Synchronization of Ovarian Stimulation with Follicle Wave Emergence in Patients undergoing in vitro fertilization with a Prior Suboptimal Response A Randomized Controlled Trial

Synchronizing ovarian stimulation with follicle wave emergence in patients with a prior suboptimal response resulted in an increase in the number of follicles that developed and serum E2 concentrations; however, corresponding improvements in oocyte, embryo, and pregnancy outcomes were not observed.

Angela Baerwald, Ph.D., Paula Anderson, R.N., B.Sc.N., Albert Yuzpe, M.D., Allison Case, M.D., Margo Fluker, M.D.

Volume 98, Issue 4, Pages 881-887.e2, October 2012


To test the hypothesis that synchronizing initiation of ovarian stimulation with follicle wave emergence would optimize IVF/intracytoplasmic sperm injection (ICSI) outcomes in patients with a prior suboptimal response.

Prospective, randomized, controlled trial.

Academic and private reproductive endocrinology and infertility centers.

Eighty women ≤43 years of age with a history of a suboptimal response.

Initiation of recombinant FSH/GnRH antagonist/recombinant LH/hCG on day 1 (n = 39) or day 4 (n = 41).

Main Outcome Measures:
Numbers of clinical and biochemical pregnancies, follicles >10 and >15 mm, oocytes collected, fertilized oocytes, cleavage-stage embryos, and blastocysts; serum estradiol concentrations. Outcomes were compared between treatment groups.

The numbers of follicles that developed to >10 and >15 mm and serum estradiol were greater when rFSH was initiated on day 1 (5.4, 4.3, 5827.2 pmol/L) versus day 4 (3.6, 2.5, 4230.1 pmol/L) (p<0.05). The numbers of collected, MII, and fertilized oocytes; cleavage-stage embryos; and blastocysts were not different between groups (p>0.05). When we evaluated only those cycles that proceeded to OPU, a lower implantation rate (16.1%, 56.0%; p=0.02), biochemical pregnancy rate (16.1%, 48.0%; p=0.01), and clinical pregnancy rate (12.9% versus 36.0%; p=0.03) were detected in the day 1 versus 4 group.

Synchronizing initiation of ovarian stimulation with follicle wave emergence in patients with a prior suboptimal response resulted in an increase in the number of dominant follicles and serum estradiol concentrations; however, improvements in oocyte, embryo or pregnancy outcomes did not occur.

Clinical Trials Registration Number:

  • Juan Giles

    In agreement with the previous comments, the first
    point of interest is the worse results of the study group compared with the
    control group in terms of implantation, biochemical and clinical pregnancy
    rate. Moreover, in poor responder
    follicular recruitment is frequently faster so we should wait theoretically worse
    results if begin stimulation on day 4.

    Nowadays we use in most of the cycles oestrogens or OCP in the proceeding lutheal phase to help
    increase follicular synchronization.

    In my
    opinion, the manuscript support the option of begin stimulation in day 4 in case of patients
    had no hormonal control prior to the cycle without a decrease in the results,
    instead of day 2 or 3 as in our normal practice.

  • William Rods

    I have my doubts about the study design. If women have either 2 or 3 waves of follicular growth, starting on day 1 or 4 in this study does not consider at all this typical characteristic growth. In other words, women starting on day 1 may have 2 (well done to start on day 1 stimulation) or 3 (not well done) waves. Thus, the study provides no new information because designs like this have been already performed and cited by the authors in their introduction

  • Micah Hill

    Given the small study size, it is rather remarkable how much worse the study group performed than the control group (10 vs 22% pregnancy in intent to treat and 13 versus 36% in the nonITT analysis). The negative effect seen in the pregnancy outcomes in this study certainly negated the mild increase in oocyte yield the study protocol generated.

    I could not tell from the methods, but the implication to me was that the patients had no hormonal control prior to the cycle (i.e. OCPs, luteal estradiol)? It has been suggested that suppressing FSH in the proceeding luteal phase generates a more heterogenous cohort of follicles. Fanchin’s papers have demonstrated estradiol or GnRH analogues in the proceeding luteal phase to help increase follicular synchronization. This would suggest the synchronization has occurred prior to day 1 of menses, as attempted in this paper. Although the animal data cited supports the authors hypothesis.

  • laurenwroth

    This is a RCT comparing stimulation for IVF starting on cycle day 1 vs. 4 in previous poor responders. Although there seems to be a good biologic foundation for the study design, the results of the study do not support the proposed biology. Although women who started stim day 1 were maybe more likely to go to retrieval, they did not have improved pregnancy rates. This is a well designed study that will not change my practice.

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