COMPARISON OF HUMAN CHORIONIC GONADOTROPIN AND GONADOTROPIN RELEASING HORMONE AGONISTS AS OVULATION TRIGGER IN ASSISTED REPRODUCTIVE TECHNOLOGY CYCLES

AN UPDATE
Dr. Prashant Joshi1* Dr. Pratap Kumar2 Abstract Ovulation trigger is being done with both, human chorionic gonadotropin (hCG) and gonadotropin releasing hormone agonists (GnRHa) in recent years. Triggering final oocyte maturation with GnRH agonist during ovarian stimulation is feasible in certain situations. Effectiveness of GnRH agonist as an alternative to hCG in ovulation trigger is reviewed in this article. Keywords: Human Chorionic Gonadotropin, Gonadotropin Releasing Hormone agonists, Ovarian hyper stimulation syndrome suggested negative effect of hCG on endometrial receptivity 9, 10 and embryo quality.11 The introduction of GnRH antagonist protocols for prevention of premature LH surge have made triggering of final oocyte maturation with single bolus of GnRHa an alternative to hCG.12,13 The GnRHa by competitive inhibition displaces GnRH antagonist from GnRH receptor and produce initial flare-up response inducing a midcycle LH and FSH surge, resembling the surge of natural cycle. The serum LH and FSH rise after 4 and 12 hours respectively, and are elevated for 24-36 hours. The amplitude of the surges are similar to those seen in normal menstrual cycle, however the LH surge induced by GnRHa consists of two phases, a short ascending limb (> 4 h) and a long descending limb (> 20 h) with a total duration of 24-36 h, 14 compared to the LH surge of the natural cycle which consists of three phases of 48 h.15 Hence, it seems to be more likely that GnRHa induces a luteal phase defect due to the short half life of the induced LH surge.16,17 GnRHa triggering of final oocyte maturation could possess several potential advantages over hCG triggering firstly in terms of a reduced if not eliminated risk of OHSS due to quick and irreversible luteolysis.18 Second, a more physiologic mid cycle gonadotropin surge may result in retrieval of more mature oocytes.19 The role of midcycle LH surge in oocyte maturation, luteinization of the granulosa theca cells and follicle rupture is well established. However, it is not well known whether the concurrent midcycle FSH surge plays any physiologic role in these periovulatory events in humans. In rats, role for FSH in the maturation of oocyte-cumulus complex has been demonstrated.20 Thirdly, a potential advantage for the use of GnRHa instead of hCG for ovulation induction is due to the short (24-36 hours) duration of the LH surge induced by

Introduction Until recently, hCG was the only effective therapy available for the induction of oocyte maturation and ovulation in stimulated cycles. The hCG is used as a substitute for the midcycle luteinizing hormone (LH) surge to trigger ovulation, due to structural and biological similarities between the two hormones. The hCG binds to and activates the same receptors as LH.1 The advantages of hCG administration are to obtain effective final oocyte maturation, as well as to provide better luteal phase support by stimulating corpus luteum. Moreover, hCG seems to be capable of positively affecting uterine receptivity by enhancing endometrial quality and stromal fibroblast function. In particular hCG may improve intrauterine environment and extend implantation window, thus increasing pregnancy rates through its action on insulin like growth factor binding protein-1 (IGFBP-1) and vascular endothelial growth factor (VEGF). 2,3,4 Despite this fact, the use of hCG for ovulation trigger as a surrogate for LH has got several drawbacks. First and foremost, a sustained luteotropic effect (because of its longer half life>24 hr versus 60 min for LH), resulting in development of multiple corpora lutea (CL) and supra physiological levels of estradiol and progesterone. This sustained luteotrophic effect may result in the development of ovarian hyper stimulation syndrome (OHSS), which is still the most frequent and severe complication of ovarian stimulation treatments.5 The threat of OHSS often leads to cycle cancellations. There is also, absence of normal follicular stimulating hormone (FSH) surge. The mid cycle FSH is thought to induce LH receptor formation in the luteinising granulosa cells thus optimising corpus luteal functions, promote nuclear maturation and cumulus expansion.6, 7, 8 Some studies have also
*

