This prospective randomized clinical pilot trial investigated the effects of GnRH-a as an addition to progesterone luteal support on implantation, clinical pregnancy and LBR, and reported the live birth and the perinatal outcomes following the administration of single-dose GnRH-a in the luteal phase of AC-FET. Recently, Ye et al. provided evidence showing that GnRH-a administration in AC-FET cycles did not increase clinical or ongoing pregnancy. However, the result showed the implantation rate was significantly higher in 35 ~ 37 years old females with GnRH-a. They suggested that GnRH-a add-up could improve the implantation rate in the peri-implantation window in aging females (about 37 years old) through a direct effect on the embryo and improving embryo developmental potential(16). In our study, better pregnancy outcomes were achieved in the intervention group. The positive pregnancy rate, implantation rate, and clinical pregnancy, as well as live birth, were higher, although the differences ranged from 8.2 to 14.7 percentage points were not statistically significant. At the same time, we found that the miscarriages were less frequent with additional GnRH-a, which accounted for the increase of LBR. Apart from the risk of miscarriage, it should be noted that the rate of twin pregnancy in the intervention group was slightly higher than that in the control group. Zhou et al. conducted a retrospective analysis to investigate the effects and safety of mid-luteal GnRH-a support. The result indicated that the GnRH-a-added group had a slightly higher twin pregnancy rate and a significantly higher rate of premature delivery, but no obvious long-term effect on the neonates(17). Therefore, with the precautions taken to control the number of implanted embryos and reduce the incidence of twinning pregnancy, mid-luteal GnRH-a administration is relatively effective and safe.
The recent meta-analysis, which includes 13 RCTs with 3,584 cycles, indicated that the females in IVF/ICSI (Intracytoplasmic Sperm Injection Cycles) received GnRH-a for luteal support had a significantly higher implantation rate and higher rates of pregnancy, clinical pregnancy, and live birth(18). At present, the exact mechanism of the beneficial effects of GnRH-a in luteal phase support is still not completely understood. GnRH-a plays a role in the treatment of LPS in fresh cycles. As novel luteal phase support, GnRH-a may act on the corpus luteum, the endometrium, and the embryo(19). GnRH-a stimulates the secretion of LH by pituitary gonadotropin cells and promotes the corpus luteum function(5). LH release stimulates angiogenetic growth factors and cytokines(20, 21). The expression of GnRH-a and its receptor were found in tissues including endometrium, ootheca, testis, placenta, and myometrium(22). Endometrium expresses GnRH and GnRH-receptor mRNA throughout all phases of the menstrual cycle, with the most intense expression during the luteal phase(23). In human embryonic implantation, there is possibly a close interaction between the endocrine and immune systems through the GnRH and its receptor(24). Experiments in vitro have shown that GnRH-a can regulate the synthesis and secretion of hCG in the preimplantation embryo and placenta and improve the development of cultured embryos(25). Two studies showed that the implantation, pregnancy, and LBR increased with mid-luteal GnRH-a administration on oocyte donation (OD) cycles. The data has implied that embryo development was potentially enhanced, which might be benefited from a GnRH-a direct effect on the embryo(4, 26). Based on this, the GnRH-a administration has also been adopted in FET cycles. However, oocyte donation cycles and autologous frozen embryo transfers were not identical because of a difference in the immunological milieu. Haas et al. reported that the addition of two injections of recombinant hCG and GnRH-a might increase clinical pregnancy rates on the day of transfer and 4d later, respectively, in the NC-FET(11). Seikkula et al. found a higher number of clinical pregnancies and live births in NC-FET with GnRH-a, although the statistical power was too low to show significance(12). Also, as the endogenous luteal activity is lacking in hormonally substituted cycles, the effect of midluteal GnRH-a can be different in natural and artificial FET cycles.
In 2015, Davar et al. designed the first prospective randomized study on GnRH-a administration in AC-FET cycles including 200 patients. On the day of the embryo transfer, the patients in the GnRH-a group were given 0.1 mg triptorelin 3 days after ET. No statistically significant difference was observed between the GnRH-a group and the controls in terms of clinical and ongoing pregnancy rates(13). While in another trial of 220 patients with AC-FET cycles, the ongoing pregnancy rate was significantly increased in the group received GnRH-a at the timepoints of day 2 embryos and vitrified blastocysts(14). Seikkula et al. found that LBR was 9.8 percentage points higher in the GnRH-a group due to the lower number of miscarriages, while the clinical pregnancy rates were similar in both groups(15). The authors called for further studies to confirm the effect of GnRH-a on trophoblast– endometrial interaction. In line with the study of Seikkula, our data showed a distinct but statistically insignificant difference in miscarriage (10.3% vs 25%) and LBR (40.7% vs 28.6%) between the patients with or without GnRH-a on the basis of the standard luteal support. But in clinical practice, a difference of 12.1 percentage points in LBR would be relevant. GnRH-a administration in the luteal phase may possibly enhance the endometrial receptivity and the embryo-endometrium dialogue through activating endocrine-paracrine mechanisms.