There is a debate regarding the best stimulation protocol which should be the first choice in a normoresponder woman. Given the high discontinuation rates when pregnancy has not been achieved
7,8, it is essential to determine the best possible stimulation protocol in normoresponder patients. We aimed to determine whether GnRH agonist long and antagonist protocols yielded significant differences in cycle parameters and treatment outcome when performed in the same normoresponder woman in a one-year period. The results of the present study showed shorter stimulation duration, lower peak E2 levels and a higher implantation rate in antagonist cycles compared to agonist long ones.
GnRH agonists have been introduced in the mid 1980s in order to prevent LH surge in IVF cycles9,10. GnRH agonist long protocol has a widespread popularity and is still the predominantly used method of ovarian stimulation in IVF. One decade later, GnRH antagonists have been introduced in the mid 1990s for the suppression of endogenous LH increase in ovarian stimulation2,11. Although antagonist protocol has been used mainly in poor responder and older women, it has been proposed as a patient friendly treatment regime which might be the most probable stimulation protocol to improve patient experience12.
Several investigators have indicated lower pregnancy rates in antagonist cycles compared to agonist ones13,14. However, the problem with GnRH antagonist protocol is its use mainly in poor responder and older patient groups and the fact that it is not the first choice of clinicians. Prior randomized and nonrandomized studies have revealed various results. Therefore, well-designed studies are needed to establish the efficacy of antagonists separately in poor responder, normoresponder and high responder-PCOS patient groups.
The preferred ovarian stimulation protocol for normoresponder women varies according to the center. While choosing the right protocol, consideration should be given to treatment cost, ease of use, treatment risk and psychological distress12. GnRH agonist long protocol is still the most commonly used one for ART cycles worldwide and antagonist protocol is not preferred in the first attempt in normoresponder women which might be due to its initial use in poor responder and older patient groups. However, in recent years antagonist protocol has gained popularity and especially in PCOS cases it is suggested as the first choice in some centers in order to prevent ovarian hyperstimulation syndrome15. Similarly in a recent prospective study, flexible GnRH antagonist protocol was found to be associated with a similar ongoing pregnancy rate compared with GnRH agonist in PCOS patients undergoing IVF16.
To the best of our knowledge, most of the studies present in the literature regarding antagonist use have been performed in poor responder and PCOS patients and also in a general IVF patient population. Studies regarding antagonist use in normoresponder women are scarce and revealed contradictory results. Antagonists are suspected to yield lower pregnancy rates compared with the agonist long protocol, therefore there is still controversy on the use of antagonist protocol as the first choice in normoresponder women. Orvieto et al.17 suggested that the GnRH agonist long protocol should be the protocol of choice in young patients in their first three IVF cycle attempts. Another study in good prognosis women (<35 years, IVF range one or two) revealed significantly lower pregnancy rates in antagonist cycles compared to agonist long ones18. However, a recent study comparing the GnRH agonist long and the antagonist protocols in young women (<35 years) with tubal factor infertility reported similar pregnancy rates supporting the hypothesis that both regimes lead to equal results6. Furthermore, it has been shown that antagonist use in ovarian stimulation for ART is at least as effective as the GnRH agonist long protocol in patients with normal ovarian response and antagonists even allow a higher flexibility in the treatment19,20. Similarly, the results of the current study revealed that the GnRH antagonist and agonist long protocols provided comparable outcomes in the same patient undergoing ART and even shorter stimulation duration and higher implantation with antagonists. We concluded that GnRH antagonist protocol might be considered as comparable and even better compared with agonist long protocol in a normoresponder woman. Accordingly, we suggest that in patients with the failure of the either protocol in the first attempt, the other one might be considered safely for the next treatment cycle instead of giving the same protocol again. Moreover, in a recent prospective study, no significant difference was found between antagonist and agonist groups in terms of pregnancy and delivery complications, neonatal outcome and risk of major malformations21.
Optimal comparisons between GnRH agonist long and antagonist protocols are still lacking. As the implantation rate was suggested to be adversely affected in antagonist cycles, we performed such a study where each patient was compared with her own previous cycle. In every patient a GnRH antagonist protocol was used in the new cycle instead of a GnRH agonist long protocol used in the previous cycle or vice versa. The probability of reduced ovarian response over time might be considered as a bias for this study. However, the time period between the two treatment cycles were 3-6 months in this normoresponder patient group and both cycles were performed within a one-year period.
In conclusion, our data comparing the most commonly used two protocols, GnRH agonist long and antagonist protocols in the same normoresponder patient cohort show a favourable outcome with antagonists. The data revealed better results in terms of stimulation duration, peak estradiol levels and implantation rate in antagonist cycles compared to agonist long ones in normoresponder patients. Further studies are needed to support our belief that a GnRH antagonist regimen might be easily considered as the first choice in normoresponder women undergoing ART.