Administration of corifollitropin alfa on Day 2 versus Day 4 of the cycle in a GnRH antagonist protocol: a randomized controlled pilot study

Hum Reprod. 2014 Jul;29(7):1500-7. doi: 10.1093/humrep/deu105. Epub 2014 May 9.


Study question: Does the initiation of corifollitropin alfa administration on cycle day 4 instead of cycle day 2 result in a reduced total rFSH consumption in a GnRH antagonist protocol?

Summary answer: Initiation of corifollitropin alfa on cycle day 4 compared with day 2 results in significantly reduced total rFSH consumption at the end of the follicular phase.

What is known already: In vitro fertilization treatment is associated with significant physical, psychological and emotional stress in infertile patients. This notion has fuelled the search for simplified treatment approaches that may reduce the treatment burden. The introduction of corifollitropin alfa has provided a more patient-friendly treatment protocol because it obviates the need for daily hormonal injections. In addition, postponing the initiation of hormonal stimulation should also reduce the total gonadotrophin consumption and the number of injections needed.

Study design, size, duration: A prospective randomized controlled pilot study was conducted in a university centre in Belgium. Between December 2011 and March 2013, 59 patients were randomized in the study and 52 of these patients received the allocated intervention.

Participants/materials, setting, methods: All patients were randomly assigned to the control group (CD2), with initiation of corifollitropin alfa on cycle day 2, or to the study group (CD4) with initiation of stimulation on day 4. The GnRH antagonist was administered from cycle day 7 onwards in both treatment arms. The main outcome measure was the total rFSH consumption at the end of the follicular phase after corifollitropin alfa treatment.

Main results and the role of chance: The total dose of rFSH at the end of the follicular phase was significantly reduced in the CD4 group compared with the CD2 group (324 (276) IU in the CD2 group versus 173 (255) IU in the CD4 group, P = 0.015, mean difference -151, 95% confidence interval (CI) -301 to -1). A significant reduction of total duration of rFSH stimulation in the CD4 group was also observed (8.6 (1.4) days in CD2 group versus 7.8 (1.2) days in the CD4 group, P = 0.008, mean difference -0.8, 95% CI -1.6 to -0.1). The number of cumulus-oocyte-complexes was comparable in both treatment groups (12.8 (7.3) in CD2 group versus 14.7 (8.8) in the CD4 group, P = 0.461, mean difference 1.8, 95% CI -2.7 to 6.4). Ongoing pregnancy rates of 48% in the CD2 group and 41% in the CD4 group were achieved (P = 0.60, relative risk (RR) 0.85, 95% CI 0.46-1.56). Final oocyte maturation was triggered with GnRH agonist instead of hCG in two patients in the CD2 group and in eight patients in the CD4 group, because of an increased risk of ovarian hyperstimulation syndrome (P = 0.078, RR 3.7 (95% CI 0.88-15.8).

Limitations, reasons for caution: Before general implementation can be advised, this trial should be validated in a much larger randomized trial. WIDER IMPLICATIONS OF THE FINDINGS If the approach of starting ovarian stimulation on Day 4 of the cycle could be implemented in a large population of infertile patients, it would result in a significant reduction of gonadotrophin consumption.

Study funding/competing interest(s): No external finance was involved in this study. C.B and N.P.P. have received fees from MSD. Otherwise the authors declare no conflict of interest regarding this study.

Trial registration number: The trial was registered at (NCT01633580).

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Belgium
  • Drug Administration Schedule*
  • Female
  • Fertilization in Vitro / methods
  • Follicle Stimulating Hormone / administration & dosage
  • Follicle Stimulating Hormone, Human / administration & dosage*
  • Gonadotropin-Releasing Hormone / antagonists & inhibitors*
  • Hormone Antagonists / administration & dosage
  • Humans
  • Infertility
  • Ovarian Follicle / drug effects
  • Ovulation Induction
  • Pilot Projects
  • Prospective Studies
  • Sperm Injections, Intracytoplasmic / methods
  • Treatment Outcome


  • Follicle Stimulating Hormone, Human
  • Hormone Antagonists
  • follicle stimulating hormone, human, with HCG C-terminal peptide
  • Gonadotropin-Releasing Hormone
  • Follicle Stimulating Hormone

Associated data