Middle East Fertility Society Journal
Volume 16, Issue 4 , Pages 254-256, December 2011

GnRH antagonist for pituitary desensitization in IVF: Is it a time for a change of practice?

Center for Reproductive Medicine, Faculty of Medicine, Cairo University, Egypt

Egyptian International Fertility IVF Center (EIFC-IVF), Cairo, Egypt

Center for Reproductive Medicine, University of Amsterdam, Netherlands

Center for Reproductive Medicine, Faculty of Medicine, Cairo University, Egypt

Egyptian International Fertility IVF Center (EIFC-IVF), Cairo, Egypt

Received 20 October 2011; accepted 1 November 2011.

Article Outline

 

Back to Article Outline

1. Introduction 

Although long GnRH agonist has been the standard and most widely used protocol for pituitary down regulation all over the world in IVF/ICSI treatment cycles for three decades (1), there are many debates about the optimal long GnRH agonist regimen to be used. First, there is no consensus as regards the type of preparation to be used, whether as a daily fixed dose injection, daily injection with decrease to half dose when starting ovarian stimulation or one injection per treatment cycle (2) or use of nasal spray. Second, there is no agreement on the day of initiation of GnRH agonist in the standard long protocol either day 21 mid-luteal or early follicular phases (3). Third, there is no consensus on the proper dealing with ovarian cysts developing under the flare up effect of GnRH agonist in the mid luteal day 21 protocols (4). Fourth, Long GnRH agonist is associated with increased risk of complications such as hypoestrogenic symptoms and the ovarian hyperstimulation syndrome (OHSS) (5). In summary, long GnRH agonist due to its associated side effects, long duration of treatment (up to 8weeks), repeated injections which might increase IVF patients discomfort and drop-out, would not be considered as a patient friendly protocol.

Recently, histamine-release free GnRH antagonists become available in the market. GnRH antagonists quickly, competitively and reversibly bind to GnRH receptors in the pituitary gland, blocking the release of LH and FSH within few hours that facilitate their use at late mid-follicular phase of the IVF cycle when the inhibition of premature LH surge is required. GnRH antagonist can be initiated according to two distinct protocols, fixed protocol which starts on day 6 of controlled ovarian stimulation and a flexible protocol which starts when the diameter of dominant follicles becomes 12–14mm. GnRH antagonists are available either as multiple daily doses or a single dose (6), (7), (8). GnRH antagonist could offer a patient friendly protocol as they do not lead to flare up effect; cyst formation or hypoestrogenic side effects associated with long GnRH agonist protocol. Furthermore, patients do not need to be closely monitored to confirm down regulation. However, to change in practice from long GnRH agonist to GnRH antagonist, safety and efficacy should be considered

Back to Article Outline

2. GnRH antagonist and safety 

Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic and a potentially morbid complication of ovarian stimulation, affecting 1–14% of all IVF/ICSI cycles (9). Preventive interventions have been used to abolish or reduce sever OHSS, including cycle cancelation, coasting (10), intravenous fluids such as hydroxyl ethyl starch (HES) and albumin administration around the time of oocyte retrieval (11). Also, GnRH agonist as an oocyte trigger in GnRH antagonist cycles (12), Dopamine agonist administration at the time of oocyte retrieval and for several days (13), or in vitro oocyte maturation (14) have all been used. Unfortunately, none of these strategies completely prevent sever OHSS.

GnRH antagonist, due to the lower dose of gonadotropin used and the shorter duration of stimulation, could present an ideal and safe preventive intervention for sever OHSS, especially in women with high risk such as those with PCOS. Recently published Cochrane systematic review with meta-analysis including 29 RCTs and involving 5417 women, found that the average OHSS rate in the GnRH agonist group was 6.4% (95% CI: 4.3–9.2), ranging from 0.8% to 38.5%. The OHSS rate in the GnRH antagonist group averaged 2.7% lower (95% CI: 0.9, 4.5; P=0.003). The relative likelihood of OHSS with GnRH antagonist treatment was 50% of that with GnRH agonist treatment (95% CI: 37–66) (Fig. 1). In eight trials involving 783 women with PCOS, the OHSS rate was 10% lower (95% CI: 7–14) with GnRH antagonist. In addition, with GnRH antagonist treatment the chance of cancellation or coasting due to high risk to develop OHSS was only 53% of that of GnRH agonist treatment (95% CI: 36–78) (15). In addition, cycle cancellation due to the risk of high ovarian response was markedly lower in GnRH antagonist protocol which provides another advantage to GnRH antagonist. In summary, GnRH antagonist dramatically reduces OHSS in high risk patients. Therefore, there is a clear benefit of choosing a GnRH antagonist-based protocol.

Back to Article Outline

3. GnRH antagonist and efficacy 

Many previous publications claimed that GnRH antagonist is associated with a lower implantation and pregnancy rates than GnRH agonist (16). Although the difference was not statistically significant, it is raised the concern of clinicians and delayed GnRH antagonist use in the IVF market. Many factors have been supposed to be behind the low pregnancy rate such as the type of GnRH antagonist protocols used; the incidence of LH instability; ideal luteal phase support (17) and OCP pretreatment (18). However, in nine trials involving 1515 women, the average live birth rate with GnRH agonist treatment was 31.5% (95% CI: 24.3–39.7). The live birth rate with GnRH antagonist treatment averaged 1.5% lower (95% CI: 2.9–5.9) (Fig. 2). In 28 RCTs involving 5014 women, the average OPR with GnRH agonist treatment was 29.8% (95% CI: 25.4–34.6) while that with GnRH antagonist treatment averaged 2.0% lower (95% CI: 0.4–4.5) (15). The adaptation of the timing of GnRH administration and the lesser frequency of LH instability associated with fixed protocol plus the improved learning curve over the last 10years might be behind the improvement of pregnancy rates in GnRH antagonist (19), (20).