Corresponding Address : Dr Prashant Joshi, Associate Professor, Dept of Obstetrics & Gynaecology, Adichunchanagiri Institute of Medical Sciences, BG Nagara, Karnataka 2 Professor, Dept of Obstetrics & Gynaecology, Kasturba Medical College, Manipal University, Manipal, Karnataka
1*

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GnRHa, which provides a more physiologic ovulatory stimulus than the extended surge (approximately 6 days) associated with hCG. This time- limited stimulus can be restricted to the few follicles that are more mature, and thus a lower frequency of multiple pregnancies could be expected in patients undergoing ovarian stimulation for the purpose of ovulation induction. This GnRHa-induced LH surge is associated with lower luteal estradiol (E2) and progesterone (P) than that seen after hCG injection. Review A recent cochrane review 21 reviewed data from eleven randomized controlled trials (RCTs) upto October 2009. This involved 1055 women and had an objective of comparing the effectiveness of a GnRH agonist with hCG for triggering final oocyte maturation in ART patients. All these women had controlled ovarian hyper stimulation with a GnRH antagonist protocol followed by embryo transfer. When GnRHa was used as ovulation trigger the dose used was triptorelin 0.2 mg sc or buserelin 0.5 mg sc or leuprorelin 0.5 mg sc. Different regimens used for luteal phase support were IM or vaginally administered progesterone and hCG. The primary outcome measured were live birth rate and development of OHSS per woman randomized. Main results were identified from the 11 RCTs (n = 1055). Eight studies assessed fresh autologous cycles and three studies assessed donor-recipient cycles. In fresh-autologous cycles, GnRH agonist was less effective than hCG in terms of the live birth rate per randomized woman (OR 0.44, 95% CI 0.29 to 0.68; 4 RCTs) and ongoing pregnancy rate per randomized woman (OR 0.45, 95% CI 0.31 to 0.65; 8 RCTs). For a group with a 30% live birth or ongoing pregnancy rate using hCG, the rate would be between 12% and 22% using an GnRH agonist. Moderate to severe OHSS incidence per randomized woman was significantly lower in the GnRH agonist group compared to the hCG group (OR 0.10, 95% CI 0.01 to 0.82; 5 RCTs). The OHSS incidence was 3% using hCG and with GnRH agonist it was between 0% and 2.6%. In donor recipient cycles, there was no evidence of a statistical difference in the live birth rate per randomized woman (OR 0.92, 95% CI 0.53 to 1.61; 1 RCT). The authors concluded that GnRH agonists should not be routinely used as a final oocyte maturation trigger in fresh autologous cycles because of lowered live birth rates and ongoing pregnancy rates. An exception could be made for women with high risk of OHSS, after appropriate counseling. The lowered reproductive outcome following GnRHa triggering could be attributed to the luteal phase insufficiency. A new study published after the Cochrane review has shown a novel approach to luteal phase support after GnRHa trigger by

