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• W2009876282 abstract "The challenges in attaining an adequate luteal phase after GnRH agonist (GnRHa) trigger to induce final oocyte maturation have resulted in different approaches focused on rescuing the luteal phase insufficiency so that a fresh transfer can be carried out without jeopardizing IVF outcomes. Over the years, two different concepts have emerged: intensive luteal support with aggressive exogenous administration of E2 and P; and low-dose hCG rescue in the form of a small dose of hCG either on the day of oocyte retrieva or on the day of GnRHa trigger (the so called “dual trigger”). Both approaches have been shown to be effective in achieving pregnancy rates similar to those obtained after conventional hCG trigger and resulting in a very low risk of ovarian hyperstimulation syndrome (OHSS). Although the idea of freezing all embryos after GnRHa trigger and transferring them in a subsequent frozen-thawed cycle has been gaining momentum, a fresh transfer leading to the live birth of a healthy child is currently considered to be the goal of IVF treatment. The challenges in attaining an adequate luteal phase after GnRH agonist (GnRHa) trigger to induce final oocyte maturation have resulted in different approaches focused on rescuing the luteal phase insufficiency so that a fresh transfer can be carried out without jeopardizing IVF outcomes. Over the years, two different concepts have emerged: intensive luteal support with aggressive exogenous administration of E2 and P; and low-dose hCG rescue in the form of a small dose of hCG either on the day of oocyte retrieva or on the day of GnRHa trigger (the so called “dual trigger”). Both approaches have been shown to be effective in achieving pregnancy rates similar to those obtained after conventional hCG trigger and resulting in a very low risk of ovarian hyperstimulation syndrome (OHSS). Although the idea of freezing all embryos after GnRHa trigger and transferring them in a subsequent frozen-thawed cycle has been gaining momentum, a fresh transfer leading to the live birth of a healthy child is currently considered to be the goal of IVF treatment. Discuss: You can discuss this article with its authors and with other ASRM members at http://fertstertforum.com/humaidanp-luteal-phase-gnrh-agonist-trigger/Ovarian hyperstimulation syndrome (OHSS) is a dangerous and potentially life threatening complication of controlled ovarian stimulation (COS). Considering that ovarian stimulation is performed on healthy uncompromised infertility patients and in healthy oocyte donors, every effort should be made to prevent or eliminate this complication. Although it has been generally assumed that OHSS is an inevitable and possibly unavoidable complication of COS, it is now largely accepted that GnRH agonist (GnRHa) administration to induce final oocyte maturation is effective in the prevention of OHSS (1Itskovitz-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.Hum Reprod. 2000; 15: 1965-1968Crossref PubMed Scopus (169) Google Scholar, 2Engmann 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.Fertil Steril. 2008; 89: 84-91Abstract Full Text Full Text PDF PubMed Scopus (348) Google Scholar, 3DiLuigi 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.Fertil Steril. 2010; 94: 1111-1114Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar). The administration of a single dose of GnRHa results in defective corpus luteum (CL) function with resultant decrease in the release of vasoactive peptides, such as vascular endothelial growth factor, that may potentially prevent OHSS (4Cerrillo 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.Fertil Steril. 2009; 91: 1526-1528Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar). This is due to the shorter half-life of the endogenous LH surge which results in defective CL function and also subsequent pituitary suppression leading to early luteolysis (5Kol S. Luteolysis induced by a gonadotropin-releasing hormone agonist is the key to prevention of ovarian hyperstimulation syndrome.Fertil Steril. 2004; 81: 1-5Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar). In addition, the supraphysiologic levels of E2 and P after COS directly inhibit LH secretion from the pituitary by means of negative feedback actions on the hypothalamic-pituitary axis (6Fauser B.C. Devroey P. Reproductive biology and IVF: ovarian stimulation and luteal phase consequences.Trends Endocrinol Metab. 