Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Journal of Assisted Reproduction and Genetics
Published in: Journal of Assisted Reproduction and Genetics 11/2017

01-11-2017 | Assisted Reproduction Technologies

GnRH antagonist administered twice the day before hCG trigger combined with a step-down protocol may prevent OHSS in IVF/ICSI antagonist cycles at risk for OHSS without affecting the reproductive outcomes: a prospective randomized control trial

Authors: Yannis Prapas, Konstantinos Ravanos, Stamatios Petousis, Yannis Panagiotidis, Achilleas Papatheodorou, Chrysoula Margioula-Siarkou, Assunta Iuliano, Giuseppe Gullo, Nikos Prapas

Published in: Journal of Assisted Reproduction and Genetics | Issue 11/2017

Login to get access

Abstract

Purpose

The purpose this study is to investigate whether a double antagonist dose (0.25 mg/12 h) administered the day before hCG trigger is effective in preventing ovarian hyperstimulation syndrome (OHSS) in GnRH antagonist IVF/intracytoplasmic sperm injection (ICSI) cycles at risk for OHSS.

Methods

This is a prospective randomized control study, conducted from November 2012 to January 2016. A total of 194 patients undergoing a IVF/ICSI GnRH antagonist cycle that were at risk of OHSS and chose to proceed with embryo transfer and avoid cycle cancellation or embryo cryopreservation were allocated into two groups. The inclusion criteria consisted of a rapid rise of oestradiol ≥ 3500 pg/ml combined with ≥ 18 follicles > 11 mm in diameter without any mature follicle > 16 mm, in any day of stimulation. Overall, 97 patients (intervention group A) received a double dose of GnRH antagonist (0.25 mg/12 h) the day before hCG while 97 patients (control group B) did not. Recombinant FSH administration was tapered to 100 IU/24 h the day of the allocation in both groups.

Results

Incidence of early-onset moderate/severe OHSS was significantly lower in intervention group A compared to control group B (0 vs 12.37%, P < 0.001). Clinical pregnancy rate per cycle (50.52 vs 42.27%, P = 0.249) was not significantly different between the two groups. Oestradiol (3263.471 ± 1271.53 vs 5233 ± 1425.17, P < 0.001), progesterone (0.93 ± 0.12 vs 1.29 ± 0.14, P < 0.001) and luteinizing hormone (1.42 ± 0.31 vs 1.91 ± 0.33, P < 0.001) were significantly lower in group A the day of the hCG triggering.

Conclusion

The administration of a rescue double GnRH antagonist dose the day before hCG trigger may represent a safe alternative preventive strategy for early OHSS without affecting the reproductive outcomes.

