II. Progesterone receptor expression in luteinizing granulosa cells.
      ,
      • Engmann L.
      • Benadiva C.
      Ovarian hyperstimulation syndrome prevention strategies: luteal support strategies to optimize pregnancy success in cycles with gonadotropin-releasing hormone agonist ovulatory trigger.
      ,
      • Humaidan P.
      • Kol S.
      • Engmann L.
      • Benadiva C.
      • Papanikolaou E.G.
      • Andersen C.Y.
      • Copenhagen Gn R.H.A.T.W.G.
      Should Cochrane reviews be performed during the development of new concepts?.
      ,
      • Humaidan P.
      • Papanikolaou E.G.
      • Kyrou D.
      • Alsbjerg B.
      • Polyzos N.P.
      • Devroey P.
      • Fatemi H.M.
      The luteal phase after GnRH-agonist triggering of ovulation: present and future perspectives.
      ,
      • Humaidan P.
      • Van Vaerenbergh I.
      • Bourgain C.
      • Alsbjerg B.
      • Blockeel C.
      • Schuit F.
      • Van Lommel L.
      • Devroey P.
      • Fatemi H.
      Endometrial gene expression in the early luteal phase is impacted by mode of triggering final oocyte maturation in recFSH stimulated and GnRH antagonist co-treated IVF cycles.
      ). A standard luteal phase support similar to that used after HCG trigger has been shown to result in significantly lower pregnancy rates after GnRHa trigger (
      • Humaidan P.
      • Bredkjaer H.E.
      • Bungum L.
      • Bungum M.
      • Grondahl M.L.
      • Westergaard L.
      • Andersen C.Y.
      GnRH agonist (buserelin) or hCG for ovulation induction in GnRH antagonist IVF/ICSI cycles: a prospective randomized study.
      ,
      • Kolibianakis E.M.
      • Schultze-Mosgau A.
      • Schroer A.
      • van Steirteghem A.
      • Devroey P.
      • Diedrich K.
      • Griesinger G.
      A lower ongoing pregnancy rate can be expected when GnRH agonist is used for triggering final oocyte maturation instead of HCG in patients undergoing IVF with GnRH antagonists.
      ). Altered endometrial gene expression after GnRHa trigger may account for the low pregnancy rates with the use of standard luteal support (
      • Bermejo A.
      • Cerrillo M.
      • Ruiz-Alonso M.
      • Blesa D.
      • Simon C.
      • Pellicer A.
      • Garcia-Velasco J.A.
      Impact of final oocyte maturation using gonadotropin-releasing hormone agonist triggering and different luteal support protocols on endometrial gene expression.
      ,
      • Humaidan P.
      • Kol S.
      • Engmann L.
      • Benadiva C.
      • Papanikolaou E.G.
      • Andersen C.Y.
      • Copenhagen Gn R.H.A.T.W.G.
      Should Cochrane reviews be performed during the development of new concepts?.
      ,
      • Humaidan P.
      • Papanikolaou E.G.
      • Kyrou D.
      • Alsbjerg B.
      • Polyzos N.P.
      • Devroey P.
      • Fatemi H.M.
      The luteal phase after GnRH-agonist triggering of ovulation: present and future perspectives.
      ,
      • Humaidan P.
      • Van Vaerenbergh I.
      • Bourgain C.
      • Alsbjerg B.
      • Blockeel C.
      • Schuit F.
      • Van Lommel L.
      • Devroey P.
      • Fatemi H.
      Endometrial gene expression in the early luteal phase is impacted by mode of triggering final oocyte maturation in recFSH stimulated and GnRH antagonist co-treated IVF cycles.
      ). Therefore, it is now widely accepted that some form of modified luteal phase support involving either an intensive luteal phase steroidal support or low-dose HCG supplementation is required to circumvent the abnormal luteal phase after GnRHa trigger (
      • Engmann L.
      • Benadiva C.
      Ovarian hyperstimulation syndrome prevention strategies: luteal support strategies to optimize pregnancy success in cycles with gonadotropin-releasing hormone agonist ovulatory trigger.
      ,
      • Engmann L.
      • DiLuigi A.
      • Schmidt D.
      • Nulsen J.
      • Maier D.
      • 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 prospective randomized controlled study.
      ,
      • Griffin D.
      • Benadiva C.
      • Kummer N.
      • Budinetz T.
      • Nulsen J.
      • Engmann L.
      Dual trigger of oocyte maturation with gonadotropin-releasing hormone agonist and low-dose human chorionic gonadotropin to optimize live birth rates in high responders.
      ,
      • Humaidan P.
      Luteal phase rescue in high-risk OHSS patients by GnRHa triggering in combination with low-dose HCG: a pilot study.
      ,
      • Humaidan P.
      • Bungum L.
      • Bungum M.
      • Yding Andersen C.
      Rescue of corpus luteum function with peri-ovulatory HCG supplementation in IVF/ICSI GnRH antagonist cycles in which ovulation was triggered with a GnRH agonist: a pilot study.
      ,
      • Humaidan P.
      • Polyzos N.P.
      • Alsbjerg B.
      • Erb K.
      • Mikkelsen A.L.
      • Elbaek H.O.
      • Papanikolaou E.G.
      • Andersen C.Y.
      GnRHa trigger and individualized luteal phase hCG support according to ovarian response to stimulation: two prospective randomized controlled multi-centre studies in IVF patients.
      ,
      • Humaidan P.
      • Thomsen L.H.
      • Alsbjerg B.
      GnRHa trigger and modified luteal support with one bolus of hCG should be used with caution in extreme responder patients.