2003; 14: 236-242Abstract Full Text Full Text PDF PubMed Scopus (192) Google Scholar, 7Tavaniotou A. Albano C. Smitz J. Devroey P. Comparison of LH concentrations in the early and mid-luteal phase in IVF cycles after treatment with hMG alone or in association with the GnRH antagonist cetrorelix.Hum Reprod. 2001; 16: 663-667Crossref PubMed Scopus (82) Google Scholar, 8Tavaniotou A. Devroey P. Effect of human chorionic gonadotropin on luteal luteinizing hormone concentrations in natural cycles.Fertil Steril. 2003; 80: 654-655Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar). Importantly, LH plays a significant role during the luteal phase, not only for CL function, but also for the up-regulation of growth factors and cytokines involved in early implantation (9Sugino N. Kashida S. Takiguchi S. Karube A. Kato H. Expression of vascular endothelial growth factor and its receptors in the human corpus luteum during the menstrual cycle and in early pregnancy.J Clin Endocrinol Metab. 2000; 85: 3919-3924Crossref PubMed Scopus (103) Google Scholar, 10Licht P. Russu V. Wildt L. On the role of human chorionic gonadotropin (hCG) in the embryo-endometrial microenvironment: implications for differentiation and implantation.Semin Reprod Med. 2001; 19: 37-47Crossref PubMed Scopus (172) Google Scholar, 11Wang T.H. Horng S.G. Chang C.L. Wu H.M. Tsai Y.J. Wang H.S. et al.Human chorionic gonadotropin–induced ovarian hyperstimulation syndrome is associated with up-regulation of vascular endothelial growth factor.J Clin Endocrinol Metab. 2002; 87: 3300-3308Crossref PubMed Scopus (134) Google Scholar). The amount of LH needed to support CL function and early implantation is currently unknown, so LH levels can not be used for monitoring the luteal phase.One of the associated consequences of defective CL function is significantly lower luteal levels of serum E2 and P, resulting in a potential detrimental effect on endometrial receptivity (12Beckers N.G. Macklon N.S. Eijkemans M.J. Ludwig M. Felberbaum R.E. Diedrich K. et al.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.J Clin Endocrinol Metab. 2003; 88: 4186-4192Crossref PubMed Scopus (243) Google Scholar). The mean duration of the nonsupplemented luteal phase after GnRHa trigger in oocyte donors may be as short as 4 days, compared with 13 days after hCG trigger, suggesting a markedly defective CL function (13Acevedo B. Gomez-Palomares J.L. Ricciarelli E. Hernandez E.R. Triggering ovulation with gonadotropin-releasing hormone agonists does not compromise embryo implantation rates.Fertil Steril. 2006; 86: 1682-1687Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar). Even with intramuscular (IM) P supplementation in the luteal phase, significantly lower luteal-phase serum P as well as E2 levels have been reported (14Fauser B.C. de Jong D. Olivennes F. Wramsby H. Tay C. Itskovitz-Eldor J. et al.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.J Clin Endocrinol Metab. 2002; 87: 709-715Crossref PubMed Scopus (198) Google Scholar, 15Engmann 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.Reprod Biomed Online. 2006; 13: 639-644Abstract Full Text PDF PubMed Scopus (61) Google Scholar). It is therefore critical that strategies to improve the luteal-phase steroidal profile and endometrial receptivity are optimized to maintain adequate live birth rates without increasing the risk of OHSS development.The initial experience of using GnRHa to trigger final oocyte maturation resulted in very disappointing results. A number of early studies reported significantly higher miscarriage rates and lower ongoing pregnancy rates after GnRHa trigger (16Humaidan P. Bredkjaer H.E. Bungum L. Bungum M. Grondahl M.L. Westergaard L. et al.GnRH agonist (buserelin) or hCG for ovulation induction in GnRH antagonist IVF/ICSI cycles: a prospective randomized study.Hum Reprod. 2005; 20: 1213-1220Crossref PubMed Scopus (371) Google Scholar, 17Kolibianakis E.M. Schultze-Mosgau A. Schroer A. van Steirteghem A. Devroey P. Diedrich K. et al.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.Hum Reprod. 