using a total of two boluses of 1500 IU hCG; on the day of oocyte retrieval and 4 days later. Neither progesterone nor estradiol was administered for luteal support. These preliminary results suggest that two boluses of 1500 IU hCG revert the luteolysis after a GnRHa trigger in the normoresponder patient. Importantly, no additional luteal support is needed. The novel concept combines the potential advantages of a physiological dual trigger (LH and FSH) with a simple, patient friendly, luteal support.22 If the results are corroborated in a larger series of normo-responder patients, this protocol could lead to a paradigm shift in luteal support policy. Radesic et al23 conducted a retrospective study including 71 women at high risk of severe OHSS and who received an agonist trigger for final oocyte maturation. All the patients were given 1500 IU of hCG within an hour of the oocyte retrival. The transfer of a solitary embryo produced a biochemical pregnancy rate of 60.6% and a clinical ongoing pregnancy rate of 52.1%. Only one patient was hospitalised with severe OHSS (1.4%), despite average patient producing nearly 17 oocytes per cycle. The authors concluded that oocyte maturation employing GnRH agonist trigger in combination with low-dose hCG luteal phase support produces excellent clinical pregnancy rates, while not compromising the ability of GnRH agonist trigger to prevent severe OHSS. Another way of providing luteal phase support after GnRHa triggering could theoretically be repeated doses of recombinant LH (rLH). The advantage of rLH over hCG is the significantly shorter half-life, which could further reduce the risk of OHSS. To explore this concept, a pilot study was performed by Papanikolaou et al. 24 Ovarian stimulation was performed using a fixed dose of 187.5 IU FSH starting on cycle day 2, in a fixed stimulation day 6 GnRH antagonist protocol in a total of 35 IVF/ICSI patients. Ovulation triggering was performed with 0.2 mg triptorelin administered as soon as three follicles of 17 mm were present. Six alternate doses of 300 IU rLH were administered starting on the day of ovum pick up (OPU) and repeated on days OPU + 2, OPU + 4, OPU + 6, OPU + 8 and OPU + 10 - in addition to vaginally administered micronized progesterone (600 mg daily). The control group (n =17), consisted of patients undergoing the same stimulation protocol, having hCG to trigger ovulation. A comparable number of oocytes (13.8 versus 11.7) and embryos (8.3 versus 7.9) were seen in the GnRHa and hCG group, respectively. All patients underwent elective single blastocyst transfer, resulting in a non-significant difference in delivery rate in the rLH group versus the hCG group [22.20% (n =4/18) versus 23.5% (n = 4/17) P = 0.91, respectively]. No OHSS case was recorded in either group, but a larger sample size is necessary to draw conclusions regarding the efficacy and dose of rLH for luteal support after GnRHa triggering.

