Letter to the editor |
GnRH agonist (buserelin) or HCG for ovulation induction in GnRH antagonist IVF/ICSI cycles: a prospective randomized study
The Center for Advanced Reproductive Services, Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, University of Connecticut Health Center, Dowling South Building, 263 Farmington Avenue, Farmington, CT 06030-6224, USA
1 To whom correspondence should be addressed. E-mail: engmann{at}gme.uchc.edu
Sir,We read with interest the study by Humaidan et al. (2005)
involving the use of GnRH agonist to trigger the final stages of oocyte maturation and wish to commend the authors for conducting this important trial. Previous studies have suggested that the use of GnRH agonist to trigger oocyte maturation may be effective in preventing the development of ovarian hyperstimulation syndrome (OHSS) (Lewit et al., 1996; Itskovitz-Eldor, 2000). Although the primary objective was not to evaluate its effect on the prevention of OHSS, this study is still important because it validates the effectiveness of using GnRH agonist to achieve oocyte maturation after co-treatment with GnRH antagonist during ovarian stimulation for IVF. Furthermore, results of this study as well other previous studies (Fauser et al., 2002; Nevo et al., 2003) have shown without question that the use of GnRH agonist to trigger oocyte maturation alters the luteal phase steroidogenic profile which may, indeed, adversely affect implantation if the appropriate supplementation is not utilized. If this strategy is to be adopted routinely for the prevention of OHSS during IVF cycles, optimal luteal phase supplementation should be utilized to improve the abnormal luteal phase and to maintain normal implantation rates.
The lower implantation and ongoing pregnancy rates after GnRH agonist trigger reported by Humaidan et al. (2005) may be due to the type and duration of luteal support used in the study. All the patients in the study received luteal phase supplementation with micronized progesterone vaginally, 90 mg a day and estradiol (E2) 4 mg a day per os, commencing from the day following oocyte retrieval and continuing until the day of pregnancy test (day 12 after embryo transfer). In our practice, patients triggered with GnRH agonist therapy receive luteal phase supplementation from the day after oocyte retrieval in the form of three transdermal E2 patches (0.1mg each) replaced every other day and i.m. progesterone 50 mg every day until negative pregnancy test or positive fetal heart on ultrasound at 
7 weeks of gestation. We increase the dose of E2 or progesterone supplementation if the serum E2 level is <200 pg/ml or progesterone level is <20 ng/ml respectively. In our experience, we have not noticed any adverse impact on our implantation rates using this protocol for over a year. In a recent abstract presented at the 53rd Annual Meeting of the Pacific Coast Reproductive Society (Engmann et al., 2005), we retrospectively evaluated the use of this protocol in patients with PCOS and previous high responders compared to a group of patients who received HCG for oocyte maturation. We confirmed the significantly lower luteal phase serum E2 and progesterone profiles, which have also been previously shown by other workers (Fauser et al., 2002; Nevo et al., 2003). However, the implantation rates (46.7 versus 42.7%), clinical pregnancy rates (75 versus 60.9%) and ongoing pregnancy rates (70 versus 56.5%) were similar between patients who were triggered with GnRH agonist or hCG respectively (Engmann et al., 2005).
In view of the overwhelming evidence of abnormal luteal phase steroid profile after GnRH agonist trigger, the authors should clarify certain questions arising from the luteal phase supplementation protocol used in the study.
First, can the authors explain further why they discontinued luteal phase supplementation on the day of pregnancy test? The authors have shown clearly that, even with luteal phase supplementation, both the serum E2 and progesterone levels were lower in the buserelin group compared to the hCG group during the luteal phase. The authors argue that their policy for many years has been to discontinue luteal support 12 days after embryo transfer without any adverse effect on their pregnancy rates. Further, they suggested that such practice is supported by a previous study which showed that prolongation of luteal phase support beyond day 14 after embryo transfer did not influence miscarriage or birth rates (Nyboe Anderson et al., 2002). However, it is important to note that all the patients in the study by Nyboe Anderson et al. (2002) received HCG, not GnRH agonist, for final oocyte maturation. It is clear that the abnormal luteal phase from early luteolysis requires adequate E2 and progesterone supplementation and should probably be continued until the feto-placental unit is fully established. It is also evident from their results that although there were no differences in the pregnancy rates performed at 12 days after embryo transfer, the clinical pregnancy rates were significantly lower in the GnRH agonist trigger group after discontinuation of steroid supplementation. This is due to the higher early pregnancy loss rate in the GnRH agonist trigger arm of the study. With an early pregnancy loss rate of 79% (compared to 4% in the hCG group), it is reasonable to attribute this, partly, to the early discontinuation of E2 and progesterone supplementation. Moreover, a study by Nevo et al. (2003) suggested that the endogenous rise in hCG during early pregnancy may not rescue the early luteolysis that occurs after GnRH agonist trigger. This further supports our suggestion that luteal supplementation should be continued through the early part of the first trimester.
Second, although the optimal route of progesterone administration after pituitary suppression and controlled ovarian stimulation is still debatable (Daya and Gunby, 2004), the daily i.m. route may be preferable when GnRH agonist is used for trigger because of the severe luteal phase abnormalities. Furthermore, the route of E2 supplementation may also be important and it is likely that the use of transdermal E2 patches may be preferable because it avoids the first-pass effect of oral E2.
It is important to resolve these questions especially if GnRH agonist therapy is to be utilized widely in the prevention of OHSS. We are currently conducting a randomized controlled trial evaluating the use of GnRH agonist to trigger oocyte maturation in the prevention of OHSS and using the luteal phase steroid supplementation described above. The findings of this ongoing trial should hopefully shed more light on this important clinical problem.
References
Daya S and Gunby J (2004) Luteal phase support in assisted reproduction cycles. Cochrane Database Syst Rev (3):CD004830.
Engmann L, Hartnett J, Siano L, Schmidt D, Nulsen J, Maier D and Benadiva C (2005) The use of GnRH agonist to trigger final stages of oocyte maturation in patients with polycystic ovarian syndrome (PCOS) and high responders during IVF treatment. Fertil Steril 83(Suppl 1), S26–S27.
Fauser BC, de Jong D, Olivennes F, Wramsby H, Tay C, Itskovitz-Eldor J and van Hooren HG (2002) 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 87,709–715.
Humaidan P, Ejdrup Bredkjaer H, Bungum L, Bungum M, Grondahl ML, Westergaard L and Yding Andersen C (2005) GnRH agonist (buserelin) or hCG for ovulation induction in GnRH antagonist IVF/ICSI cycles: a prospective randomized study. Hum Reprod 20,1213–1220.
Itskovitz-Eldor J, Kol S and Mannaerts B (2000) 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 15, 1965–1968.
Lewit N, Kol S, Manor D and Itskovitz-Eldor J (1996) 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. Hum Reprod 11,1399–1402.
Nevo O, Eldar-Geva T, Kol S and Itskovitz-Eldor J (2003) 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 79,1123–1128.[CrossRef][ISI][Medline]
Nyboe Andersen A, Popovic-Todorovic B, Schmidt KT, Loft A, Lindhard A, Hojgaard A, Ziebe S, Hald F, Hauge B and Toft B (2002) Progesterone supplementation during early gestations after IVF or ICSI has no effect on the delivery rates: a randomized controlled trial. Hum Reprod 17,357–361.
Submitted on May 26, 2005; accepted on June 9, 2005.
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