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.