      ,
      • Iliodromiti S.
      • Blockeel C.
      • Tremellen K.P.
      • Fleming R.
      • Tournaye H.
      • Humaidan P.
      • Nelson S.M.
      Consistent high clinical pregnancy rates and low ovarian hyperstimulation syndrome rates in high-risk patients after GnRH agonist triggering and modified luteal support: a retrospective multicentre study.
      ,
      • Iliodromiti S.
      • Lan V.T.
      • Tuong H.M.
      • Tuan P.H.
      • Humaidan P.
      • Nelson S.M.
      Impact of GnRH agonist triggering and intensive luteal steroid support on live-birth rates and ovarian hyperstimulation syndrome: a retrospective cohort study.
      ,
      • Imbar T.
      • Kol S.
      • Lossos F.
      • Bdolah Y.
      • Hurwitz A.
      • Haimov-Kochman R.
      Reproductive outcome of fresh or frozen-thawed embryo transfer is similar in high-risk patients for ovarian hyperstimulation syndrome using GnRH agonist for final oocyte maturation and intensive luteal support.
      ,
      • Kol S.
      • Breyzman T.
      • Segal L.
      • Humaidan P.
      ‘Luteal coasting’ after GnRH agonist trigger – individualized, HCG-based, progesterone-free luteal support in ‘high responders’: a case series.
      ,
      • Kol S.
      • Humaidan P.
      • Alsbjerg B.
      • Engmann L.
      • Benadiva C.
      • Garcia-Velasco J.A.
      • Fatemi H.
      • Andersen C.Y.
      The updated Cochrane review 2014 on GnRH agonist trigger: repeating the same errors.
      ,
      • Shapiro B.S.
      • Daneshmand S.T.
      • Garner F.C.
      • Aguirre M.
      • Hudson C.
      Comparison of ‘triggers’ using leuprolide acetate alone or in combination with low-dose human chorionic gonadotropin.
      ,
      • Shapiro B.S.
      • Daneshmand S.T.
      • Restrepo H.
      • Garner F.C.
      • Aguirre M.
      • Hudson C.
      Efficacy of induced luteinizing hormone surge after ‘trigger’ with gonadotropin-releasing hormone agonist.
      ).

      Failure to induce oocyte maturation and empty follicle syndrome

      The efficacy of GnRHa to induce optimal oocyte maturation has been questioned in some circles in view of reports of failed oocyte maturation (
      • Griesinger G.
      • Berndt H.
      • Schultz L.
      • Schultze-Mosgau A.
      • Diedrich K.
      • von Otte S.
      Intensified ovarian stimulation in a GnRH antagonist protocol with agonist triggering: a prospective, clinical feasibility study.
      ,
      • Griesinger G.
      • Schultz L.
      • Bauer T.
      • Broessner A.
      • Frambach T.
      • Kissler S.
      Ovarian hyperstimulation syndrome prevention by gonadotropin-releasing hormone agonist triggering of final oocyte maturation in a gonadotropin-releasing hormone antagonist protocol in combination with a ‘freeze-all’ strategy: a prospective multicentric study.
      ,
      • Honnma H.
      • Hashiba Y.
      • Asada Y.
      • Endo T.
      Failure of triggering oocyte maturation with a GnRH agonist in polycystic ovary syndrome: two case reports.
      ). This concern has contributed to the lack of universal adoption of this approach of trigger. The risk of EFS after GnRHa trigger has been reported to be between 1.4% (
      • Kummer N.E.
      • Feinn R.S.
      • Griffin D.W.
      • Nulsen J.C.
      • Benadiva C.A.
      • Engmann L.L.
      Predicting successful induction of oocyte maturation after gonadotropin-releasing hormone agonist (GnRHa) trigger.
      ) and 3.5% (
      • Castillo J.C.
      • Garcia-Velasco J.
      • Humaidan P.
      Empty follicle syndrome after GnRHa triggering versus hCG triggering in COS.
      ), which is similar to the incidence after HCG trigger of 0.1-2% (
      • Ben-Shlomo I.
      • Schiff E.
      • Levran D.
      • Ben-Rafael Z.
      • Mashiach S.
      • Dor J.
      Failure of oocyte retrieval during in vitro fertilization: a sporadic event rather than a syndrome.
      ,
      • Zegers-Hochschild F.
      • Fernandez E.
      • Mackenna A.
      • Fabres C.
      • Altieri E.
      • Lopez T.
      The empty follicle syndrome: a pharmaceutical industry syndrome.
      ,
      • Quintans C.J.
      • Donaldson M.J.
      • Blanco L.A.
      • Pasqualini R.S.
      Empty follicle syndrome due to human errors: its occurrence in an in-vitro fertilization programme.
      ,
      • Mesen T.B.
      • Yu B.
      • Richter K.S.
      • Widra E.
      • DeCherney A.H.
      • Segars J.H.
      The prevalence of genuine empty follicle syndrome.
      ,
      • Baum M.
      • Machtinger R.
      • Yerushalmi G.M.
      • Maman E.
      • Seidman D.S.
      • Dor J.
      • Hourvitz A.
      Recurrence of empty follicle syndrome with stimulated IVF cycles.
      ).
      The factors that contribute to failed GnRHa trigger have been extensively reviewed by different studies and may be similar to those of failed HCG trigger (
      • Castillo J.C.
      • Garcia-Velasco J.
      • Humaidan P.
      Empty follicle syndrome after GnRHa triggering versus hCG triggering in COS.