2005; 20: 2887-2892Crossref PubMed Scopus (264) Google Scholar). In 2006, a very early meta-analysis including three randomized clinical trials (RCTs) showed a significantly lower chance of pregnancy and higher risk of miscarriage, which resulted in two trials being prematurely discontinued (18Griesinger 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.Hum Reprod Update. 2006; 12: 159-168Crossref PubMed Scopus (215) Google Scholar). It became clear that the use of standard luteal phase support after GnRHa trigger is inadequate and almost invariably results in lower conception rates. The authors of the initial meta-analysis, therefore, prematurely suggested that GnRHa to trigger final oocyte maturation should not be recommended for clinical use. Likewise, a recent updated Cochrane review on GnRHa trigger (19Youssef M.A. van der Veen F. Al-Inany H.G. Mochtar M.H. Griesinger G. Nagi Mohesen M. et al.Gonadotropin-releasing hormone agonist versus HCG for oocyte triggering in antagonist-assisted reproductive technology.Cochrane Database Syst Rev. 2014; : CD008046PubMed Google Scholar) reached the same general conclusion that GnRHa trigger is associated with a lower ongoing pregnancy rate compared with conventional hCG trigger. Unfortunately, data were compiled from studies that were not comparable due to different luteal phase protocols being used. The Cochrane analysis therefore missed the fact that it is the luteal support that is the variable that affects the pregnancy rate and not the use of the GnRHa trigger for final oocyte maturation (20Yding Andersen C. Vilbour Andersen K. Improving the luteal phase after ovarian stimulation: reviewing new options.Reprod Biomed Online. 2014; 28: 552-559Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar).In searching for an optimal luteal phase protocol, Engmann et al. hypothesized that using a modified intensive hormonal replacement regimen similar to the one used for agonadal oocyte donor recipients would overcome the CL dysfunction and result in adequate implantation rates (15Engmann 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.Reprod Biomed Online. 2006; 13: 639-644Abstract Full Text PDF PubMed Scopus (61) Google Scholar). Around the same time, Humaidan et al. explored the use of low-dose hCG to rescue the luteal phase, also with very favorable results (21Humaidan 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.Reprod Biomed Online. 2006; 13: 173-178Abstract Full Text PDF PubMed Scopus (145) Google Scholar). In view of the more encouraging results obtained with these new approaches, a consensus was beginning to emerge that the time had arrived to reconsider the use of GnRHa for triggering of final oocyte maturation (22Humaidan P. Papanikolaou E.G. Tarlatzis B.C. GnRHa to trigger final oocyte maturation: a time to reconsider.Hum Reprod. 2009; 24: 2389-2394Crossref PubMed Scopus (84) Google Scholar). An international group of experts met in Denmark in November 2009 to evaluate the existing evidence on the use of GnRHa to trigger final oocyte maturation. The members of the Copenhagen GnRH Agonist Triggering Workshop Group agreed that the time had come for a paradigm shift in the ovulation triggering concept in ART. The discussions and expert opinions of the group were reported in a consensus paper published in 2011, setting the foundation for future research developments and continuing international collaboration in this area of investigation (23Humaidan P. Kol S. Papanikolaou E.G. Copenhagen GnRH Agonist Triggering Workshop Group. GnRH agonist for triggering of final oocyte maturation: time for a change of practice?.Hum Reprod Update. 2011; 17: 510-524Crossref PubMed Scopus (248) Google Scholar).In the present article, we summarize the current status of the different approaches available for the management of the luteal phase after GnRHa trigger.Intensive luteal support (the “American” approach)Optimal luteal-phase steroidal supplementation after GnRHa is important because of the vast amount of evidence in the literature regarding the abnormal luteal phase steroid profile (12Beckers N.G. Macklon N.S. Eijkemans M.J. Ludwig M. Felberbaum R.E. Diedrich K. et al.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.J Clin Endocrinol Metab. 2003; 88: 4186-4192Crossref PubMed Scopus (243) Google Scholar, 14Fauser B.C. de Jong D. Olivennes F. Wramsby H. Tay C. Itskovitz-Eldor J. et al.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.J Clin Endocrinol Metab. 