Multifollicular ovarian stimulation for IVF: more may not be better

The aim to stimulate a high number of follicles has dominated ART practice for many years. The rationale behind this is that the more follicles developed, the higher the number of embryos available for transfer and, hence, the higher the chance of achieving a pregnancy. Nevertheless, concerns have been raised regarding a potential negative effect that multiple follicular stimulation might exert, either on endometrial receptivity or on oocyte quality.

In ovarian stimulation for IVF, multifollicular development leads to supraphysiological levels of steroid hormones (namely progesterone and estradiol). As a result, endometrial advancement has been described in endometrium biopsies taken in early luteal phase (1) and, furthermore, when the advancement was more than 3 days on the day of oocyte retrieval, the pregnancy rate was zero (2). Interestingly, the group of patients with >3 days advancement had significantly higher progesterone levels on the day of HCG. As early as 1991, it was shown that modest preovulatory increases in serum progesterone levels are associated with lower pregnancy rates and higher pregnancy loss. The mechanism proposed to explain the adverse pregnancy outcome, following the premature progesterone rise, is that of a negative impact on endometrium receptivity.

In a recent observational study in patients undergoing ovarian stimulation with a GnRH-antagonist/recFSH protocol and single cleavage-stage embryo transfer, Papanikolaou et al. reported that there was a statistically significant decrease in the clinical pregnancy rate (from 37.5 to 15.7%), when progesterone values on the day of HCG administration increased from 0.73 to above 1.54 ng/ml (3). The authors proposed that high follicular progesterone (premature luteinization) might exceedingly advance the endometrium in the early luteal phase and, therefore, the replacement of a day 3 embryo in an asynchronous endometrial milieu results in failure to establish embryo-endometrium cross dialogue and, in turn, in embryo demise and failure of implantation.

On the other hand, the high incidence of chromosomal abnormalities in human preimplantation embryos raises the question whether multi-follicular ovarian stimulation for IVF affects oocyte chromosomal competency. In a recent randomised controlled IVF trial comparing two ovarian stimulation regimens, patients were random to receive either the conventional dose of 225 IU recFSH or a milder protocol of 150 IU. Preimplantation genetic diagnosis was applied on the cleavage stage embryos obtained and aneuploidy rates were compared between the groups. Although mild stimulation yielded fewer oocytes and embryos, the resulting embryos showed a lower incidence of aneuploidies. Consequently, the number of chromosomally normal embryos available for transfer was similar in both groups (4). This observation suggests that the milder stimulation protocols simulate more closely the natural cycle, by allowing less follicles to develop which, however, contain more competent oocytes.

In conclusion, more rational ovarian stimulation protocols aiming to produce chromosomally normal embryos and not an excessive number of oocytes will also be beneficial by distorting less the endometrial receptivity, thus enhancing the probability of a couple to achieve a singleton delivery.