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Table of Contents
ORIGINAL ARTICLE
Year : 2016  |  Volume : 3  |  Issue : 1  |  Page : 46-49

Outcomes of GnRH agonist and GnRH antagonist regimens for IVF in women aged up to 40


GENESIS – Center for Assistance in Human Reproduction, Brasília, Distrito Federal, Brazil

Date of Web Publication5-Jul-2017

Correspondence Address:
Bruno Ramalho de Carvalho
Bruno Ramalho de Carvalho. Genesis - Center for Assistance in Human Reproduction. SHLS 716, Bloco“L”, Salas “L” 328/331, Centro Clínico Sul - Ala Leste. Brasília, Distrito Federal
Brazil
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Source of Support: None, Conflict of Interest: None


DOI: 10.5530/ami.2016.1.11

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  Abstract 


Objective: To compare outcomes among good-prognosis patients undergoing in vitro fertilization and intracytoplasmic sperm injection followed by embryo transfer (IVF/ICSI-ET) in GnRH-agonist (GnRH-a) and GnRH-antagonist (GnRH-ant) regimens.
Methods: Retrospective analysis of 434 IVF/ICSI-ET cycles performed in a private center, in women aged up to 40: GnRH-a (n = 291) and GnRH-ant (n = 143). Pre-gestational, gestational and perinatal outcomes were evaluated. Statistical analysis was performed by unpaired t-test, Mann-Whitney test and Fisher's exact test. Significance was set at p < 0.05.
Results: GnRH-a regimen was associated with higher amounts of total oocytes (10.7 ± 5.7 vs 9.3 ± 5.7, p < 0.001), mature oocytes (8.2 ± 4,5 vs 6.8 ± 4.4, p < 0.001) and good quality embryos transferred (1.7 ± 0.8 vs 1.5 ± 0.9; p < 0.05). Rates of fertilization, embryo implantation and live births were also higher in GnRH-a (72.8%, 27.6% and 48.8%, respectively) compared to GnRH-ant (65.3%, 14.7% and 26.6%, respectively; p < 0.0001). There were no significant differences between rates of preterm delivery or low birth weight, comparing the two groups.
Conclusion: Our results suggest that the long GnRH-a regimen is the one that offers the best reproductive outcomes among in women aged up to 40 undergoing IVF/ICSI-ET.

Keywords: GnRH agonist, GnRH antagonist, IVF, ICSI, Reproductive outcomes


How to cite this article:
de Souza Jordao &V, Nakagawa HM, Estrela FS, de Morais RB, Gomes-Sobrinho DB, de Carvalho BR. Outcomes of GnRH agonist and GnRH antagonist regimens for IVF in women aged up to 40. Acta Med Int 2016;3:46-9

How to cite this URL:
de Souza Jordao &V, Nakagawa HM, Estrela FS, de Morais RB, Gomes-Sobrinho DB, de Carvalho BR. Outcomes of GnRH agonist and GnRH antagonist regimens for IVF in women aged up to 40. Acta Med Int [serial online] 2016 [cited 2017 Sep 20];3:46-9. Available from: http://www.actamedicainternational.com/text.asp?2016/3/1/46/209719






  Introduction Top


In the last two decades, much has been discussed about the results of assisted reproduction protocols using third generation gonadotropin-releasing hormone antagonist analogues (GnRH-ant), compared with those using GnRH agonist analogues (GnRH-a). GnRH-ant promotes immediate blockage of the pituitary without the flare-up effect caused by GnRH-a. Then, GnRH- ant appears to allow a significant reduction in ovarian stimulation time and lower circulating estradiol levels.[1],[2],[3],[4],[5] Moreover, the use of GnRH-ant considerably reduces the risk of moderate or severe ovarian hyperstimulation syndrome.[6]

Despite the important advantages of GnRH-ant over GnRH-a, some studies suggest superiority of GnRH-a over GnRH-ant in relation to the number of mature oocytes retrieved, good quality embryos for transfer and clinical pregnancy rates, even for patients with poor prognosis.[7],[8],[9],[10]

This study compared the results obtained from women considered as good prognosis patients undergoing controlled ovarian stimulation for in vitro fertilization and intracytoplasmic sperm injection followed by embryo transfer (IVF/ICSI-ET), in protocols with GnRH-a and GnRH-ant.