2002; 87: 709-715Crossref PubMed Scopus (198) Google Scholar). Several studies have attempted to supplement the luteal phase after GnRHa trigger with the use of luteal phase support similar to that used after hCG trigger, with disappointing results.Fauser et al. (14Fauser B.C. de Jong D. Olivennes F. Wramsby H. Tay C. Itskovitz-Eldor J. et al.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.J Clin Endocrinol Metab. 2002; 87: 709-715Crossref PubMed Scopus (198) Google Scholar) utilized only IM P (50 mg) as luteal support for ≥2 weeks and obtained an ongoing pregnancy rate of 18% and 20% for patients triggered with triptorelin or leuprolide, respectively. All the patients in the study by Humaidan et al. (16Humaidan P. Bredkjaer H.E. Bungum L. Bungum M. Grondahl M.L. Westergaard L. et al.GnRH agonist (buserelin) or hCG for ovulation induction in GnRH antagonist IVF/ICSI cycles: a prospective randomized study.Hum Reprod. 2005; 20: 1213-1220Crossref PubMed Scopus (371) Google Scholar) received micronized P vaginally and oral E2 daily starting on the day after oocyte retrieval and continued until the day of pregnancy test, obtaining a clinical pregnancy rate of only 6%. These poor results may have been attributed to the premature discontinuation of the hormonal supplementation (24Engmann L. Benadiva C. GnRH agonist (buserelin) or hCG for ovulation induction in GnRH antagonist IVF/ICSI cycles: a prospective randomized study.Hum Reprod. 2005; 20 (author reply 3260): 3258-3260Crossref PubMed Scopus (12) Google Scholar). In the study by Kolibianakis et al. (17Kolibianakis E.M. Schultze-Mosgau A. Schroer A. van Steirteghem A. Devroey P. Diedrich K. et al.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.Hum Reprod. 2005; 20: 2887-2892Crossref PubMed Scopus (264) Google Scholar), one of the participant centers used micronized vaginal P (600 mg in three separate doses) and oral E2 (4 mg/d) from the day after oocyte retrieval until 7 weeks of gestation, achieving an ongoing pregnancy rate of 5.6%. The other center in the study used only vaginal and IM P, without E2 support, until 7 weeks' gestation and reported an ongoing pregnancy rate of 2.9%. The trial was prematurely discontinued owing to the low ongoing pregnancy rates.Adopting the approach that regular supplementation is suboptimal, in a randomized controlled trial our group used intensive luteal phase support and monitoring of serum steroid levels after GnRHa trigger with an excellent ongoing pregnancy rate of 53.3% (2Engmann 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.Fertil Steril. 2008; 89: 84-91Abstract Full Text Full Text PDF PubMed Scopus (348) Google Scholar). All of the patients received 50 mg IM P daily starting the evening after oocyte retrieval and continued until ∼10 weeks' gestation. In addition, they received three 0.1-mg E2 transdermal patches every other day starting on the day after oocyte retrieval. Serum E2 and P were measured on the day of embryo transfer, 1 week after oocyte retrieval, and weekly thereafter. The dose of transdermal E2 patches was increased, if necessary, to a maximum of four 0.1-mg patches every other day, and/or addition of oral micronized E2 to maintain the serum E2 level >200 pg/mL. The IM P dose was also increased, if necessary, to a maximum of 75 mg daily and/or addition of micronized vaginal P to maintain serum P level >20 ng/mL.The ideal type of luteal phase support after GnRH agonist is still under investigation, however it is evident that some form of aggressive steroidal support and serum monitoring with appropriate dose adjustment is essential. The ideal route of P administration after COS is still debatable (25Pritts E.A. Atwood A.K. Luteal phase support in infertility treatment: a meta-analysis of the randomized trials.Hum Reprod. 2002; 17: 2287-2299Crossref PubMed Scopus (254) Google Scholar, 26Daya S. Gunby J. Luteal phase support in assisted reproduction cycles.Cochrane Database Syst Rev. 2004; : CD004830PubMed Google Scholar), although it is likely that the IM route will be preferable after GnRHa trigger because of the abnormal luteal phase and the need for adequate supplementation and monitoring. Although the evidence for E2 supplementation after hCG trigger in IVF treatment is weak (25Pritts E.A. Atwood A.K. Luteal phase support in infertility treatment: a meta-analysis of the randomized trials.Hum Reprod. 