Trial registration number

ISRCTN02750360
Literature
1.
Al-Inany HG, Abou-Setta AM, Aboulghar M. Gonadotrophin-releasing hormone antagonists for assisted conception: a Cochrane review. Reprod BioMed Online. 2007;14:640–9.CrossRefPubMed
2.
Griesinger G, Diedrich K, Tarlatzis BC, Kolibianakis EM. GnRH-antagonists in ovarian stimulation for IVF in patients with poor response to gonadotrophins, polycystic ovary syndrome, and risk of ovarian hyperstimulation: a meta-analysis. Reprod BioMed Online. 2006;13:628–38.CrossRefPubMed
3.
Pundir J, Sunkara SK, El-Toukhy T, Khalaf Y. Meta-analysis of GnRH antagonist protocols: do they reduce the risk of OHSS in PCOS? Reprod BioMed Online. 2012;24:6–22.CrossRefPubMed
4.
Mathur R, Hayman G, Bansal A, Jenkins J. Serum vascular endothelial growth factor levels are poorly predictive of subsequent ovarian hyperstimulation syndrome in highly responsive women undergoing assisted conception. Fertil Steril. 2002;78:1154–8.CrossRefPubMed
5.
Papanikolaou EG, Pozzobon C, Kolibianakis EM, et al. Incidence and prediction of ovarian hyperstimulation syndrome in women undergoing gonadotropin-releasing hormone antagonist in vitro fertilization cycles. Fertil Steril. 2006;85:112–20.CrossRefPubMed
6.
Papanikolaou EG, Humaidan P, Polyzos NP, Tarlatzis B. Identification of the high-risk patient for ovarian hyperstimulation syndrome. Semin Reprod Med. 2010;28:458–62.CrossRefPubMed
7.
Kol S, Humaidan P. GnRH agonist triggering: recent developments. Reprod BioMed Online. 2013;26:226–30.CrossRefPubMed
8.
Mansour RT, Aboulghar MA, Serour GI, Amin YM, Abou-Setta AM. Criteria of a successful coasting protocol for the prevention of severe ovarian hyperstimulation syndrome. Hum Reprod. 2005;20:3167–72.CrossRefPubMed
9.
García-Velasco JA, Isaza V, Quea G, Pellicer A. Coasting for the prevention of ovarian hyperstimulation syndrome: much ado about nothing? Fertil Steril. 2006;85:547–54.CrossRefPubMed
10.
Engmann L, Benadiva C. Agonist trigger: what is the best approach? Agonist trigger with aggressive luteal support. Fertil Steril. 2012;97:531–3.CrossRefPubMed
11.
Yu B, Ruman J, Christman G. The role of peripheral gonadotropin-releasing hormone receptors in female reproduction. Fertil Steril. 2011;95:465–73.CrossRefPubMed
12.
Cheng CK, Yeung CM, Chow BK, Leung PC. Characterization of a new upstream GnRH receptor promoter in human ovarian granulosa-luteal cells. Mol Endocrinol. 2002;16:1552–64.CrossRefPubMed
13.
Engel JB, Riethmüller-Winzen H, Diedrich K. Extrapituitary effects of GnRH antagonists in assisted reproduction: a review. Reprod BioMed Online. 2005;10:230–4.CrossRefPubMed
14.
Humaidan P, Kol S, Papanikolaou EG, Copenhagen GnRH Agonist Triggering Workshop Group. GnRH agonist for triggering of final oocyte maturation: time for a change of practice? Hum Reprod Update. 2011;17:510–24.CrossRefPubMed
15.
Asimakopoulos B, Nikolettos N, Nehls B, Diedrich K, Al-Hasani S, Metzen E. Gonadotropin-releasing hormone antagonists do not influence the secretion of steroid hormones but affect the secretion of vascular endothelial growth factor from human granulosa luteinized cell cultures. Fertil Steril. 2006;86:636–41.CrossRefPubMed
16.
Prapas Y, Panagiotidis I, Kalogiannidis I, et al. Double GnRH-antagonist dose before HCG administration may prevent OHSS in oocyte-donor cycles: a pilot study. Reprod BioMed Online. 2010;21:159–65.CrossRefPubMed
17.
Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome. Fertil Steril 2004;81:19-25.
18.
Lainas GT, Kolibianakis EM, Sfontouris IA et al. Pregnancy and neonatal outcomes following luteal GnRH antagonist administration in patients with severe early OHSS. Hum Reprod 2013;28:1929-42
19.
Lainas TG,  Sfontouris IA, Zorzovilis IZ et al.  Management of severe OHSS using GnRH antagonist and blastocyst cryopreservation in PCOS patients treated with long protocol. Reprod Biomed Online. 2009b;18(1):15-20.
20.
Grossman LC, Michalakis KG, Browne H, Payson MD, Segars JH. The pathophysiology of ovarian hyperstimulation syndrome: an unrecognized compartment syndrome. Fertil Steril. 2010;94:1392-8.
21.
