Interpretation
The results of the study suggest that the PPOS regimen is probably not as good as the antagonist protocol in term of the pregnancy outcomes of FET and indicated that the embryos originating from the PPOS protocol may have a reduced development potential to those from the antagonist group. While most researches indicate that elevated progesterone levels on trigger day do not have a negative impact on the FET results of stimulated cycles using PPOS9, 11, 14, there are some reports of a negative effect of elevated progesterone on oocyte quality 15, 16 and cumulative live birth rate per retrieval cycle 17. The reasons for this possible impairment are still unknown. Studies in animal experiments showed that oocyte competence was regulated by progesterone-responsive genes18,19. Differences in the expression of OCT-4 and MATER in bovine oocytes with diverse progesterone concentration was found by Urrego et al. (2015) and indicated that lower progesterone concentration could increase bovine oocyte developmental competence in vitro by up-regulating MATER and OCT-4 gene expression20.
Progesterone is a steroid hormone and is responsible for preparing the endometrium for uterine implantation of the fertilized egg. On the other hand, progesterone is known to have an inhibitory effect on ovulation by blocking the LH surge21,22. Its inhibitory effect on ovulation has been at the base of the design of progestin-only contraceptives, which suppress follicular growth and thus inhibit ovulation after a sustained administration. Progesterone priming seems to slow the LH pulse frequency, augments the pulse amplitude and reduces the mean plasma LH concentrations compared with those in untreated women in some studies23,24 .
No significant difference was found in the incidence of premature LH surge and premature ovulation in the PPOS group compared with the antagonist group, but LH level on HCG day were significantly lower in the antagonist group indicated progesterone can be used as an alternative to GnRH antagonist for suppressing premature LH surges during ovarian stimulation in IVF cycles, but the effect is weaker compared with the antagonist. However, we also found that the PPOS protocol may lead to stronger pituitary suppression and thus may require a higher dosage of gonadotrophin than that of the conventional ovarian stimulation protocol 9. No patient experienced moderate or severe OHSS in both group during the study,owning to both protocols is applicable for the use of a GnRHa for ovulation trigger or co-trigger by GnRHa and a low dose of hCG and freezeing all embryos.
In PPOS, freezing of all embryos and FET in subsequent cycles are required. Some situations in which fresh embryo transfer are not required such as fertility preservation, oocyte donation or preimplantation genetic testing, PPOS may be used as a first-line treatment25,26. The potential harmful effects of the hormonal environment on endometrial receptivity are therefore avoided. Other patients who can benefit from this protocol are those at risk of OHSS since for these patients there is very frequently the application of the “freeze-all” strategy, and triggering can be exerted by the GnRH agonist, which helps to avoid early-onset OHSS.
Other advantages over the use of a progestin are oral administration, easier access and more control over LH concentrations10. PPOS is also more patient-friendly as fewer injections are required and medroxyprogesterone is much cheaper compared to antagonist12. However, our study showed the total amount of stimulation with FSH/HMG was higher in PPOS protocol, the total cost related to medicine is therefore comparable between the two protocols. The cost-effectiveness of progestins compared with GnRH antagonists has been studied in a recent article by Evans and colleagues27, but this study was only limited to planned freeze-only cycles and to high-responder patients for whom a “freeze only” is likely and the risk of OHSS is high. Since many women with normal ovarian reserve are suitable for fresh embryo transfer in antagonist protocols, the extra cost produced by embryo cryopreserved–thawed, and delayed transfer in the PPOS protocol should be considered.
Current evidence about the safety of MPA use in ovarian stimulation is limited, and MPA was contraindicated in human pregnancy28. The long-term safety for children conceived with ovarian stimulation using MPA is still under investigation. In contrast, GnRH antagonist has been extensively used worldwide for IVF treatment. Our data also demonstrated that antagonist administration produced a comparable number of top-quality embryos and pregnancy outcomes are better compared with MPA. For long-term safety considerations, GnRH antagonist is safer than medroxyprogesterone during ovarian stimulation.
Strengths and weaknesses
Different from previous study,12 patients in our study used their own oocytes, and perhaps this is a more appropriate model for comparing the pregnancy outcomes, and can control for all potential confounding factors. However, our study is limited by its retrospective design, a small sample size and reporting ongoing pregnancy rates. Some imbalanced characteristics were found in this study and logistic regression analysis was carried out for controlling the basis. Cancellation or postponement of FET was different in the two groups. Hence, reproductive results should be interpreted with caution. Further randomised trials with adequate sample size would be needed to confirm these findings. The comparison of cumulative outcomes after one IVF cycle has not been performed between two groups.