In conclusion, GnRH antagonist proved its safety by reducing or eliminating the OHSS risk and its efficacy by producing comparable pregnancy rates with GnRH agonist protocols, together with providing higher patient convenience by reducing the treatment burden. Accordingly, these benefits would justify the shift toward GnRH antagonist for pituitary desensitization.

Back to Article Outline

References 

  1. Porter RN, et al. Induction of ovulation for in-vitro fertilisation using buserelin and gonadotropins. Lancet. 1984;2(8414):1284–1285
  2. Albuquerque LE, Saconato H, Maciel MC. Depot versus daily administration of gonadotrophin releasing hormone agonist protocols for pituitary desensitization in assisted reproduction cycles. Cochrane Database Syst Rev. 2005;1:CD002808
  3. Kondaveeti-Gordon U, et al. A randomized prospective study of early follicular or midluteal initiation of long protocol gonadotropin-releasing hormone in an in vitro fertilization program. Fertil Steril. 1996;66(4):582–586
  4. Qublan HS, Amarin Z, Tahat YA, Smadi AZ, Kilani M. Ovarian cyst formation following GnRH agonist administration in IVF cycles: incidence and impact. Hum Reprod. 2006;21(3):640–644
  5. Mancini F, et al. Gonadotrophin-releasing hormone-antagonists vs long agonist in in-vitro fertilization patients with polycystic ovary syndrome: a meta-analysis. Gynecol Endocrinol. 2011;27(3):150–155
  6. Hsieh YY, Chang CC, Tsai HD. Comparisons of different dosages of gonadotropin-releasing hormone (GnRH) antagonist, short-acting form and single, half-dose, long-acting form of GnRH agonist during controlled ovarian hyperstimulation and in vitro fertilization. Taiwan J Obstet Gynecol. 2009;47(1):66–74
  7. Ekerhovd E. Use of GnRH antagonist for in vitro fertilization. Tidsskr Nor Laegeforen. 2011;131(17):1649–1652
  8. Gilliam ML. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology. Obstet Gynecol. 2011;118(3):706–707
  9. Garcia-Velasco JA, Pellicer A. New concepts in the understanding of the ovarian hyperstimulation syndrome. Current opinion in obstetrics & Gynecoogy. 2003;15:251–256
  10. Garcia-Velasco JA, Isaza V, Quea G, Pellicer A. Coasting for the prevention of ovarian hyperstimulation syndrome: much ado about nothing. Fertil Steril. 2006;85:547–554
  11. Youssef MA, Al-Inany HG, Evers JL, Aboulghar M. Intra-venous fluids for the prevention of severe ovarian hyperstimulation Syndrome. Cochrane Database Syst Rev. 2011;16(2):CD001302
  12. Youssef MA, Van der Veen F, Al-Inany HG, Griesinger G, Mochtar MH, Aboulfoutouh I, et al. Gonadotropin-releasing hormone agonist versus HCG for oocyte triggering in antagonist assisted reproductive technology cycles. Cochrane Database Syst Rev. 2011;19(1):CD008046
  13. Youssef MA, van Wely M, Hassan MA, Al-Inany HG, Mochtar M, Khattab S, et al. Can dopamine agonists reduce the incidence and severity of OHSS in IVF/ICSI treatment cycles? A systematic review and meta-analysis. Hum Reprod Update. 2010;16(5):459–466
  14. Loutradis D, Kiapekou E, Zapanti E, Antsaklis A. Oocyte maturation in assisted reproductive techniques. Ann N Y Acad Sci. 2006;1092:235–246
  15. Al-Inany HG, et al. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology. Cochrane Database Syst Rev. 2011;5:CD001750
  16. Fauser BC, et al. Minimal ovarian stimulation for IVF: appraisal of potential benefits and drawbacks. Hum Reprod. 1999;14(11):2681–2686
  17. Fatemi H, Kolibianakis EM, Camus M, Tournaye H, Van Steirteghem A. Devroey P progesterone versus progesterone combined with estradiol as luteal support in cycles stimulated with GnRH antagonist/rec-FSH for IVF: a randomized clinical trial. Fertil Steril. 2005;84(Supplement 1):S322
  18. Griesinger G, Kolibianakis EM, Venetis C, Diedrich K, Tarlatzis B. Oral contraceptive pretreatment significantly reduces ongoing pregnancy likelihood in gonadotropin-releasing hormone antagonist cycles: an updated meta-analysis. Fertil Steril. 2010;94(6):2382–2384
  19. Bonduelle M, et al. Large prospective, pregnancy and infant follow-up trial assures the health of 1000 fetuses conceived after treatment with the GnRH antagonist ganirelix during controlled ovarian stimulation. Hum Reprod. 2010;25(6):1433–1440
  20. Lainas TG, et al. Flexible GnRH antagonist protocol versus GnRH agonist long protocol in patients with polycystic ovary syndrome treated for IVF: a prospective randomised controlled trial (RCT). Hum Reprod. 2010;25(3):683–689

PII: S1110-5690(11)00108-7

doi:10.1016/j.mefs.2011.11.001

Middle East Fertility Society Journal
Volume 16, Issue 4 , Pages 254-256, December 2011

Article Tools

* Image Usage & Resolution