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.