A Proof-of-Concept Clinical Trial of A Single Luteal Use of Long-Acting Gonadotropin-Releasing Hormone Antagonist Degarelix in Controlled Ovarian Stimulation for In Vitro Fertilization: Long Antagonist Protocol

Evangelos G Papanikolaou, Hakan Yarali, Evi Timotheou, Michael Grynberg, Odysseas Zafeiratis, Herman Tournaye, Robert Najdecki, Evangelos G Papanikolaou, Hakan Yarali, Evi Timotheou, Michael Grynberg, Odysseas Zafeiratis, Herman Tournaye, Robert Najdecki

Abstract

Introduction: A drawback of gonadotropin-releasing hormone (GnRH) antagonist protocols in in vitro fertilization (IVF) is that they have limited flexibility in cycle programming. This proof of concept study explored the efficacy of a single-dose, long-acting GnRH antagonist IVF protocol. Trial registration number is NCT03240159, retrospectively registered on March 08, 2017.

Materials and methods: The efficacy of a single-dose long-acting antagonist, degarelix, was explored initially in healthy donors and subsequently in infertile patients. In the first part, five healthy oocyte donors underwent ovarian stimulation with this new protocol: in the late luteal phase, at day 24, a bolus injection of degarelix was administered subcutaneously to control the LH surge in the follicular phase. Ovarian stimulation with gonadotropins was initiated subsequently from day 7 to day 10. End points were first to inhibit the LH surge later in the follicular phase and, second, to retrieve mature oocytes for IVF. In the second part, five infertile women received the same bolus injection of degarelix administered during the luteal phase at day 24. Different gonadotropin starting days (day 2 through day 8) were tested in order to observe possible differences in ovarian stimulation. In these infertile patients, fresh embryo transfers were performed to assess the pregnancy efficacy of this protocol on pregnancy outcomes and to address any possible negative effects on endometrium receptivity.

Results: In the first part of the study, all donors were effectively downregulated with a single luteal dose of 0.5 ml of degarelix for up to 22 days until the final oocyte maturation triggering day. Mature oocytes were retrieved after 36 h from all patients and all produced 2-7 blastocysts. In the second part, all five infertile patients achieved sufficient LH downregulation and completed ovarian stimulation without any LH surge. All patients (except one with freeze all strategy) had blastocysts transferred and pregnancy occurred in three out of five women.

Conclusion: A single dose of the long-acting antagonist degarelix during the luteal phase appears to be effective in downregulating hypophysis during ovarian stimulation. This represents a possible new protocol for IVF, which should be further elucidated in RCTs.

Keywords: antagonist protocol; degarelix; in vitro fertilization; long agonist protocol; long antagonist protocol; ovarian stimulation; pregnancy.

Figures

Figure 1
Figure 1
Long Antagonist Protocol with flexible starting day of gonadotropin (just indicative in the current image).
Figure 2
Figure 2
Endocrinological data (E2 and LH variation) during long antagonist protocol (patient ID-05).

References

    1. Caspi E, Ron-El R, Golan A, Nachum H, Arie Herman MD, Yigal Soffer MD, et al. Results of in vitro fertilization and embryo transfer by combined long-acting gonadotropin-releasing hormone analog D-Trip-6-luteinizing hormone-releasing hormone and gonadotropins. Fertil Steril (1989) 51:95–9.10.1016/S0015-0282(16)60435-1
    1. Barbieri RL, Friedman AJ. Gonadotropin Releasing Hormone Analogues. New York: Elsevier; (1991). p. 1–15.
    1. Humaidan P, Quartarolo J, Papanikolaou EG. Preventing ovarian hyperstimulation syndrome: guidance for the clinician. Fertil Steril (2010) 94(2):389–400.10.1016/j.fertnstert.2010.03.028
    1. Al-Inany HG, Youssef MA, Ayeleke RO, Brown J, Lam WS, Broekmans FJ. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology. Cochrane Database Syst Rev (2016) 5:CD001750.10.1002/14651858.CD001750.pub4
    1. Tur-Kaspa, Fauser B. The Use of GnRH Agonist in IVF Protocols. IVF Worldwide; (2010). , Last accessed on 31/12/2017
    1. Papanikolaou EG, Pados G, Grimbizis G, Bili E, Kyriazi L, Polyzos NP, et al. GnRH-agonist versus GnRH-antagonist IVF cycles: is the reproductive outcome affected by the incidence of progesterone elevation on the day of HCG triggering? A randomized prospective study. Hum Reprod (2012) 27(6):1822–8.10.1093/humrep/des066
    1. 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) 94:2382–4.10.1016/j.fertnstert.2010.04.025
    1. Blockeel C, Riva A, De Vos M, Haentjens P, Devroey P. Administration of a gonadotropin-releasing hormone antagonist during the 3 days before the initiation of the in vitro fertilization/intracytoplasmic sperm injection treatment cycle: impact on ovarian stimulation. Fertil Steril (2011) 95(5):e1–2.10.1016/j.fertnstert.2011.01.028
    1. Broqua P, Riviere PJ, Conn PM, Rivier JE, Aubert ML, Junien JL. Pharmacological profile of a new, potent, and long-acting gonadotropin-releasing hormone antagonist: degarelix. J Pharmacol Exp Ther (2002) 301(1):95–102.10.1124/jpet.301.1.95
    1. Sciarra A, Fasulo A, Ciardi A, Petrangeli E, Gentilucci A, Maggi M, et al. A meta-analysis and systematic review of randomized controlled trials with degarelix versus gonadotropin-releasing hormone agonists for advanced prostate cancer. Medicine (Baltimore) (2016) 95(27):e3845.10.1097/MD.0000000000003845
    1. Gonzalez-Bulnes A, Souza CJ, Scaramuzzi RJ, Campbell BK, Baird DT. Long-term suppression of reproductive function by a single dose of gonadotropin-releasing hormone antagonists in a sheep model. Fertil Steril (2006) 86(4 Suppl):1121–8.10.1016/j.fertnstert.2006.02.104
    1. García-Velasco JA, Kupesic S, Pellicer A, Bourgain C, Simón C, Mrazek M, et al. Follicular and endocrine profiles associated with different GnRH-antagonist regimens: a randomized controlled trial. Reprod Biomed Online (2012) 24(2):153–62.10.1016/j.rbmo.2011.10.016

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