This was the first randomized control trial to compare the clinical outcome of the fixed GnRH antagonist protocol with the flexible protocol in IVF/ICSI for the patients with predicted high ovary response except PCOS, we found no difference in total number of oocytes retrieved in the fixed protocol compared with the flexible protocol. Except the treatment duration of GnRH antagonist in the flexible protocol group was shorter than that in the fixed protocol group, no significant difference was between the two groups in term of the treatment duration and total dose of rFSH, premature LH surges, implantation, clinical pregnancy, ongoing pregnancy and cumulative live birth rate.
Previous published studies generally focused on ovulatory women and PCOS women arrived at the different outcomes. The early meta-analysis for the patients with normal ovarian response showed us that pregnancy outcome and LH surge suppression were similar between two protocols and the total treatment dose of Gn and GnRH antagonist in the flexible protocol group was less . The original purpose to explore the flexible addition was to delay the initiation timing of GnRH antagonist, the flexible protocol would reduce the injection naturally but ask for more times of monitoring . Distinctly, our study for women with predicted high ovarian response except PCOS reached the analogous results as for normal ovary responders, which may be ascribed to similar follicular development trajectory during ovarian stimulation for the two types of patients.
However, the only 1 RCT for PCOS women revealed the diverse results that the total number of oocyte retrieval and good-quality embryo in the flexible group were remarkably more than those in the fixed group . As the special type of high ovarian responders, the sensibility of follicles to FSH in PCOS patients usually was considered as lower than normal ovarian responder and other high ovarian responders . Given the uncertain follicle development, slow ovarian response or hyperstimulation would easily occur during ovarian stimulation either due to inappropriate ovarian stimulation by exogenous FSH. So that the flexible protocol seems to be beneficial for PCOS women in clinical outcome, which is also recommended for PCOS women and poor ovarian responders by the clinical consensus on GnRH antagonist protocol in China .
Furthermore, the possible reason why there was no significantly difference in clinical outcome between two protocols of our study is that the initiation timing of GnRH antagonist was also similar. As we known, the fixed protocol is commenced on Gn stimulation day 5 or 6, regardless of follicular development. However, the flexible protocol is administrated only when adequate follicular development (follicular size 12–14 mm) and/or E2 production by the developing follicles may give rise to premature LH surge . Anyway, both of standards are not completely evidence based. In the flexible group of our study, according to the pre-determined initiation standards, the actual initiation timing of GnRH antagonist especially after the same dose of rFSH start was very close to fixed initiation on stimulation day 5, which both appeared to be a little earlier than other published study.
Despite the initiation timing of GnRH antagonist in the flexible group was slightly later and accordingly there were more follicles with diameter of more than 12 mm and higher serum estradiol level on antagonist initiation day, few premature LH rise was observed in two groups, rather than the premature LH surge that we concerned mostly to result the failure of ovarian stimulation. Apparently, later initiation of GnRH antagonist in the flexible protocol didn’t cause a bad influence on the clinical outcome.So far there is actually not a uniform addition standard of GnRH antagonist in flexible protocol, the GnRH antagonist initiation is mainly relied on the doctor’s experience, consequently the times of monitoring and test might be increased in the clinical practice.
Meanwhile, we should realize that the number of available oocytes in ovarian stimulation depends on ovarian reserve and sufficient stimulation by exogenous FSH. For the predicted high ovarian responders except PCOS, the suitable ovarian stimulation including the dose of FSH starting and dose adjustment obviously seems to be more important in the follicle recruitment. Base on the theory of FSH threshold window, unexpected poor ovarian stimulation might be mostly attributed to insufficient FSH stimulation, GnRH antagonist is administrated too earlier with sufficient stimulation as well . Then the flexible initiation of GnRH antagonist by ultrasound monitoring and serum hormone test has its advantages to avoid the predicament. Undeniably, the fixed protocol have an advantage over the flexible protocol in the aspect of reducing the treatment burden for both patients and doctors.
Certainly, our study has some limitations. First, there is no generally accepted definition of high ovarian responder, which may cause patients heterogeneity especially when sample size is not big enough. Second, RCTs per se frequently have methodological weaknesses, limiting their usefulness in clinical practice. For instance, fixed FSH starting dose may not be sufficient for all the patients, that may reduce the number of oocytes retrieved and influence the outcomes for specific patients. In addition, cumulative pregnancy rate/live birth rate including the frozen–thawed cycles might be more appropriate as key endpoint, of course that should be proven with a larger sample size. we also noted that, for the fresh embryo transfer cycles, the clinical/ongoing pregnancy rate in fixed protocol was a little numerically higher than in flexible protocol and nearly 50% cycle achieved freezing-all embryo in our study due to high risk of OHSS.