Discussion
INADEQUATE LUTEAL PHASE
The correlation between low serum progesterone levels around the timing of embryo transfer and decreased LBR has been demonstrated in artificial and natural frozen embryo transfer cycles (The lower limit of serum progesterone concentration indicative of an adequate luteal phase in natural cycles is not yet clear. However, mid-luteal serum concentrations of about 10 ng/mL are mostly accepted as adequate progesterone production by the corpus luteum during a natural cycle (Our study is the first study in patients undergoing t-NC FET to evaluate the feasibility of the alternative approach, reserving the initiation of progesterone support when the serum levels of progesterone are below 10 ng/mL on the day of ET. If this approach had been practical, it might have rescued nearly half of the tNC-FET cycles with adequate serum progesterone concentrations from unnecessary progesterone supplementation.The major finding of our study is that rescue protocol by adding SC progesterone is effective and as a result no significant difference could be shown in terms of OPR. At the same time, CPR in patients with low serum progesterone concentrations on ET day was lower despite LPS with sc progesterone supplementation. Our study has found that although pregnancy rates are similar, CPR is inferior in cycles with low serum progesterone despite the initiation of SC progesterone on ET day because of a higher incidence of biochemical pregnancies in this group. Therefore, SC progesterone supplementation can not sustain the essential luteal phase support when initiated on the day of ET if the endogenous CL function is inadequate. There are two possible explanations for this finding: Either we are too late to initiate luteal phase rescue, or the support dose/mode (sc) is inadequate. According to our best knowledge, our study is the first study to evaluate the effect of sc progesterone supplementation on PRs in tNC-FET based on serum progesterone level on ET day. Our previous study in programmed artificial FET cycles evaluated the effect of additional rescue. SC progesterone supplementation for restoring serum progesterone level in patients with low serum progesterone concentration on ET day, two days after the rescue treatment (Bjuresten et al. reported an improvement in LBRs with 400 mg twice daily of vaginal progesterone in NC-FETs in their RCT, including 435 women (30% vs. 20%, P = 0.02), compared to those without supplementation (We have previously mentioned a debate in the literature related to the beneficial effect of progesterone supplementation as LPS in tNC-FET. For tNC-FETs, it remains an open question about how to support the luteal phase, which dosages and agents to use, and the LPS’s efficacy for these selected agents in clinical practice. In this regard, our study may shed more light on our knowledge to affect the current practice for NC-FET.There are few points related to the current study as limitations. The first limitation is that it is a retrospective study with a relatively small sample size and that we did not report LBRs. We do not think patients with low serum progesterone concentrations on ET day can be refrained from progesterone supplementation because of the well-documented strong relationship between adequate serum progesterone concentrations and successful implantation and pregnancy outcome. Furthermore, the design of our practice to add LPS rescue with SC 25 mg progesterone is a clinically proven mode of action in artificial FET cycles when serum progesterone levels are found in a suboptimal range for a successful outcome on the day of ET. The only difference was that this strategy was never validated in tNC-FET cases. We were expecting the same beneficial effect of this strategy in tNC-FET cases since we have an additional functioning CL in a natural cycle. The second limitation is that serum progesterone concentrations were not measured after starting progesterone supplementation to confirm the attainment of adequate levels with sc progesterone. The design of our study, SC progesterone supplementation as LPS in natural cycles FET based on serum progesterone level on ET day, might be considered as the strength of our study.In conclusion, according to our results, almost half of the patients who undergo tNC-FET might need LPS because of low serum progesterone concentrations on ET day. The measurement of serum progesterone level on ET day may create the opportunity for progesterone supplementation for patients with low serum progesterone concentrations. On the other hand, daily 25 mg sc progesterone supplementation may achieve similar OPR. Starting luteal phase support earlier than the day of embryo transfer in all NC-FET cases may be a better clinical decision in this setting until cut-off levels of P on the day of ET in tNC-FET is established and the benefit of rescue protocol is proven by RCTs. Further well-designed randomised controlled trials with large samples of patients are needed to evaluate the cutoff level of serum progesterone, which determine the necessity of LPS and the effect of sc progesterone supplementation as LPS on LBR during NC-FET.