      ,
      • Chen S.L.
      • Ye D.S.
      • Chen X.
      • Yang X.H.
      • Zheng H.Y.
      • Tang Y.
      • He Y.X.
      • Guo W.
      Circulating luteinizing hormone level after triggering oocyte maturation with GnRH agonist may predict oocyte yield in flexible GnRH antagonist protocol.
      ,
      • Kummer N.E.
      • Feinn R.S.
      • Griffin D.W.
      • Nulsen J.C.
      • Benadiva C.A.
      • Engmann L.L.
      Predicting successful induction of oocyte maturation after gonadotropin-releasing hormone agonist (GnRHa) trigger.
      ,
      • Shapiro B.S.
      • Daneshmand S.T.
      • Garner F.C.
      • Aguirre M.
      • Hudson C.
      Comparison of ‘triggers’ using leuprolide acetate alone or in combination with low-dose human chorionic gonadotropin.
      ,
      • Shapiro B.S.
      • Daneshmand S.T.
      • Restrepo H.
      • Garner F.C.
      • Aguirre M.
      • Hudson C.
      Efficacy of induced luteinizing hormone surge after ‘trigger’ with gonadotropin-releasing hormone agonist.
      ).
      • Kummer N.E.
      • Feinn R.S.
      • Griffin D.W.
      • Nulsen J.C.
      • Benadiva C.A.
      • Engmann L.L.
      Predicting successful induction of oocyte maturation after gonadotropin-releasing hormone agonist (GnRHa) trigger.
      evaluated 508 cycles using GnRHa trigger and showed that all the cases of EFS could be attributed to a failure of induction of an optimal endogenous LH surge or progesterone rise after GnRHa trigger. Appropriate selection of patients is important, and those with hypothalamic dysfunction are not candidates for GnRHa trigger as they may not reliably respond to GnRHa administration. It has also been proposed that prolonged use of oral contraceptive pill may result in a lack of response to GnRHa trigger, although there is currently no evidence to support this.
      Other possible reasons for failed GnRHa trigger, including administration error and variability in the in-vivo biological activity of some batches of commercially available GnRHa cannot be ruled out. Although there is no clear serum LH or progesterone cut-off level to predict the retrieval of an optimal number of mature oocytes, all cases of failed trigger occurred in patients with post-trigger LH less than 15 IU/l (
      • Kummer N.E.
      • Feinn R.S.
      • Griffin D.W.
      • Nulsen J.C.
      • Benadiva C.A.
      • Engmann L.L.
      Predicting successful induction of oocyte maturation after gonadotropin-releasing hormone agonist (GnRHa) trigger.
      ). Therefore, monitoring of serum LH 12 h after trigger may serve as a warning sign for a failed endogenous LH surge and additional steps could be taken to re-trigger with HCG (
      • Honnma H.
      • Hashiba Y.
      • Asada Y.
      • Endo T.
      Failure of triggering oocyte maturation with a GnRH agonist in polycystic ovary syndrome: two case reports.
      ,
      • Kummer N.E.
      • Feinn R.S.
      • Griffin D.W.
      • Nulsen J.C.
      • Benadiva C.A.
      • Engmann L.L.
      Predicting successful induction of oocyte maturation after gonadotropin-releasing hormone agonist (GnRHa) trigger.
      ).

      More intense luteal supplementation and monitoring

      In view of the abnormal luteal phase, intensive supplementation with steroids including both oestradiol and progesterone (
      • Engmann L.
      • DiLuigi A.
      • Schmidt D.
      • Nulsen J.
      • Maier D.
      • 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 prospective randomized controlled study.
      ,
      • Iliodromiti S.
      • Blockeel C.
      • Tremellen K.P.
      • Fleming R.
      • Tournaye H.
      • Humaidan P.
      • Nelson S.M.
      Consistent high clinical pregnancy rates and low ovarian hyperstimulation syndrome rates in high-risk patients after GnRH agonist triggering and modified luteal support: a retrospective multicentre study.
      ,
      • Iliodromiti S.
      • Lan V.T.
      • Tuong H.M.
      • Tuan P.H.
      • Humaidan P.
      • Nelson S.M.
      Impact of GnRH agonist triggering and intensive luteal steroid support on live-birth rates and ovarian hyperstimulation syndrome: a retrospective cohort study.
      ,
      • Imbar T.
      • Kol S.
      • Lossos F.
      • Bdolah Y.
      • Hurwitz A.
      • Haimov-Kochman R.
      Reproductive outcome of fresh or frozen-thawed embryo transfer is similar in high-risk patients for ovarian hyperstimulation syndrome using GnRH agonist for final oocyte maturation and intensive luteal support.
      ,
      • Shapiro B.S.
      • Daneshmand S.T.
      • Garner F.C.
      • Aguirre M.
      • Hudson C.
      Comparison of ‘triggers’ using leuprolide acetate alone or in combination with low-dose human chorionic gonadotropin.
      ,
      • Shapiro B.S.
      • Daneshmand S.T.
      • Restrepo H.
      • Garner F.C.
      • Aguirre M.
      • Hudson C.
      Efficacy of induced luteinizing hormone surge after ‘trigger’ with gonadotropin-releasing hormone agonist.
      ) or low-dose HCG supplementation (
      • Castillo J.C.
      • Dolz M.
      • Bienvenido E.
      • Abad L.
      • Casan E.M.
      • Bonilla-Musoles F.
      Cycles triggered with GnRH agonist: exploring low-dose HCG for luteal support.
      ,
      • Humaidan P.