Golan A, Ron-el R, Herman A, Soffer Y, Weinraub Z, Caspi E. Ovarian hyperstimulation syndrome: an update review. Obstet Gynecol Surv. 1989;44(6):430-40. 
22.
Lainas TG, Sfontouris IA, Zorzovilis IZ, Petsas GK, Lainas GT, Kolibianakis EM. Management of severe early ovarian hyperstimulation syndrome by re-initiation of GnRH antagonist. Reprod Biomed Online. 2007;15:408-12.
23.
Griesinger G, Berndt H, Schultz L, Depenbusch M, Schultze-Mosgau A. Cumulative live birth rates after GnRH-agonist triggering of final oocyte maturation in patients at risk of OHSS: a prospective, clinical cohort study. Eur J Obstet Gynecol Reprod Biol. 2010;149:190–4.
24.
Gardner DK, Lane M, Stevens J, Schlenker T, Schoolcraft WB. Blastocyst score affects implantation and pregnancy outcome: towards a single blastocyst transfer. Fertil Steril. 2000;73(6):1155-8. 
25.
Griesinger G, Berndt H, Schultz L, Depenbusch M, Schultze-Mosgau A. Cumulative live birth rates after GnRH-agonist triggering of final oocyte maturation in patients at risk of OHSS: a prospective, clinical cohort study. Eur J Obstet Gynecol Reprod Biol. 2010;149:190-4.
26.
Kolibianakis EM, Venetis CA, Bontis J, Tarlatzis BC. Significantly lower pregnancy rates in the presence of progesterone elevation in patients treated with GnRH antagonists and gonadotrophins: a systematic review and meta-analysis. Curr Pharm Biotechnol. 2012;13:464-70.
27.
Manzanares MA, Gómez-Palomares JL, Ricciarelli E, Hernández ER. Triggering ovulation with gonadotropin-releasing hormone agonist in in vitro fertilization patients with polycystic ovaries does not cause ovarian hyperstimulation syndrome despite very high estradiol levels. Fertil Steril. 2010;93:1215-9.
28.
Gustofson RL, Segars JH, Larsen FW. Ganirelix acetate causes a rapid reduction in estadiol levels without adversely affecting oocyte maturation in women pretreated with leuprolide acetate who are at risk of ovarian hyperstimulation syndrome. Hum Reprod. 2006;21:2830-7.
29.
Aboulghar MA, Mansour RT, Amin YM, Al-Inany HG, Aboulghar MM, Serour GI. A prospective randomized study comparing coasting with GnRH antagonist administration in patients at risk for severe OHSS. Reprod Biomed Online. 2007;15:271-9.
30.
Hill MJ, Chason RJ, Payson MD, Segars JH, Csokmay JM. GnRH antagonist rescue in high responders at risk for OHSS results in excellent assisted reproduction outcomes. Reprod Biomed Online. 2012;25:284-91.
31.
Minaretzis D, Jakubowski M, Mortola JF, Pavlou SN. Gonadotropin-releasing hormone receptor gene expression in human ovary and granulosa-lutein cells. J Clin Endocrinol Metab. 1995;80(2):430-4.
32.
Hillensjö T, LeMaire WJ. Gonadotropin releasing hormone agonists stimulate meiotic maturation of follicle-enclosed rat oocytes in vitro. Nature. 1980;287(5778):145-6.
33.
Singh P, Krishna A. Effects of GnRH agonist treatment on steroidogenesis and folliculogenesis in the ovary of cyclic mice. J Ovarian Res. 2010;3:26.
34.
Singh P, Krishna A. Effects of GnRH agonist treatment on steroidogenesis and folliculogenesis in the ovary of cyclic mice. J Ovarian Res. 201;3:26.
35.
Bonilla-Musoles FM, Raga F, Castillo JC, Sanz M, Dolz M, Osborne N. High doses of GnRH antagonists are efficient in the management of severe ovarian hyperstimulation syndrome. Clin Exp Obstet Gynecol. 2009;36(2):78-81.
36.
Ding LJ, Wang B, Shen XY et al. Withdrawal of GnRH agonist decreases oestradiol and VEGF concentrations in high responders. Reprod Biomed Online. 2013;27:131-9.
37.
Aboulghar MA. Prediction of ovarian stimulation syndrome (OHSS). Estradiol levels has an important role in the prediction of OHSS. Hum Reprod. 2003;18:1140-1.
38.
Centurione L, Giampietro F, Sancilio S et al. Morphometric and ultrastructural analysis of human granulosa cells after gonadotrophin-releasing hormone agonist or antagonist. Reprod Biomed Online. 2010;20:625-33.
39.
Khalaf M, Mittre H, Levallet J et al. GnRH agonist and GnRH antagonist protocols in ovarian stimulation: differential regulation pathway of aromatase expression in human granulosa cells. Reprod Biomed Online. 2010;21:56-65.
40.
Lindheim SR, Morales AJ. GnRH antagonists followed by a decline in serum estradiol results in adverse outcomes in donor oocyte cycles. Hum Reprod. 2003;10:2048-2051.