2002; 17: 2287-2299Crossref PubMed Scopus (254) Google Scholar, 27Engmann L. DiLuigi A. Schmidt D. Benadiva C. Maier D. Nulsen J. The effect of luteal phase vaginal estradiol supplementation on the success of in vitro fertilization treatment: a prospective randomized study.Fertil Steril. 2008; 89: 554-561Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar, 28Jee B.C. Suh C.S. Kim S.H. Kim Y.B. Moon S.Y. Effects of estradiol supplementation during the luteal phase of in vitro fertilization cycles: a meta-analysis.Fertil Steril. 2010; 93: 428-436Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar), it may be required after GnRHa trigger because of the defective CL function. Additionally, the route of E2 administration may be important in correcting the abnormal luteal phase, and it is possible that the use of transdermal E2 patches may be preferable because it avoids the first-pass effect of oral E2. The use of vaginal or IM E2 in the setting of GnRHa trigger has not been investigated. Steroid supplementation during the luteal phase and early pregnancy should not be discontinued early, because it has been shown that the endogenous rise of hCG during early pregnancy may not be sufficient to rescue the early luteolysis that occurs after GnRHa trigger (29Nevo 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.Fertil Steril. 2003; 79: 1123-1128Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar). It is noteworthy that other groups that have applied a similar intensive luteal support protocol have also reported favorable results with fresh transfers (30Imbar 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.Hum Reprod. 2012; 27: 753-759Crossref PubMed Scopus (44) Google Scholar, 31Iliodromiti S. Blockeel C. Tremellen K.P. Fleming R. Tournaye H. Humaidan P. et al.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.Hum Reprod. 2013; 28: 2529-2536Crossref PubMed Scopus (79) Google Scholar, 32Shapiro 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.Fertil Steril. 2011; 95: 2715-2717Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar).Low-dose Adjuvant hCG AdministrationDespite our encouraging results, we recognized that intensive luteal-phase supplementation with E2 and P may not be the solution for the abnormal luteal phase and low conception rates in all cases. We previously evaluated the factors that predict the probability of successful outcome after GnRHa trigger and found that peak serum E2 ≥4,000 pg/mL and serum LH levels on the day of trigger are the most important predictive factors for success (33Kummer 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.Fertil Steril. 2011; 96: 63-68Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar). The implantation (34.4% vs. 25.3%; P=.02) and clinical pregnancy rates (53.6% vs. 38.1%; P=.02) were significantly higher in patients with peak E2 levels ≥4,000 pg/mL compared with those with peak E2 levels <4,000 pg/mL. Moreover, patients with higher peak E2 levels also had significantly higher serum LH levels on the day of trigger. We hypothesized that patients with high serum E2 and LH levels may also have higher luteal-phase LH levels, which may rescue a few CLs and result in more optimal luteal-phase E2 and P levels and implantation rates. It is therefore likely that some form of low-dose LH-like activity could rescue a few CLs to improve implantation in patients with low peak serum E2 levels without significantly increasing the risk of OHSS. Following the experience of the European approach, we attempted to restore CL function and improve conception rates by administering low-dose adjuvant hCG in women with peak serum E2 <4,000 pg/mL.Shapiro et al. (34Shapiro 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.Fertil Steril. 