      • Ejdrup Bredkjaer H.
      • Westergaard L.G.
      • Yding Andersen C.
      1,500 IU human chorionic gonadotropin administered at oocyte retrieval rescues the luteal phase when gonadotropin-releasing hormone agonist is used for ovulation induction: a prospective, randomized, controlled study.
      ,
      • Humaidan P.
      • Polyzos N.P.
      • Alsbjerg B.
      • Erb K.
      • Mikkelsen A.L.
      • Elbaek H.O.
      • Papanikolaou E.G.
      • Andersen C.Y.
      GnRHa trigger and individualized luteal phase hCG support according to ovarian response to stimulation: two prospective randomized controlled multi-centre studies in IVF patients.
      ,
      • Humaidan P.
      • Thomsen L.H.
      • Alsbjerg B.
      GnRHa trigger and modified luteal support with one bolus of hCG should be used with caution in extreme responder patients.
      ,
      • Iliodromiti S.
      • Blockeel C.
      • Tremellen K.P.
      • Fleming R.
      • Tournaye H.
      • Humaidan P.
      • Nelson S.M.
      Consistent high clinical pregnancy rates and low ovarian hyperstimulation syndrome rates in high-risk patients after GnRH agonist triggering and modified luteal support: a retrospective multicentre study.
      ,
      • Iliodromiti S.
      • Lan V.T.
      • Tuong H.M.
      • Tuan P.H.
      • Humaidan P.
      • Nelson S.M.
      Impact of GnRH agonist triggering and intensive luteal steroid support on live-birth rates and ovarian hyperstimulation syndrome: a retrospective cohort study.
      ,
      • Radesic B.
      • Tremellen K.
      Oocyte maturation employing a GnRH agonist in combination with low-dose hCG luteal rescue minimizes the severity of ovarian hyperstimulation syndrome while maintaining excellent pregnancy rates.
      ) in the luteal phase is essential to maintain optimal conception rates. It has been debated whether luteal phase oestradiol supplementation is necessary after GnRHa trigger. The intensive luteal phase support used after GnRHa trigger is based on the premise that the corpus luteum is dysfunctional. Therefore, the design of the luteal phase protocol was initially derived from protocols used for oocyte recipient cycles where there are no functional corpora lutea, and which have always included both oestradol and progesterone supplementation. Several of the studies that used protocols without oestradiol supplementation after GnRHa trigger have resulted in low pregnancy rates (
      • Fauser B.C.
      • de Jong D.
      • Olivennes F.
      • Wramsby H.
      • Tay C.
      • Itskovitz-Eldor J.
      • van Hooren H.G.
      Endocrine profiles after triggering of final oocyte maturation with GnRH agonist after cotreatment with the GnRH antagonist ganirelix during ovarian hyperstimulation for in vitro fertilization.
      ,
      • Kolibianakis E.M.
      • Schultze-Mosgau A.
      • Schroer A.
      • van Steirteghem A.
      • Devroey P.
      • Diedrich K.
      • Griesinger G.
      A lower ongoing pregnancy rate can be expected when GnRH agonist is used for triggering final oocyte maturation instead of HCG in patients undergoing IVF with GnRH antagonists.
      ). Studies have also showed that monitoring of steroid levels in the luteal phase may be essential in maintaining optimal conception rates (
      • Engmann L.
      • DiLuigi A.
      • Schmidt D.
      • Nulsen J.
      • Maier D.
      • 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 prospective randomized controlled study.
      ,
      • Shapiro B.S.
      • Daneshmand S.T.
      • Garner F.C.
      • Aguirre M.
      • Hudson C.
      Comparison of ‘triggers’ using leuprolide acetate alone or in combination with low-dose human chorionic gonadotropin.
      ,
      • Shapiro B.S.
      • Daneshmand S.T.
      • Restrepo H.
      • Garner F.C.
      • Aguirre M.
      • Hudson C.
      Efficacy of induced luteinizing hormone surge after ‘trigger’ with gonadotropin-releasing hormone agonist.
      ). This may involve regular clinic visits for serum monitoring as well as the use of intramuscular injections, which may be painful and place an undue burden on patients compared with HCG triggering.

      No consensus for GnRHa trigger dose

      Although, several studies have been published over the past 2 decades evaluating the use of GnRHa for trigger of oocyte maturation, to the best of our knowledge, only one study has compared the efficacy and doses of different types of GnRHa currently in use (
      • Parneix I.
      • Emperaire J.C.
      • Ruffie A.
      • Parneix P.
      Comparison of different protocols of ovulation induction, by GnRH agonists and chorionic gonadotropin.
      ). Several different doses and regimens of GnRHa have been used without prior dose-finding studies to determine the optimal dose required for induction of oocyte maturation and prevention of OHSS that will exert minimal detrimental effect on the luteal phase. It is plausible that the use of different types and dosages may account for the differences in efficacy of GnRHa trigger as well as its effects on pregnancy rates and risk of OHSS development.
      Single doses of leuprolide acetate (
      • Engmann L.
      • DiLuigi A.
      • Schmidt D.
      • Nulsen J.
      • Maier D.
      • 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 prospective randomized controlled study.
      ,
      • Fauser B.C.
      • de Jong D.
      • Olivennes F.
      • Wramsby H.
      • Tay C.
      • Itskovitz-Eldor J.
      • van Hooren H.G.
      Endocrine profiles after triggering of final oocyte maturation with GnRH agonist after cotreatment with the GnRH antagonist ganirelix during ovarian hyperstimulation for in vitro fertilization.