41.
Fisher S, Grin A, Paltoo A et al. Falling estradiol levels as a result of intentional reduction in gonadotrophin dose are not associated with poor IVF outcomes, whereas spontaneously falling estradiol levels result in low clinical pregnancy rates. Hum Reprod. 2005;20:84-8.
42.
Abdalla H, Nicopoulos JD. The effect of duration of coasting and estradiol drop on the outcome of assisted reproduction: 13 years of experience in 1068 coasted cycles to prevent ovarian hyperstimulation. Fertil Steril. 2010;94:1757-63.
43.
Dovey S, McIntyre K, Jacobson D, Catov J, Wakim A. Is a premature rise in luteinizing hormone in the absence of increased progesterone levels detrimental to pregnancy outcome in GnRH antagonist in vitro fertilization cycles. Fertil Steril. 2011;96:585-589.
44.
Doody KJ, Devroey P, Leader A, Witjes H, Mannaerts BM. No association between endogenous LH and pregnancy in a GnRH antagonist protocol: part I, corifollitropin alfa. Reprod Biomed Online. 2011;23:449-456.
45.
Griesinger G, Schultz L, Bauer T et al. Ovarian hyperstimulation syndrome prevention by gonadotropin-releasing hormone agonist triggering of final oocyte maturation in a gonadotropin-releasing hormone antagonist protocol in combination with a "freeze-all" strategy: a prospective multicentric study. Fertil Steril. 2011;95:2029-33.
46.
de Ziegler D. Hormonal control of endometrial receptivity. Hum Reprod. 1995;10:4-7.
47.
The Ganirelix Dose-Finding Study Group. A double-blind, randomized, does-finding study to assess the efficacy of the gonadotropin-releasing hormone antagonist ganirelix (Org 37462) to prevent premature luteinization hormone surges in women undergoing ovarian stimulation with recombinant follicle stimulating hormone. Hum Reprod. 1998;13:3023-3031.
48.
.Fauser BC, Devroey P. 2005 Why is the clinical acceptance of gonadotrophin-releasing hormone antagonist co-treatment during ovarian hyperstimulation for in vitro fertilization so slow? Fertil Steril. 2005;83:1607-11.
49.
Hernandez ER. Embryo implantation: the Rubicon for GnRH antagonists. Hum Reprod. 2000;15:211-1216.
50.
Huirne JAF. Dose-finding study of daily GnRH antagonist for the prevention of premature LH surges in IVF/ICSI patients: optimal changes in LH and progesterone for clinical pregnancy. Human Reproduction. 2004;20(2):359-367.
Metadata
Title
GnRH antagonist administered twice the day before hCG trigger combined with a step-down protocol may prevent OHSS in IVF/ICSI antagonist cycles at risk for OHSS without affecting the reproductive outcomes: a prospective randomized control trial
Authors
Yannis Prapas
Konstantinos Ravanos
Stamatios Petousis
Yannis Panagiotidis
Achilleas Papatheodorou
Chrysoula Margioula-Siarkou
Assunta Iuliano
Giuseppe Gullo
Nikos Prapas
Publication date
01-11-2017
Publisher
Springer US
Published in
Journal of Assisted Reproduction and Genetics / Issue 11/2017
Print ISSN: 1058-0468
Electronic ISSN: 1573-7330
DOI
https://doi.org/10.1007/s10815-017-1010-7

Other articles of this Issue 11/2017

Journal of Assisted Reproduction and Genetics 11/2017 Go to the issue

Review

Selection of mitochondria in female germline cells: is Balbiani body implicated in this process?

Fertility Preservation

Acute pain crisis in a patient with sickle cell disease undergoing ovarian simulation for fertility preservation prior to curative stem cell transplantation: case report and literature review

Fertility Preservation

Subcutaneous ovarian tissue transplantation in nonhuman primates: duration of endocrine function and normalcy of subsequent offspring as demonstrated by reproductive competence, oocyte production, and telomere length

Reproductive Physiology and Disease

The relationship between fat and progesterone, estradiol, and chorionic gonadotropin levels in Quebec cow’s milk

Fertility Preservation

Fertility preservation for trans men: frozen-thawed in vitro matured oocytes collected at the time of ovarian tissue processing exhibit normal meiotic spindles

Embryo Biology

Natural selection between day 3 and day 5/6 PGD embryos in couples with reciprocal or Robertsonian translocations