Comparison of early versus late initiation of GnRH antagonist co-treatment for controlled ovarian stimulation in IVF: a randomized controlled trial.

STUDY QUESTION: What is the impact of initiating GnRH antagonist co-treatment for in vitro fertilization (IVF) on cycle day (CD) 2 compared with CD 6 on live birth rate (LBR) per started cycle and on the cumulative live birth rate (CLBR)? SUMMARY ANSWER: Early initiation of GnRH antagonist does not appear to improve clinical outcomes of IVF compared with midfollicular initiation. WHAT IS KNOWN ALREADY: During ovarian stimulation for IVF, GnRH antagonist co-treatment is usually administered from the midfollicular phase onwards. Earlier initiation may improve the follicular phase hormonal milieu and therefore overall clinical outcomes. STUDY DESIGN, SIZE, DURATION: This open-label, multicentre randomized controlled trial was conducted between September 2009 and July 2011. A web-based program was used for randomization and 617 IVF-intracytoplasmic sperm injection (ICSI) patients were included. PARTICIPANTS/MATERIALS, SETTING, METHODS: Recombinant FSH (150-225 IU) was administered daily from CD 2 onwards in both groups. The study group (CD2; n = 308) started GnRH antagonist co-treatment on CD 2, whereas the control group (CD6; n = 309) started on CD 6. MAIN RESULTS AND THE ROLE OF CHANCE: There were no significant differences in clinical outcomes between the two groups. A non-significant trend towards a higher LBR per started cycle and CLBR was observed in the CD6 group compared with the CD2 group (LBR: 24.0 versus 21.5%, P = 0.5; CLBR: 29.9 versus 26.7%, P = 0.6). LIMITATIONS, REASONS FOR CAUTION: The study was terminated prematurely because no significant difference was observed in clinical outcomes after 617 inclusions. A much larger study population would be needed to detect a small significant difference in favour of either study arm, which raises the question of whether this would be relevant for clinical practice. WIDER IMPLICATIONS OF THE FINDINGS: The present study shows that the additional treatment burden and costs of starting GnRH antagonist on CD 2 instead of on CD 6 are not justified, as early initiation of GnRH antagonist does not improve LBRs. STUDY FUNDING/COMPETING INTEREST(S): This study was partially supported by a grant from Merck Serono. O.H., M.J.C.E, A.V., P.A.D., R.E.B., G.J.E.O., C.A.G.H., G.C.D.M., H.J.V., P.F.M.H. and A.B. have nothing to declare. F.J.B. has received fees and grant support from the following companies (in alphabetic order): Ferring, Gedeon Richter, Merck Serono, MSD and Roche. B.J.C. has received fees and grant support from the following companies (in alphabetic order): Ferring, Merck Serono and MSD. C.B.L has received fees and grant support from the following companies (in alphabetic order): Auxogen, Ferring, Merck Serono and MSD. B.C.J.M.F. has received fees and grant support from the following companies (in alphabetic order): Andromed, Ardana, Ferring, Genovum, Merck Serono, MSD, Organon, Pantharei Bioscience, PregLem, Schering, Schering Plough, Serono and Wyeth. J.S.E.L. has received fees and grant support from the following companies (in alphabetic order): Ferring, Gennovum, MSD, Merck Serono, Organon, Schering Plough and Serono. N.S.M. has received fees and grant support from the following companies (in alphabetic order): Anecova, Ferring, Merck Serono, MSD, Organon and Serono. TRIAL REGISTRATION NUMBER: www.clinicaltrials.gov, no. NCT00866034.

Comparison of ovarian stimulation regimens for in vitro fertilization (IVE) with and without a gonadotropin-releasing hormone (GnRH) agonist: results of a randomized study.

In order to diminish the cancellation rate due to a premature endogeneous LH surge and/or to a poor ovarian response and thus increasing the pregnancy rate, a GnRH agonist (Buserelin) was applied in patients starting their first ovarian stimulation with gonadotropins for IVF. All patients suffered from tubal infertility and were not older than 40 years. Each woman was allocated randomly to one of three groups: the conventional treatment with hMG alone (group I), patients from group II started the hMG treatment shortly after the LH rise caused by the GnRH agonist and patients in group III commenced the hMG treatment when an hypogonadotropic state was achieved after a long treatment of Buserelin. All male partners had a normal spermiogram. A reduction of poor responders to the superovulation is seen in the short-term group (6%), compared with the other two groups (14%). In some cases from group III ovarian cyst formation led to the cancellation of the treatment. The long-term group differs significantly from the other two in the duration of the gonadotropin stimulation and the number of ampoules hMG used. A severe ovarian overstimulation syndrome was not observed. There is no difference in the number of retrieved oocytes and the fertilization rate among the three groups. The pregnancy rate per cycle or per patient in the group with a short-term GnRH-agonist regimen is significantly higher compared to that of the group using the conventional hMG treatment.

In vitro fertilization at the Leiden Academic Hospital. Initial experiences.

At the Leiden University Hospital the first IVF treatment was initiated November 1st, 1985. In the following year 139 cycles with ovarian stimulation have been started with 75 patients. Thirty percent of these stimulations have been cancelled before oocyte retrieval due to suboptimal response. Totally 97 pick-ups have been carried out on 65 patients resulting in 78 embryo transfers to 54 patients. Fourteen clinical pregnancies were obtained. Four ended with a first trimester abortion, one was a tubal pregnancy and 9 are ongoing or have been already delivered.