      ,
      • Oktay K.
      • Turkcuoglu I.
      • Rodriguez-Wallberg K.A.
      GnRH agonist trigger for women with breast cancer undergoing fertility preservation by aromatase inhibitor/FSH stimulation.
      ,
      • Shapiro B.S.
      • Daneshmand S.T.
      • Garner F.C.
      • Aguirre M.
      • Ross R.
      Comparison of human chorionic gonadotropin and gonadotropin-releasing hormone agonist for final oocyte maturation in oocyte donor cycles.
      ), as well as two doses, have been previously used (
      • Parneix I.
      • Emperaire J.C.
      • Ruffie A.
      • Parneix P.
      Comparison of different protocols of ovulation induction, by GnRH agonists and chorionic gonadotropin.
      ). No consensus has been reached on the dosage required for optimal induction of oocyte maturation and several different dosages have been used for leuprolide acetate ranging from 0.5 mg (
      • Fauser B.C.
      • de Jong D.
      • Olivennes F.
      • Wramsby H.
      • Tay C.
      • Itskovitz-Eldor J.
      • van Hooren H.G.
      Endocrine profiles after triggering of final oocyte maturation with GnRH agonist after cotreatment with the GnRH antagonist ganirelix during ovarian hyperstimulation for in vitro fertilization.
      ), 1 mg (
      • Engmann L.
      • DiLuigi A.
      • Schmidt D.
      • Nulsen J.
      • Maier D.
      • 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 prospective randomized controlled study.
      ,
      • Ling L.P.
      • Phoon J.W.
      • Lau M.S.
      • Chan J.K.
      • Viardot-Foucault V.
      • Tan T.Y.
      • Nadarajah S.
      • Tan H.H.
      GnRH agonist trigger and ovarian hyperstimulation syndrome: relook at ‘freeze-all strategy’.
      ,
      • Oktay K.
      • Turkcuoglu I.
      • Rodriguez-Wallberg K.A.
      GnRH agonist trigger for women with breast cancer undergoing fertility preservation by aromatase inhibitor/FSH stimulation.
      ), 1.5 mg (
      • Castillo J.C.
      • Dolz M.
      • Bienvenido E.
      • Abad L.
      • Casan E.M.
      • Bonilla-Musoles F.
      Cycles triggered with GnRH agonist: exploring low-dose HCG for luteal support.
      ), 2 mg (
      • Radesic B.
      • Tremellen K.
      Oocyte maturation employing a GnRH agonist in combination with low-dose hCG luteal rescue minimizes the severity of ovarian hyperstimulation syndrome while maintaining excellent pregnancy rates.
      ) to 4 mg (
      • Shapiro B.S.
      • Daneshmand S.T.
      • Garner F.C.
      • Aguirre M.
      • Hudson C.
      Comparison of ‘triggers’ using leuprolide acetate alone or in combination with low-dose human chorionic gonadotropin.
      ,
      • Shapiro B.S.
      • Daneshmand S.T.
      • Restrepo H.
      • Garner F.C.
      • Aguirre M.
      • Hudson C.
      Efficacy of induced luteinizing hormone surge after ‘trigger’ with gonadotropin-releasing hormone agonist.
      ). The dose of triptorelin has been most consistent, and almost all studies have used 0.2 mg (
      • Babayof R.
      • Margalioth E.J.
      • Huleihel M.
      • Amash A.
      • Zylber-Haran E.
      • Gal M.
      • Brooks B.
      • Mimoni T.
      • Eldar-Geva T.
      Serum inhibin A, VEGF and TNFalpha levels after triggering oocyte maturation with GnRH agonist compared with HCG in women with polycystic ovaries undergoing IVF treatment: a prospective randomized trial.
      ,
      • Beckers N.G.
      • Macklon N.S.
      • Eijkemans M.J.
      • Ludwig M.
      • Felberbaum R.E.
      • Diedrich K.
      • Bustion S.
      • Loumaye E.
      • Fauser B.C.
      Nonsupplemented luteal phase characteristics after the administration of recombinant human chorionic gonadotropin, recombinant luteinizing hormone, or gonadotropin-releasing hormone (GnRH) agonist to induce final oocyte maturation in in vitro fertilization patients after ovarian stimulation with recombinant follicle-stimulating hormone and GnRH antagonist cotreatment.
      ,
      • Fauser B.C.
      • de Jong D.
      • Olivennes F.
      • Wramsby H.
      • Tay C.
      • Itskovitz-Eldor J.
      • van Hooren H.G.
      Endocrine profiles after triggering of final oocyte maturation with GnRH agonist after cotreatment with the GnRH antagonist ganirelix during ovarian hyperstimulation for in vitro fertilization.
      ,
      • Imbar T.
      • Kol S.
      • Lossos F.
      • Bdolah Y.
      • Hurwitz A.
      • Haimov-Kochman R.
      Reproductive outcome of fresh or frozen-thawed embryo transfer is similar in high-risk patients for ovarian hyperstimulation syndrome using GnRH agonist for final oocyte maturation and intensive luteal support.
      ,
      • Itskovitz-Eldor J.
      • Kol S.
      • Mannaerts B.
      Use of a single bolus of GnRH agonist triptorelin to trigger ovulation after GnRH antagonist ganirelix treatment in women undergoing ovarian stimulation for assisted reproduction, with special reference to the prevention of ovarian hyperstimulation syndrome: preliminary report: short communication.
      ,
      • Kolibianakis E.M.
      • Schultze-Mosgau A.
      • Schroer A.
      • van Steirteghem A.
