Discussion
The main finding of this study was that the CLBR in women with normal ovarian reserve after the one oocyte retrieval including fresh and all subsequent frozen embryo cycles were significant lower in the PPOS group compared with that in long agonist group, 40.5% versus 63.2% respectively. Moreover,the time to pregnancy and live birth was significantly shorter in the long agonist group compared with that in the PPOS group.
The results of the study indicated that progestins were capable of effectively preventing premature ovulation in IVF cycles. No significant difference was found in the incidence of premature LH surge and premature ovulation between the PPOS group and the long agonist group, although serum LH levels on HCG day were significantly lower in the long agonist group. The inhibitory effect of progestin on ovulation has been the basis of the design of progestin-only contraceptives, which suppress follicular growth and thus inhibit ovulation after a sustained administration. Progestin 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 studies22 23 .
Progestin cycles have been shown to require more gonadotropins compared with short GnRH agonist cycles11-17 . However, in the present study we found total gonadotropin dose was lower and the day of stimulation was shorter in the PPOS group compared to that in long GnRH agonist group. This may be due to prolonged pituitary suppression in the long agonist protocol which was started from the mid-luteal phase of the previous cycle, and prolonged pituitary down-regulation by GnRHa might contribute to improved endometrial receptivity24.
In this study we found number of oocytes obtained, number of oocytes fertilized, number of cleaving embryos and number of transferable embryos was lower in the PPOS group as compared to that in the long agonist group. The results are in contrast with previous studies which showed comparable embryological characteristics in progestin and short GnRH agonist cycles11-17. Studies with FET cycles provide an opportunity to estimate two different protocols on oocyte quality and subsequent embryo development penitential. In the first and total FET cycles, we found significantly lower clinical pregnancy and live birth rate per frozen embryo transfer as well as implantation rate in PPOS group compared to those in long agonist group. Furthermore, if we combined data from fresh and FFT cycles, the total implantation rate and pregnancy rate per transfer was still significantly lower in the PPOS group indicating the embryos originating from the PPOS protocol may have a reduced development potential to those from the long agonist group. While some researches indicate that elevated progesterone levels do not have a negative impact on the FET results of stimulated cycles using PPOS10 16 25, in most trials, the efficacy and reproductive outcomes of PPOS regimen were compared to short GnRH agonist protocol, which is now rarely used and is recommended to be replaced by the long agonist or the antagonist protocol 26 27. One randomized trial28 compared use of medroxyprogesterone versus a GnRH antagonist on the number of mature oocytes retrieved in oocyte donation cycles. Though no difference was found in the number of mature oocytes between the two groups, the clinical pregnancy rate was 31% versus 46% (P = 0.006) and the ongoing pregnancy rate 27% versus 40% (P = 0.015) for medroxyprogesterone and GnRH antagonists, respectively. This suggests a possible impairment of oocyte quality when medroxyprogesterone was used in ovarian stimulation.
It is difficult to directly compare our results with previous studies as none of the available study evaluated the effect of PPOS on cumulative live birth rates nor assessed time to ongoing pregnancy. In this study we report cumulative live birth rates in one complete cycle, which is the outcome of interest for infertile couples. Not only just single fresh or FET cycle live birth, but also results from one IVF cycle including all subsequent frozen embryo cycles performed within an 18-month period were evaluated,thereby giving the actual efficacy of these two strategies in the daily practice can be compared. Other strengths include none of the patients lost to follow-up in the study, leading to an increased reliability of our outcomes. Furthermore, we performed a Kaplan-Meier analysis to compare cumulative success rate in each group,as it assumed that women who did not return for subsequent FET cycles had the same chance of a pregnancy resulting in a live birth as those who returned for treatment19. Time to pregnancy was much shorter in the long agonist group which is also an important factor to evaluate the efficacy of IVF treatment29 and further strengthen the overall result as PPOS is not beneficial with respect to the cumulative outcomes in two groups.
Safety profile such as ectopic pregnancy rate,miscarriage rate was similar in progestin and GnRH agonist cycles. No patient experienced moderate or severe OHSS in the PPOS group owning to it is applicable for the use of a GnRHa for ovulation trigger and freezing all embryos30. In contrast, though not reaching significant difference, there were four cases of severe OHSS in the long agonist group in which HCG trigger was used and fresh embryo transfer was undertaken in the stimulated cycle. Therefore, PPOS may be more suitable for high responders but not for normal responders in whom a freeze all is likely and OHSS risk is high31 32.
A cost-effectiveness study comparing PPOS with the short GnRH agonist and GnRH antagonist protocols suggested that PPOS was associated with significantly higher cost per live birth when conventional protocols using GnRH analogues were completed with a fresh transfer33. According to data shown in this study, we do not think that PPOS combined with an elective freeze all approach is currently justified for all IVF cycles, because avoiding a fresh transfer does not seem beneficial in the absence of a medical indication when a fresh embryo transfer is not intended34 35.
Our study is limited by its retrospective design. Although we did not calculate the sample size, around 500 cases in each group had enough power to distinguish the 20% difference of the cumulative live birth between the two groups. Cox regression analysis was carried out for controlling the basis possibly produced by imbalanced characteristics between the two groups. Further randomized trials with adequate sample size would be needed to confirm these findings.
In conclusion, in women with a normal ovarian reserve, progestin primed ovarian stimulation was associated with a lower cumulative live birth rates and a long time to pregnancy /live birth than the long agonist protocol.