  Materials and Methods Top


Retrospective analysis of 650 IVF/ICSI-ET cycles performed between January 2008 and December 2012, in a private center for assistance in human reproduction. Inclusion criteria were: cycles performed either with long GnRH-a protocol or with GnRH-ant protocol; oocytes were fertilized with sperm from partner in freshly obtained semen; and embryos transferred in the treatment cycle. Exclusion criteria were: intrauterine insemination cycles converted to IVF/ICSI (n = 41) or cycles performing pre-implantation genetic diagnosis (n = 5), women older than 40 years (n = 144) and oocyte donors (n = 26). The final sample consisted of 434 cycles, divided into two groups: GnRH-a (n = 291) and GnRH-ant (n = 143). Pre-gestational, gestational and perinatal outcomes were evaluated, considering statistical significance at p < 0.05.

The Institutional Research Committee approved the study. All patients gave written consent for assisted reproduction technology treatment, and gave oral consent for data confidential use for research. For this study, a specific written informed consent was not considered necessary, since research data were obtained exclusively from patient files.

Statistical analysis was performed by GraphPad Prism software, version 5.00 (GraphPad Software, Inc, 2007)Samples with normal distribution were analyzed by unpaired t-test, and the Mann-Whitney test was used for samples with non-parametric distribution. Fisher's exact test was used to compare pregnancy rates between groups. The level of significance was set at p < 0.05 in all analyses.


  Results Top


No significant differences were observed in patients' average age, duration of ovarian stimulation, endometrium thickness and number of dominant follicles between the groups. Patients in the GnRH-a group presented significantly higher amounts of total oocytes and mature oocytes [Table 1].
Table 1: Characteristics and stimulation results among good prognosis patients undergoing IVF/ICSI in GnRH-agonists (GnRH-a) and GnRH-antagonists (GnRH-ant) regimens

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Fertilization rate, number of good quality embryos transferred, embryo implantation rate and live birth rate were higher for GnRH-a group compared to GnRH-ant. There were no differences between rates of pregnancy loss and, thus, rates of live births were also higher for the former [Table 2].
Table 2: Reproductive outcomes among good prognosis patients undergoing IVF/ICSI in GnRH-agonists (GnRH-a) and GnRH-antagonists (GnRH-ant) regimens

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There were no significant differences of birth weight, gestational age at birth or rates of preterm delivery between the two groups [Table 3].
Table 3: Perinatal outcomes among good prognosis patients undergoing IVF/ICSI in GnRH-agonists (GnRH-a) and GnRH-antagonists (GnRH-ant) regimens

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  Discussion Top


Much has been debated about the results of protocols with GnRH-a and GnRH-ant in stimulated cycles for IVF/ ICSI.[11] Although GnRH-a results appeared to be better than those obtained with GnRH-ant, studies on the topic raised controversial conclusions.[2],[3],[6],[8],[9],[12]

Regarding endometrial thickness and implantation rate, our results are consistent with those presented by Orvieto and colleagues[13] and the meta-analysis of Al-Inany and colleagues,[12] which is supposed to be due to a deleterious effect of the GnRH-ant on the synthesis of endometrial growth factors[14] and the beneficial effect of the GnRH-a over it.[11] Ruan and colleagues[15] demonstrated a greater expression of endometrial receptivity biomarkers in GnRH-a cycles when compared to GnRH-ant cycles.