      • Devroey P.
      • Diedrich K.
      • Griesinger G.
      A lower ongoing pregnancy rate can be expected when GnRH agonist is used for triggering final oocyte maturation instead of HCG in patients undergoing IVF with GnRH antagonists.
      ). Two dose-finding studies have been published to date using buserelin (
      • Buckett W.M.
      • Bentick B.
      • Shaw R.W.
      Induction of the endogenous gonadotrophin surge for oocyte maturation with intra-nasal gonadotrophin-releasing hormone analogue (buserelin): effective minimal dose.
      ) and triptorelin (
      • Ngoc Lan Vuong T.
      • Tuong Ho M.
      • Duc Ha T.
      • Tuan Phung H.
      • Bao Huynh G.
      • Humaidan P.
      Gonadotropin-releasing hormone agonist trigger in oocyte donors co-treated with a gonadotropin-releasing hormone antagonist: a dose-finding study.
      ). It has been shown that the most effective minimum dose of buserelin to consistently induce the gonadotrophin surge and oocyte maturation was 0.5 mg, and this is the dose that has been used in previous studies (
      • Humaidan P.
      • Polyzos N.P.
      • Alsbjerg B.
      • Erb K.
      • Mikkelsen A.L.
      • Elbaek H.O.
      • Papanikolaou E.G.
      • Andersen C.Y.
      GnRHa trigger and individualized luteal phase hCG support according to ovarian response to stimulation: two prospective randomized controlled multi-centre studies in IVF patients.
      ,
      • Humaidan P.
      • Thomsen L.H.
      • Alsbjerg B.
      GnRHa trigger and modified luteal support with one bolus of hCG should be used with caution in extreme responder patients.
      ). A recent randomized controlled trial explored three different doses of triptorelin (0.2, 0.3 and 0.4 mg) in oocyte donors, and reported no differences in number of metaphase II oocytes, fertilization rates, embryo development and pregnancy rates in the recipients between the different doses used (
      • Ngoc Lan Vuong T.
      • Tuong Ho M.
      • Duc Ha T.
      • Tuan Phung H.
      • Bao Huynh G.
      • Humaidan P.
      Gonadotropin-releasing hormone agonist trigger in oocyte donors co-treated with a gonadotropin-releasing hormone antagonist: a dose-finding study.
      ).

      Opportunities

      Development of individualized luteal phase regimens

      The use of GnRHa trigger in IVF for the first time allows the separation of the induction of final oocyte maturation from the luteal phase, which opens an opportunity for a ‘tailored’ approach to the luteal phase support, taking into account the ovarian response to stimulation of each individual patient (Table 2) (
      • Beckers N.G.
      • Macklon N.S.
      • Eijkemans M.J.
      • Ludwig M.
      • Felberbaum R.E.
      • Diedrich K.
      • Bustion S.
      • Loumaye E.
      • Fauser B.C.
      Nonsupplemented luteal phase characteristics after the administration of recombinant human chorionic gonadotropin, recombinant luteinizing hormone, or gonadotropin-releasing hormone (GnRH) agonist to induce final oocyte maturation in in vitro fertilization patients after ovarian stimulation with recombinant follicle-stimulating hormone and GnRH antagonist cotreatment.
      ,
      • Humaidan P.
      • Polyzos N.P.
      • Alsbjerg B.
      • Erb K.
      • Mikkelsen A.L.
      • Elbaek H.O.
      • Papanikolaou E.G.
      • Andersen C.Y.
      GnRHa trigger and individualized luteal phase hCG support according to ovarian response to stimulation: two prospective randomized controlled multi-centre studies in IVF patients.
      ,
      • Humaidan P.
      • Thomsen L.H.
      • Alsbjerg B.
      GnRHa trigger and modified luteal support with one bolus of hCG should be used with caution in extreme responder patients.
      ,
      • Kol S.
      • Humaidan P.
      • Itskovitz-Eldor J.
      GnRH agonist ovulation trigger and hCG-based, progesterone-free luteal support: a proof of concept study.
      ).
      Although, serum oestradiol on the day of trigger has been shown to be predictive of reproductive success after GnRHa trigger (
      • Kummer N.
      • Benadiva C.
      • Feinn R.
      • Mann J.
      • Nulsen J.
      • Engmann L.
      Factors that predict the probability of a successful clinical outcome after induction of oocyte maturation with a gonadotropin-releasing hormone agonist.
      ), another study did not confirm this finding (
      • Iliodromiti S.
      • Blockeel C.
      • Tremellen K.P.
      • Fleming R.
      • Tournaye H.
      • Humaidan P.
      • Nelson S.M.
      Consistent high clinical pregnancy rates and low ovarian hyperstimulation syndrome rates in high-risk patients after GnRH agonist triggering and modified luteal support: a retrospective multicentre study.
      ,
      • Iliodromiti S.
      • Lan V.T.
      • Tuong H.M.
      • Tuan P.H.
      • Humaidan P.
      • Nelson S.M.
      Impact of GnRH agonist triggering and intensive luteal steroid support on live-birth rates and ovarian hyperstimulation syndrome: a retrospective cohort study.
      ), which may be explained by differences in patient characteristics and laboratory assays. Moreover, it has been suggested that intensive luteal phase supplementation alone may be sufficient for patients with serum oestradiol greater than 4000 pg/ml in view of the optimal pregnancy rates (
      • Kummer N.
      • Benadiva C.
      • Feinn R.
      • Mann J.
      • Nulsen J.
      • Engmann L.
