During COH for treatment by assisted reproductive technology, oestrogen levels are far above normal physiological levels due to the development of multiple follicles. Some patients may also have elevated serum progesterone levels in the late follicular phase. Excessive progesterone can affect the embryo implantation rate and clinical pregnancy rate[4, 5]. This is mainly because excessive progesterone causes asynchronization between the endometrium and embryo development[6]. Therefore, if the progesterone level is too high in the late follicular phase, cancellation of the fresh embryo transplantation cycle and freezing of the embryos are recommended[7]. Compared with that of the fresh embryo cycle, the pregnancy rate of the frozen embryo transfer cycle is higher[8]. Recent studies have shown that excessive progesterone can also affect embryo quality. Vannie et al. studied 986 GnRH antagonist IVF/ICSI cycles, and the results demonstrated that a high-quality blastocyst rate was negatively correlated with high progesterone levels[9]. In cases of high progesterone levels, the “freeze-all" strategy is not the best way to solve the problem because the embryo utilization rate is significantly reduced[10]. However, a previous meta-analysis showed that elevated progesterone levels on the HCG day were not associated with pregnancy rates[11].
There are many progesterone elevation-related indicators for predicting pregnancy outcomes. The simplest indicator is serum P level on the day of HCG injection. Li Rong et al. proposed that serum P levels on the day of HCG injection can predict IVF pregnancy outcomes, but the predictive efficacy is poor (AUC = 0.599). For patients with P levels exceeding 6.0 nmol/L, cancellation of fresh cycle transplantation and freezing ofembryos for frozen embryo transfer with natural cycles are recommended[12]. It is well known that serum P levels during COH are associated with the ovarian response and increase in follicle count and oestradiol levels[13]. Therefore, P/E2 may be more effective for predicting pregnancy outcome than serum P alone[14, 15], but its predictive efficacy is still poor[14, 16]. Shufaro et al. studied women with a normal ovarian response undergoing GnRH agonist and GnRH antagonist protocols, and the results demonstrated that the PFI can better predict the clinical pregnancy rate than serum P[17]. Matheus et al. performed a stratified analysis of patient age during treatment with the GnRH antagonist protocol and found that PFI with a cut-off value of 0.075 is a good predictor for IVF outcome among patients of all ages[18]. Cynthia et al. found that the PMOI was negatively correlated with the clinical pregnancy rate, live birth rate, and implantation rate. The PMOI could predict the live birth rate, while serum P had no predictive value[19]. The researchers also believe that the PFI is affected by the ultrasound equipment and the experience of the examiner and that the PMOI is more reproducible. In addition, studies have indicated that for patients with a PMOI exceeding 0.32, fresh cycle transplantation is recommended[20].
Although there are many studies on the predictive value of P-related indicators for IVF/ICSI pregnancy outcomes, no researchers have included these four commonly used indicators into one study to compare their predictive efficacies. The results of this study showed that there was no significant difference in serum P or P/E2 between the pregnant group and the non-pregnant group in cases where P was < 2.5 ng/ml. The PFI and PMOI of the pregnant group were significantly lower than those of the non-pregnant group. According to the stratified analysis of the ovarian response, the results showed that only in the normal ovarian response group were the PMI and PMOI of the pregnant group lower than those of the non-pregnant group, and the differences were statistically significant. This may be because factors affecting pregnancy outcomes are more complicated among patients with a poor ovarian response or high ovarian response, including the number of retrieved oocytes and higher levels of oestrogen such that the effect of elevated P levels on pregnancy outcomes is relatively small. In this study, ROC analysis was performed to determine the predictive value of these indicators. The results showed that in cases of progesterone < 2.5 ng/ml, the PFI and PMOI had some value in predicting clinical pregnancy outcomes in the normal ovarian response group, but their predictive efficacies were poor. Compared with the PFI and PMOI, the prediction efficiency was approximately equal. Therefore, in the process of clinical practice, each clinical centre can choose one of the indicators according to their actual situation. For example, some centres do not always know the number of follicles (≥ 14 mm) on HCG day; in these cases, the PMOI can be used.
We speculate that there is a threshold for P levels and that below this threshold, the P level does not affect embryo quality, endometrial receptivity, or the clinical pregnancy rate. Different studies have different definitions of thresholds for excessive P levels[11], and our reproductive centre recommends cancelling fresh cycle transplantation when P exceeds 2.5 ng/ml[12]. Therefore, this study was conducted mainly to compare the predictive value of P-related indicators for pregnancy outcome of women undergoing the short-acting GnRH agonist long protocol when P is < 2.5 ng/ml.
The limitation of this study is that we cannot explore the predictive value of P-related indicators for pregnancy outcome when P exceeds 2.5 ng/ml due to ethical issues. Instead, we can use animal models to further explore the highest threshold for P that does not affect pregnancy outcomes.