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Discussion Although described 20 years ago, it was not until GnRH antagonist protocols were introduced for the prevention of a premature LH surge that GnRHa triggering of final oocyte maturation became an option again as an alternative to hCG triggering. Despite the fact that hCG effectively secures final oocyte maturation and ovulation, its use as a surrogate for LH has got several drawbacks like OHSS. In contrast, GnRHa is as effective as hCG for the induction of ovulation with fewer incidences of OHSS. Apart from an endogenous LH surge, an FSH surge is also elicited, similar to the natural mid-cycle surge of gonadotropins which may have a good impact on ovulation. Youssef et al 21 comparing GnRHa versus hCG for triggering of final oocyte maturation in the Cochrane review concluded that GnRH agonists for a final oocyte maturation trigger in fresh autologous cycles should not be routinely used due to the associated significantly lower live birth rate, on going pregnancy rate (pregnancy beyond 12 weeks). Furthermore, in the conclusion of 'Implications for research', it states: 'In view of the poor reproductive outcomes following oocyte triggering with GnRH agonist we believe there is no indication for further research with GnRH agonists for oocyte triggering in ART in fresh autologous cycles'. Thus, prospective randomized studies reported a poor clinical outcome when GnRHa was used to trigger final oocyte maturation in IVF/ICSI GnRH antagonist protocols, presumably due to a luteal phase deficiency, despite standard luteal phase supplementation with progesterone and estradiol. As GnRHa triggering of final oocyte maturation could possess advantages over hCG triggering not only in terms of a reduced if not eliminated risk of OHSS, but also the retrieval of more mature oocytes, and a higher patient convenience, the challenge has been to rescue the luteal phase. Kol et al 22 report a luteal phase rescue with two doses of 1500 IU of hCG with a reproductive outcome comparable to that of hCG induced final oocyte maturation. Thus, although more research is needed to further explore the optimal luteal phase support after GnRHa triggering, this mode of triggering is now a valid alternative with potential benefits. The lower pregnancy rates with GnRH agonist triggering when compared to hCG triggering is definitely not due to the lower quality of oocytes or embryos. In high-risk IVF patients for OHSS, a favorable clinical outcome is observed after elective cryopreservation of zygotes or embryos post GnRH agonist triggering suggesting that oocyte development potential and embryo quality is unaffected by GnRH agonist triggering. 25,26 Conclusion In summary, present evidence suggests that agonist trigger is lesser effective than hCG in ovulation trigger because of luteal phase insufficiency due to early luteolysis. Aggressive luteal
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phase support is necessary if agonist is used. Agonist trigger can be utilized to reliably and completely prevent OHSS. References 1. Huirne JA et al. Contemporary pharmacological manipulation in assisted reproduction. Drugs. 2004;64(3):297-322. 2. Drakakis P et al. Small doses of LH activity are needed early in ovarian stimulation for better quality oocytes in IVF-ET. Eur J Obstet Gynecol Reprod Biol. 2005 Jul 1;121(1):77-80. 3. Filicori M et al. Novel concepts of human chorionic gonadotropin: reproductive system interactions and potential in the management of infertility. Fertil Steril. 2005 Aug;84(2):275-84. 4. Fleming R, Lloyd F, Herbert M, Fenwick J, Griffiths T, Murdoch A. Effects of profound suppression of luteinizing hormone during ovarian stimulation on follicular activity, oocyte and embryo function in cycles stimulated with purified follicle stimulating hormone. Hum Reprod. 1998 Jul;13(7):1788-92. 5. Golan A, Ron-el R, Herman A, Soffer Y, Weinraub Z, Caspi E. Ovarian hyperstimulation syndrome: an update review. Obstet Gynecol Surv. 1989 Jun;44(6):430-40. 6. Strickland S, Beers WH. Studies on the role of plasminogen activator in ovulation. In vitro response of granulosa cells to gonadotropins, cyclic nucleotides, and prostaglandins. J Biol Chem. 1976 Sep 25;251(18):5694-702. 7. Zelinski-Wooten MB, Hutchison JS, Hess DL, Wolf DP, Stouffer RL. Follicle stimulating hormone alone supports follicle growth and oocyte development in gonadotrophinreleasing hormone antagonist-treated monkeys. Hum Reprod. 1995 Jul;10(7):1658-66. 8. Yding Andersen C, Leonardsen L, Ulloa-Aguirre A, BarriosDe-Tomasi J, Moore L, Byskov AG. FSH-induced resumption of meiosis in mouse oocytes: effect of different isoforms. Mol Hum Reprod. 1999 Aug;5(8):726-31. 9. Simn C et al. Increasing uterine receptivity by decreasing estradiol levels during the preimplantation period in high responders with the use of a follicle-stimulating hormone step-down regimen. Fertil Steril. 1998 Aug;70(2):234-9. 10. Forman R, Fries N, Testart J, Belaisch-Allart J, Hazout A, Frydman R. Evidence for an adverse effect of elevated serum estradiol concentrations on embryo implantation. Fertil Steril. 1988 Jan;49(1):118-22. 11. Valbuena D, Martin J, de Pablo JL, Remoh J, Pellicer A, Simn C. Increasing levels of estradiol are deleterious to embryonic implantation because they directly affect the embryo. Fertil Steril. 2001 Nov;76(5):962-8. 12. Albano C, Smitz J, Camus M, Riethmller-Winzen H, Van

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20. Moor R.M, Osborn J.C, Cran O.G, Walter DE. Selective effect of gonadotrophins on cell coupling, nuclear maturation oocytes. J Embryol Exp Morphol 1981;61: 34765. 21. Youssef MA et al. Gonadotropin-releasing hormone agonist versus HCG for oocyte triggering in antagonist assisted reproductive technology cycles. Cochrane Database Syst Rev. 2010 Nov 10;(11):CD008046. 22. Kol S et al. GnRH agonist ovulation trigger and hCG-based, progesterone-free luteal support: a proof of concept study. Hum Reprod. 2011 Oct;26(10):2874-7. 23. Radesic B et al. 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. Hum Reprod. 2011 Dec;26(12):3437-42. 24. Papanikolaou EG et al. 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. Fertil Steril. 2011 Mar 1;95(3):1174-7. 25. Griesinger G et al. Mid-cycle serum levels of endogenous LH are not associated with the likelihood of pregnancy in artificial frozen-thawed embryo transfer cycles without pituitary suppression. Hum Reprod. 2007 Oct;22(10):2589-93. 26. Griesinger G et al. Triggering of final oocyte maturation with gonadotropin-releasing hormone agonist or human chorionic gonadotropin. Live birth after frozen-thawed embryo replacement cycles. Fertil Steril. 2007 Sep;88(3):616-21.