      Factors that predict the probability of a successful clinical outcome after induction of oocyte maturation with a gonadotropin-releasing hormone agonist.
      ). In contrast, low-dose HCG supplementation, such as the dual trigger with low-dose HCG, may be required in women with peak oestradiol levels below 4000 pg/ml (
      • Griffin D.
      • Benadiva C.
      • Kummer N.
      • Budinetz T.
      • Nulsen J.
      • Engmann L.
      Dual trigger of oocyte maturation with gonadotropin-releasing hormone agonist and low-dose human chorionic gonadotropin to optimize live birth rates in high responders.
      ). It has also been shown that women with less than 25 follicles would benefit from adjuvant administration of 1500 IU of HCG at time of oocyte retrieval, whereas those with over 25 follicles may benefit from a freeze all strategy (
      • Humaidan P.
      • Polyzos N.P.
      • Alsbjerg B.
      • Erb K.
      • Mikkelsen A.L.
      • Elbaek H.O.
      • Papanikolaou E.G.
      • Andersen C.Y.
      GnRHa trigger and individualized luteal phase hCG support according to ovarian response to stimulation: two prospective randomized controlled multi-centre studies in IVF patients.
      ,
      • Humaidan P.
      • Thomsen L.H.
      • Alsbjerg B.
      GnRHa trigger and modified luteal support with one bolus of hCG should be used with caution in extreme responder patients.
      ,
      • Humaidan P.
      • Engmann L.
      • Benadiva C.
      Luteal phase supplementation after gonadotropin-releasing hormone agonist trigger in fresh embryo transfer: the American versus European approaches.
      ). Others, however, have recommended freezing all embryos in women with 18 or more follicles measuring 10–14 mm in diameter to prevent development of OHSS (
      • Seyhan A.
      • Ata B.
      • Polat M.
      • Son W.Y.
      • Yarali H.
      • Dahan M.H.
      Severe early ovarian hyperstimulation syndrome following GnRH agonist trigger with the addition of 1500 IU hCG.
      ).
      Other forms of low-dose HCG regimens in the luteal phase have been tried, although this approach may lead to a higher risk of OHSS (
      • Castillo J.C.
      • Dolz M.
      • Bienvenido E.
      • Abad L.
      • Casan E.M.
      • Bonilla-Musoles F.
      Cycles triggered with GnRH agonist: exploring low-dose HCG for luteal support.
      ). Recently a randomized GnRHa trigger study showed that a very low dose of daily HCG administration (125 IU) effectively rescued the corpus luteum function and secured good clinical pregnancy rates. Importantly, no other luteal phase support was used, and this study further introduces the concept of the exogenous progesterone free luteal phase in assisted reproduction techniques (
      • Elbaek H.O.
      • Alsbjerg B.
      • Laursen R.
      • Povlsen B.B.
      • Mikkelsen A.T.
      • Andersen C.Y.
      • Humaidan P.
      The exogenous progesterone free luteal phase in IVF – exploring a new concept.
      ).
      • Kol S.
      • Breyzman T.
      • Segal L.
      • Humaidan P.
      ‘Luteal coasting’ after GnRH agonist trigger – individualized, HCG-based, progesterone-free luteal support in ‘high responders’: a case series.
      ,
      • Kol S.
      • Humaidan P.
      • Alsbjerg B.
      • Engmann L.
      • Benadiva C.
      • Garcia-Velasco J.A.
      • Fatemi H.
      • Andersen C.Y.
      The updated Cochrane review 2014 on GnRH agonist trigger: repeating the same errors.
      recently introduced the concept of ‘luteal coasting’ after GnRHa trigger, which suggested that the luteal phase rescue HCG bolus of 1500 IU is administered only when serum progesterone levels drop significantly. Interestingly, no other luteal support was given in that study (
      • Kol S.
      • Breyzman T.
      • Segal L.
      • Humaidan P.
      ‘Luteal coasting’ after GnRH agonist trigger – individualized, HCG-based, progesterone-free luteal support in ‘high responders’: a case series.
      ,
      • Kol S.
      • Humaidan P.
      • Alsbjerg B.
      • Engmann L.
      • Benadiva C.
      • Garcia-Velasco J.A.
      • Fatemi H.
      • Andersen C.Y.
      The updated Cochrane review 2014 on GnRH agonist trigger: repeating the same errors.
      ).

      Improved safety for oocyte donors

      Oocyte donors are usually young healthy women, donating oocytes for altruistic reasons and it behoves all clinicians to make the process safe and seamless. Overwhelming evidence shows that GnRHa trigger is effective in inducing optimal oocyte maturation and preventing OHSS development in oocyte donors as well as maintaining excellent pregnancy rates in the recipients (
      • Acevedo B.
      • Gomez-Palomares J.L.
      • Ricciarelli E.
      • Hernandez E.R.
      Triggering ovulation with gonadotropin-releasing hormone agonists does not compromise embryo implantation rates.
      ,
      • Bodri D.
      • Sunkara S.K.
      • Coomarasamy A.
      Gonadotropin-releasing hormone agonists versus antagonists for controlled ovarian hyperstimulation in oocyte donors: a systematic review and meta-analysis.
      ,
      • Galindo A.
      • Bodri D.
      • Guillen J.J.
      • Colodron M.
      • Vernaeve V.
      • Coll O.
      Triggering with HCG or GnRH agonist in GnRH antagonist treated oocyte donation cycles: a randomised clinical trial.
      ,
      • Hernandez E.R.
      • Gomez-Palomares J.L.
      • Ricciarelli E.