Another aspect to be considered is related to the fact that the use of GnRH-ant in assisted reproduction cycles is relatively recent in comparison to GnRH-a,[1] which should result in management inexperience by some clinicians. Also, GnRH-ant has been used for a long period as an alternative protocol for poor responders or those patients presenting implantation failure,[11] which should be the cause for poor results both in our sample as in other studies.

In the update of a previous meta-analysis,[6] Al-Inany and colleagues found that cycles using GnRH-ant presented equivalent pregnancy rates when compared to GnRH-a protocols in good prognosis patients. And recent comparative studies have favored the use of GnRH- ant regimens in cycles with hormonal contraceptives pretreatment,[15] modified final follicular maturation,[16] specific criteria for patients selection,[17]s and those conducted by experienced clinicians.[6]

Also contrary to findings of our study, the equivalence between GnRH-a and GnRH-ant in supposed normal responders was also demonstrated in the recent meta- analysis of twenty-three randomized controlled trials, regarding endometrial thickness, ongoing pregnancy rate, live birth rate, miscarriage rate, and cycle cancellation.[18]

In contrast, according to Orvieto,[13] the GnRH-a protocol would be of first choice for good prognosis women, except those with risk of OHSS, in which the choice would be on the antagonist and because of the possibility to trigger ovulation with GnRH-a. Poor responders, as a result of the profound suppression of the pituitary gland caused by GnRH-a, or those with repeated implantation failures should also be appropriate to use GnRH-ant protocols.

The existence of biases related to the retrospective design of this study cannot be excluded and our results may be considered with caution. The results presented in this study contemplated the use of the GnRH-ant protocol since its implementation in our daily practice. Notwithstanding data stratification by year did not result in recent improvements in our success rates, some results may have been caused by the learning curve by our clinicians. Also, there may be differences between results in GnRH-ant fixed and flexible regimens,[19] which were not evaluated in our study, so we prefer not to advocate the use of one or other analogue based only on data from the sample in analysis.

In conclusion, our data suggested superiority of GnRH-a to GnRH-ant regarding the number of mature oocytes, fertilization rates, good quality embryos transferred, and live birth rates, in women aged up to 40. As a matter of fact, controversies are raised in literature and the authors recognize that additional research is needed to confirm such superiority or the equivalence between protocols.


  Acknowledgements Top


The authors acknowledge the contribution of Adelino Amaral Silva, MD, Antônio César Paes Barbosa, MD, and Íris de Oliveira Cabral, BS, at the writing-up process and on debating the results.



 
  References Top

1.
Karten MJ, Hoeger, CA, Hooh WA. The development of safer antagonists: strategy and status. In: Bouchard P, Haour F, Franchimont P, Schatz B, eds). Recent Progress on LH-RH and Gonadal Peptides. Paris: Elsevier; 1990:147–158.  Back to cited text no. 1
    
2.
Ludwig M, Katalinic A, Diedrich K. Use of GnRH antagonists in ovarian stimulation for assisted reproductive technologies compared to the long protocol. Meta-analysis. Arch Gynecol Obstet. 2001;265(4):175–182.  Back to cited text no. 2
    
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Al-Inany H, Aboulghar M. GnRH antagonist for assisted conception: a Cochrane review. Hum Reprod. 2002;17(4):874–885.  Back to cited text no. 3
    
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Gilliam ML. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology. Obstet Gynecol. 2011;118(3):706–707.  Back to cited text no. 4
    
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Huirne JA, Homburg R, Lambalk CB: Are GnRH antagonists comparable to agonists for use in IVF, Hum Reprod. 2007, 22(11):2805–2813.  Back to cited text no. 5
    
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Al-Inany HG, Youssef MA, Aboulghar M, Broekmans F, Sterrenburg M, Smit J, et al. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology. Cochrane Database of Systematic Reviews. 2011;11(5):CD001750.  Back to cited text no. 6
    