2008; 90: 231-233Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar) first reported the use of dual GnRHa and low-dose hCG trigger. They administered at trigger a combination of 4 mg leuprolide acetate and hCG in a dose ranging from 1,000 IU to 2,500 IU depending on body weight and risk of OHSS. They reported a good pregnancy rate, although the study was not controlled and their higher dose of hCG may potentially increase the risk of OHSS.We performed a retrospective study with the use of a dual trigger of oocyte maturation with 1 mg leuprolide acetate and a fixed dose of 1,000 IU hCG in combination with intensive luteal phase support in patients at risk of OHSS with peak serum E2 levels <4,000 pg/mL. We showed significantly higher implantation (41.9% vs. 22.1%; P<.01) and live birth rates (58.8% vs. 36.8%; P=.03) after dual trigger compared with GnRHa trigger alone (35Griffin DW B.C. Kummer N.E. Elassar A.A. Nulsen J.C. Engmann L.L. Dual trigger of oocyte maturation with gonadotropin releasing hormone agonist (GnRHa) and low dose human chorionic gonadotropin (hCG) to optimize conception rates in high responders.Fertil Steril. 2011; 96: S20Abstract Full Text Full Text PDF Google Scholar). We observed only one case of mild OHSS after dual trigger compared with none after GnRHa alone.In summary, we have found that intensive luteal phase supplementation is effective in maintaining optimal conception rates in patients with peak E2 levels ≥4,000 pg/mL. However, patients with peak E2 levels <4,000 pg/mL may benefit from dual trigger with GnRHa and 1,000 IU hCG to optimize conception rates while still avoiding significant OHSS.It remains unclear, however, if the dual trigger approach is any different than the Humaidan protocol administering a low dose of 1,500 IU hCG on the morning of oocyte retrieval. An earlier study from the same author indicated that the timing of the low-dose hCG administration (12 h vs. 35 h) had a significant effect on pregnancy outcomes (21Humaidan 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.Reprod Biomed Online. 2006; 13: 173-178Abstract Full Text PDF PubMed Scopus (145) Google Scholar). When hCG was given 12 hours after GnRHa triggering, the midluteal P concentration and the pregnancy outcomes were poor. The authors speculated that there might be a refractory period in the early CL during which the granulosa cells are nonresponsive to exogenous stimulation with hCG.It is conceivable that the dual trigger with GnRHa plus low-dose hCG allows for a potential effect of the hCG on oocyte maturation, whereas the low-dose hCG administered at the time of oocyte retrieval can exert its effects only on corpus luteum function and endometrial receptivity. To answer this question, we are currently conducting a double-blinded placebo-controlled RCT (Clinicaltrials.gov NCT01815138) comparing the dual trigger approach versus low-dose hCG at the time of retrieval for high-risk patients with peak E2 levels <4,000 pg/mL. One should caution that although adjuvant low-dose hCG supplementation appears to be associated with good conception rates, it may also result in the development of early or late OHSS, thereby defeating the main purpose for its use (36Bodri D. Low-dose hCG supplementation after GnRH agonist triggering: don’t be too quick on the trigger.Hum Reprod. 2013; 28: 2315-2317Crossref PubMed Scopus (13) Google Scholar, 37Seyhan 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.Hum Reprod. 2013; 28: 2522-2528Crossref PubMed Scopus (113) Google Scholar). For patients with peak E2 levels >4,000 pg/mL, we still advocate triggering only with GnRHa, followed by our intensive luteal support protocol.GnRHa trigger and hCG supplementation (the “European approach”)Following the disappointing reports from the first larger clinical trials with the use of GnRHa trigger for final follicular maturation in combination with standard luteal phase support (16Humaidan P. Bredkjaer H.E. Bungum L. Bungum M. Grondahl M.L. Westergaard L. et al.GnRH agonist (buserelin) or hCG for ovulation induction in GnRH antagonist IVF/ICSI cycles: a prospective randomized study.Hum Reprod. 2005; 20: 1213-1220Crossref PubMed Scopus (371) Google Scholar, 17Kolibianakis E.M. Schultze-Mosgau A. Schroer A. van Steirteghem A. Devroey P. Diedrich K. et al.A lower ongoing pregnancy rate can be expected when GnRH agonist is used for triggering final oocyte maturation instead" @default.
• W2009876282 created "2016-06-24" @default.
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• W2009876282 date "2015-04-01" @default.
• W2009876282 modified "2023-10-13" @default.
• W2009876282 title "Luteal phase supplementation after gonadotropin-releasing hormone agonist trigger in fresh embryo transfer: the American versus European approaches" @default.
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