      No room for cancellation, coasting, or ovarian hyperstimulation syndrome in oocyte donation cycles.
      ,
      • Melo M.
      • Busso C.E.
      • Bellver J.
      • Alama P.
      • Garrido N.
      • Meseguer M.
      • Pellicer A.
      • Remohi J.
      GnRH agonist versus recombinant HCG in an oocyte donation programme: a randomized, prospective, controlled, assessor-blind study.
      ). The reduction in luteal phase ovarian volume and fluid in the cul de sac (
      • Garcia-Velasco J.A.
      • Motta L.
      • Lopez A.
      • Mayoral M.
      • Cerrillo M.
      • Pacheco A.
      Low-dose human chorionic gonadotropin versus estradiol/progesterone luteal phase support in gonadotropin-releasing hormone agonist-triggered assisted reproductive technique cycles: understanding a new approach.
      ) results in less abdominal discomfort and bloating and a better quality of life. Taking these facts into consideration, GnRHa should be the first line trigger concept in oocyte donors.

      Ideal protocol for specific clinical situations

      All patients undergoing elective cryopreservation of all oocytes or embryos are ideal candidates for GnRHa trigger as there will be no concerns about the luteal phase. These include patients undergoing fertility preservation for medical or social reasons and those undergoing preimplantation genetic screening or diagnosis, with a plan for trophectoderm biopsy and a ‘freeze all’ for subsequent transfer. Other specific clinical situations for ‘freeze all’ are cycles with a premature progesterone elevation.
      The use of GnRHa trigger for oocyte and embryo cryopreservation in cancer patients undergoing fertility preservation is ideal because it significantly reduces luteal circulating oestradiol levels in patients with oestradiol receptor positive breast cancer (
      • Oktay K.
      • Turkcuoglu I.
      • Rodriguez-Wallberg K.A.
      GnRH agonist trigger for women with breast cancer undergoing fertility preservation by aromatase inhibitor/FSH stimulation.
      ,
      • Reddy J.
      • Turan V.
      • Bedoschi G.
      • Moy F.
      • Oktay K.
      Triggering final oocyte maturation with gonadotropin-releasing hormone agonist (GnRHa) versus human chorionic gonadotropin (hCG) in breast cancer patients undergoing fertility preservation: an extended experience.
      ), thereby reducing the risk of exposure to high oestradiol levels. Moreover, it allows a quick resolution to a normal baseline status, preventing a potential delay in initiating chemotherapy (
      • Oktay K.
      • Turkcuoglu I.
      • Rodriguez-Wallberg K.A.
      GnRH agonist trigger for women with breast cancer undergoing fertility preservation by aromatase inhibitor/FSH stimulation.
      ).
      Recently, trophectoderm biopsy with elective cryopreservation of all embryos and subsequent transfer in a natural cycle has been advocated as the modality of choice for patients undergoing preimplantation genetic screening or diagnosis (
      • Schoolcraft W.B.
      • Katz-Jaffe M.G.
      Comprehensive chromosome screening of trophectoderm with vitrification facilitates elective single-embryo transfer for infertile women with advanced maternal age.
      ,
      • Schoolcraft W.B.
      • Fragouli E.
      • Stevens J.
      • Munne S.
      • Katz-Jaffe M.G.
      • Wells D.
      Clinical application of comprehensive chromosomal screening at the blastocyst stage.
      ,
      • Schoolcraft W.B.
      • Treff N.R.
      • Stevens J.M.
      • Ferry K.
      • Katz-Jaffe M.
      • Scott Jr., R.T.
      Live birth outcome with trophectoderm biopsy, blastocyst vitrification, and single-nucleotide polymorphism microarray-based comprehensive chromosome screening in infertile patients.
      ). Trophectoderm biopsy offers several advantages over blastomere biopsy (
      • Schoolcraft W.B.
      • Fragouli E.
      • Stevens J.
      • Munne S.
      • Katz-Jaffe M.G.
      • Wells D.
      Clinical application of comprehensive chromosomal screening at the blastocyst stage.
      ,
      • Scott Jr., R.T.
      • Upham K.M.
      • Forman E.J.
      • Zhao T.
      • Treff N.R.
      Cleavage-stage biopsy significantly impairs human embryonic implantation potential while blastocyst biopsy does not: a randomized and paired clinical trial.
      ) and, importantly, in most cases the biopsy results may not be available for a day 5 or 6 transfer.
      Premature serum progesterone elevation has been associated with lower pregnancy rates in some studies (
      • Bosch E.
      • Labarta E.
      • Crespo J.
      • Simon C.
      • Remohi J.
      • Jenkins J.
      • Pellicer A.
      Circulating progesterone levels and ongoing pregnancy rates in controlled ovarian stimulation cycles for in vitro fertilization: analysis of over 4000 cycles.
      ,
      • Huang C.C.
      • Lien Y.R.
      • Chen H.F.
      • Chen M.J.
      • Shieh C.J.
      • Yao Y.L.
      • Chang C.H.
      • Chen S.U.
      • Yang Y.S.
      The duration of pre-ovulatory serum progesterone elevation before hCG administration affects the outcome of IVF/ICSI cycles.
      ,
      • 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.
      ), and it has been proposed that elective oocyte and embryo cryopreservation will allow transfer in a subsequent non-stimulated cycle to optimize conception rates (
      • Shapiro B.S.
      • Daneshmand S.T.
      • Garner F.C.
      • Aguirre M.
      • Hudson C.
      • Thomas S.
      Embryo cryopreservation rescues cycles with premature luteinization.