During the FET cycle, the protocol of HRT with GnRH-a pretreatment for endometrial preparation contributed to a higher live birth rate than using HRT alone in both singleton and twin live birth, mainly due to the better implantation rate. The HRT with GnRH-a cycles and the HRT cycles had similar rates of pregnancy loss. GnRHa-HRT cycles resulted in a higher singleton birth weight than the HRT cycles, but also a higher risk of fetal macrosomia.
Compared with previous studies, the results of this study were different. Several previous randomized controlled trials (RCTs) and retrospective studies have shown that GnRH-a pretreated HRT did not significantly improve pregnancy outcomes. (5, 16–20) Because of this, most of them did not recommend using GnRH-a pretreated HRT for endometrial preparation because of the side effects and high medical costs associated with GnRH-a. After analyzing the above research, we found that the embryo transfer stage and the number of embryos were not among the inclusion criteria in these RCTs. Furthermore, the number of cases of GnRHa-HRT cycles was very limited in the studies mentioned above. The stage and number of embryos transferred will affect the pregnancy outcome to a certain extent. In this study, we verified that the live birth rate of the single cleavage embryo transfer cycle was much lower than that of the other number and type embryo transfer cycles. In addition, studies have shown that compared with cleavage-stage embryo transfer, blastocyst-stage may offer a better chance of live birth. (21–23) A recent RCT study took this into account, but the number of cases also was minimal. (24) In this study, the number and stage of the embryo have no statistical difference in the two groups. Additional this study has multitudes of cases with a similar number of cases and similar baselines in both groups.
Considering the two key factors affecting FET outcome: embryo quality and endometrial receptivity. First, our inclusion criteria were the transfer cycle of high-quality embryos, excluding patients with chromosomal chromosomes. Secondly, we excluded cases of diseases associated with abnormal uterine anatomy and women aged 40 years or older. Moreover, to increase comparability between the two groups, conditions that severely affected pregnancy rates were also excluded: a history of repeated pregnancy loss, tuberculosis, and severe systemic diseases.
Considering that embryo type and number can affect pregnancy rate, we compared the live birth rates in the different numbers and stages of embryo transferred between HRT with and without GnRH-a pretreatment. Our data suggest that HRT with GnRH-a cycle had remarkedly higher in double cleavages transferred cycles, single blastocyst, double blastocysts, and had similar live birth rates in single cleavage, as well as cleavage and blastocyst transferred cycles. Compared to other types, the live birth rate of single-cleavage embryo transfer is low, and GnRH-a pretreatment did not improve the pregnancy rate effectively. This result may be due to the insufficient number of cases of single cleavage and cleavage and blastocyst. But what is certain is that these results can give clinicians some insights into what endometrial preparation protocol to choose and what number and type of embryo to choose.
The GnRHa-HRT group had higher implantation, possibly because GnRH-a could improve the endometrial receptivity. However, the exact mechanism is not clear, and some studies had shown that estrogen supplementation may lead to elevated LH in the absence of GnRH agonist inhibition, thus affecting endometrial receptivity(15, 25, 26). Some studies have suggested that GnRH-a promotes elevated expression of protective endometrial tolerance markers such as HOXA10, MEIS1, and LIF.
In this study, the HRT group and the GnRHa-HRT group had similar rates of pregnancy loss, similar to previous studies(15, 27). In this setting, GnRH-a has no adverse effect on the maintenance of pregnancy.
The risk of fetal macrosomia was higher in the GnRHa-HRT group than in the HRT group, and it may result in heavier singleton in the GnRHa-HRT group than in the HRT group, similar to a previous study's results(26). The gestational age of the pregnancy and the rate of fetal growth jointly determine fetal birth weight. The gestational weeks and gestational age of singleton had no statistical significance between the two groups, and the gestational weeks and gestational age of singleton in the HRT group were numerically higher than those in the GnRHa-HRT group. This suggests that GnRH-a may cause macrosomia by affecting the rate of fetal growth rather than increasing the length of pregnancy.
The limitations of this retrospective study are as follows. 1. The evaluation of embryo quality in this study was not based on preimplantation genetic diagnosis, but on the morphology of the embryo, and the influence of aneuploidy cannot be ruled out. 2. We failed to gather more information on pregnancy-related complications and fetal and accessory abnormalities, such as gestational diabetes, gestational hypertension, placenta previa, and placental abruption, which would allow a more complete evaluation of the efficacy of GnRH-a. 3. There are significant differences in participants' infertility diagnoses. Thus, we were unable to consider the impact of which population with a particular disease can be significantly improved by GnRH-a down-regulation with HRT in FET cycles. 4. The was retrospective research, and a complete randomized, double-blind comparison is impossible.
Further well-designed prospective clinical trials are needed to investigate whether HRT with GnRH-a can improve pregnancy outcomes in specific infertility diagnoses patient subgroups such as male factors, tubal factors, and elderly patients ART. More studies on the molecular mechanisms by which GnRH-a enhances pregnancy outcomes, especially its effect on endometrial receptivity, are needed to guide treatment in specific populations.