7.
Bosch E, Labarta E, Crespo J, Simon C, Remohí J, Jenkins J, et al. Circulating progesterone levels and ongoing pregnancy rates in controlled ovarian stimulation cycles for in vitro fertilization: analysis of over 4000 cycles. Hum Reprod. 2010;25(8):2092–2100.  Back to cited text no. 7
    
8.
Orvieto R, Rabinson J, Meltzer S, Homburg R, Anteby E, Zohav E. GnRH agonist versus GnRH antagonist in ovarian stimulation: is the emperor naked? Clin Exp Obstet Gynecol. 2006;33(4):197– 199.  Back to cited text no. 8
    
9.
Orvieto R, Homburg R, Meltcer S, Rabinson J, Anteby EY, Scharf S. GnRH agonist versus GnRH antagonist in controlled ovarian hyperstimulation: their role in patients with an unfavorable prognosis a priori. Fertil Steril. 2009;91(4 Suppl):1378–1380.  Back to cited text no. 9
    
10.
Murber Á, Fancsovits P, Ledó N, Gilán ZT, Rigó J, Urbancsek J. Impact of GnRH analogues on oocyte/embryo quality and embryo development in in vitro fertilization/intracytoplasmic sperm injection cycles: a case control study. Reprod Biol Endocrinol. 2009;7:103.  Back to cited text no. 10
    
11.
Hernandez ER. Embryo implantation: the Rubicon for GnRH antagonists. Hum Reprod. 2000;15(6):1211–1216.  Back to cited text no. 11
    
12.
Al-Inany HG, Abou-Setta AM, Aboulghar M. Gonadotrophin- releasing hormone antagonists for assisted conception: a Cochrane review. Reprod Biomed Online. 2007;14(5):640–649.  Back to cited text no. 12
    
13.
Orvieto R, Melteer S, Rabinson J, Zohav E, Anteby EY, Nahum R. GnRH agonist versus GnRH antagonist in ovarian stimulation: the role of endometrial receptivity. Fertil Steril. 2008;90(4):1294–1296.  Back to cited text no. 13
    
14.
Orvieto R, Patrizio P. GnRH agonist versus GnRH antagonist in ovarian stimulation: an ongoing debate. Reprod Biomed Online. 2013;26(1):4–8.  Back to cited text no. 14
    
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Griesinger G, Venetis CA, Marx T, Diedrich K, Tarlatzis BC, Kolibianakis EM. Oral contraceptive pill pretreatment in ovarian stimulation with GnRH antagonists for IVF: a systematic review and meta-analysis. Fertil Steril. 2008;90(4):1055–1063.  Back to cited text no. 15
    
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Kosmas IP, Kolibianakis EM, Devroey P. Association of estradiol levels on the day of hCG administration and pregnancy achievement in IVF: a systematic review. Human Reprod. 2004;19(11):2446–2453.  Back to cited text no. 16
    
17.
Sbracia M, Colabianchi J, Giallonardo A,Giannini P, Piscitelli C, Morgia F, Montigiani M, Schimberni M. Cetrorelix protocol versus gonadotropin-releasing hormone analog suppression long protocol for superovulation in intracytoplasmic sperm injection patients older than 40. Fertil Steril. 2009;91(5):1842–1847.  Back to cited text no. 17
    
18.
Xiao JS, Su CM, Zeng XT. Comparisons of GnRH antagonist versus GnRH agonist protocol in supposed normal ovarian responders undergoing IVF: a systematic review and meta-analysis. PLoS One. 2014;9(9):e106854.  Back to cited text no. 18
    
19.
Kolibianakis EM, Albano C, Kahn J, Camus M, Tournaye H, Van Steirteghem AC, Devroey P. Exposure to high levels of luteinizing hormone and estradiol in the early follicular phase of gonadotropin-releasing hormone antagonist cycles is associated with a reduced chance of pregnancy. Fertil Steril. 2003;79(4):873–880.  Back to cited text no. 19
    



 
 
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