Gonadotropin releasing hormone agonist triggering of final follicular maturation for in vitro fertilization

These Views and Reviews articles examine the advantages and disadvantages of gonadotropin releasing hormone (GnRH) agonist for triggering the final stage of follicular maturation in in vitro fertilization (IVF).

Robert F. Casper, M.D

Volume 103, Issue 4, Pages 865-866


These Views and Reviews articles examine the use of GnRH agonist for triggering the final stage of follicular maturation in IVF, resulting in excellent follicle maturation. An advantage of the GnRH agonist trigger is the ability to retrieve oocytes in high responders, yet markedly reducing the risk of ovarian hyperstimulation syndrome (OHSS). However, the induction of early luteolysis after the GnRH agonist trigger requires the use of aggressive steroidal luteal support or low-dose hCG to allow successful fresh ET and live birth. With the enhanced effectiveness of vitrification, segmentation in GnRH agonist-triggered cycles with freezing all embryos for transfer in subsequent cycles may be the optimal strategy for eliminating OHSS.

  • Gonadotropin-releasing hormone agonist triggering of final follicular
    maturation for in vitro fertilization

    Dear Editor

    We read with interest the views and reviews published in the April issue of Fertility and Sterility. While we completely agree with Professor Casper, that “the four Views and Reviews articles thoroughly cover the conceptual and practical aspects of GnRH agonist triggering for assisted reproduction “(1), we still would like to highlight several points that went unnoticed.

    “Double trigger”
    A modification of the ‘‘Dual trigger”, the so-called ‘‘Double trigger” approach, has been successfully used in a patient with recurrent empty follicle syndrome (2). It was also shown to significantly improve the oocyte yield in patients with low/poor oocytes yield, despite an apparently normal follicular development and E2 levels on the day of hCG administration (3); and the proportions of metaphase-II (MII) oocytes in patients with low proportion of mature oocytes per number oocytes retrieved (4).
    The ‘‘Double trigger”, which consists of the co-administration of GnRH agonist and hCG for final oocyte maturation- 40 and 34 h prior to ovum pick-up (OPU), respectively, differs from the ‘‘Dual trigger’’ by the additional prolongation of the time between ovulation triggering and OPU. This later prolongation, may explain the beneficial effect in terms of both oocytes yield/maturation and pregnancy rate.
    GnRHa trigger and hCG supplementation- deferring the hCG bolus by 3 days
    Prompted by the retrospective study by Seyhan et al (5), that observed a 26% prevalence of severe OHSS in patients receiving the additional bolus of 1500 IU hCG 35 h after the GnRHa trigger despite a safe threshold (≤25 follicles) (6), figure that is comparable with the 20% prevalence of severe OHSS in the ostensibly high risk patients (Detection rate with 80% false positive) (7), we decided to modify our approach (8).
    Patients at risk to develop severe OHSS that were triggered with GnRHa, are instructed to start an intensive luteal support with estradiol and progesterone, the day following OPU, and are re-evaluated 3 days after oocyte retrieval (day of ET) for signs of early moderate OHSS (ultrasonographic signs of ascites as reflected by the appearance of fluid surrounding the uterus/ovaries, and/or Hct levels >40% for the degree of haemoconcentration). Only to those patients with no early signs of OHSS, one embryo is transferred, and the patient is instructed to inject 1500 IU of HCG.
    By deferring the hCG bolus by 3 days (5 days following GnRHa trigger), we are still able to rescue the corpus luteum, with an observed extremely high midluteal progesterone levels (9). Moreover, we are actually offering the hCG to 80% of the a priori at risk patients (the aforementioned- detection rate c’ 80% false positive), who are not supposed to develop severe early OHSS, while avoiding hCG administration to the “real” 20-26% (5,7) patient at risk to develop severe early-OHSS.

    Professor Raoul Orvieto MD, MMSc.
    Director, Infertility and IVF Unit, Department of Obstetrics and Gynecology, Sheba Medical Center, Ramat Gan,and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. E-mail : raoul.orvieto@sheba.health.gov.il

    1. Casper RF. Introduction: Gonadotropin-releasing hormone agonist triggering of final follicular maturation for in vitro fertilization. Fertil Steril 2015;103:865–6.
    2. Beck-Fruchter R, Weiss A, Lavee M, Geslevich Y, Shalev E. Empty follicle syndrome: successful treatment in a recurrent case and review of the literature. Hum Reprod 2012;27:1357–67.
    3. Haas J, Zilberberg E, Dar S, Kedem A, Machtinger R, Orvieto R. Co-administration of GnRH agonist and hCG for final oocyte maturation (double trigger) in patients with low number of oocytes retrieved per number of preovulatory follicles – a preliminary report. J Ovarian Res 2014;7:77.
    4. Zilberberg E, Haas J, Dar S, Kedem A, Machtinger R, Orvieto R. Co- administration of GnRH-agonist and hCG for final oocyte maturation in patients with low proportion of mature oocytes. Gyn Endocrinol 2015;31(2):145-7.
    5. Seyhan A, Ata B, Polat M, Son WY, Yarali H, Dahan M. Severe early ovarian hyperstimulation syndrome following GnRH agonist trigger with the
    addition of 1500 IU hCG. Hum Reprod 2013;28(9):2522–2528.
    6. Humaidan P, Engmann E, Benadiva C. Luteal phase supplementation after gonadotropin-releasing hormone agonist trigger in fresh embryo transfer: the American versus European approaches. Fertil Steril 2015;103:879–885
    7. Orvieto R, Ben-Rafael Z. Role of intravenous albumin in the prevention of
    severe ovarian hyperstimulation syndrome. Hum Reprod 1998;13:3306–3309.
    8. Orvieto R. Ovarian hyperstimulation syndrome – an optimal
    solution for an unresolved enigma. J Ovarian Res 2013;6:77.
    9. Haas J, Kedem A, Machtinger R, Dar S, Hourvitz A, Yerushalmi G, Orvieto R. HCG (1500IU) administration on day 3 after oocytes retrieval, following GnRH-agonist trigger for final follicular maturation, results in high sufficient mid luteal progesterone levels – a proof of concept. Journal of Ovarian Research 2014 7:35.

    • Robert Casper

      Hi Professor Orvieto,

      Thanks for your comment and the description of the double trigger in contrast to the dual trigger. I really like your idea of assessing for signs of early OHSS before adding the 1500 IU of hCG for luteal support following a GnRH agonist trigger and thereby allowing an embryo transfer to occur. This concept could really change practice if it holds up in a large series.

      Best regards,


      • Gentlemen–thanks for this amazing discussion– this is why we have the forum to expand upon the papers and share insight.

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