Increased Uterine NK cell numbers and perforin expression during the implantation phase in IVF Cycles with GnRH Antagonist Protocol

Abstract

GnRH antagonist negatively affects endometrial receptivity in in vitro fertilization (IVF) cycles, however, its underlying mechanism remains unclear. To explore its target molecules, we studied endometria in the window phase of fixed GnRH antagonist, low-dose flexible GnRH antagonist, GnRH agonist long protocol, and untreated control groups. There were 384 differentially expressed genes (DEGs) in the fixed antagonist group with greater than twofold expression change compared with the control group and 197 DEGs between the fixed antagonist and agonist groups, the majority of which were associated with the natural killer (NK) cell-mediated cytotoxicity pathway. We then analysed the PRF1 and FASLG protein levels. The perforin level were significantly higher in both the antagonist groups than in other two groups, and was higher in the fixed antagonist group. Similarly, the uNK cell numbers were higher in the antagonist groups, and the highest uNK cell number occurred in the fixed group (p < 0.05). No significant differences existed in the Fas ligand levels and apoptosis rates among the three treatment groups, but were higher in the treatment groups than the control group. Together, these data indicate that GnRH antagonist may increase the uNK cell numbers and perforin expression, and this effect may be dose-dependent.

Efficacies of different ovarian hyperstimulation protocols in poor ovarian responders classified by the POSEIDON criteria

“…Some studies have suggested that there are lower implantation rates for the GnRH-ant protocol than for the GnRH-a protocol due to differences in endometrial receptivity [23,32]. However, in our study, the implantation rates did not differ among the three ovarian hyperstimulation protocols, regardless of the POSEIDON group.…”

“…However, the effectiveness and reliability of the GnRHant protocol are still debated [20,21]. In several recent trials and meta-analyses, lower pregnancy rates and higher cancelation rates were observed with the GnRHant protocol than with the GnRH-a long protocol [22] or the GnRH-a short protocol, especially in patients with < 4 oocytes retrieved in previous controlled ovarian stimulation cycles or in those with expected POR, raising concerns about the effectiveness of the GnRHant protocol in poor ovarian responders [4,23]. A series of studies suggested that the adverse effect of the GnRH-ant on endometrial receptivity is the main reason for the lower pregnancy and clinical pregnancy rates with this protocol [24,25], and this proposal warrants further investigation.…”

Flexible Low-Dose GnRH Antagonist Protocol Is Effective in Patients With Sufficient Ovarian Reserve in IVF

“…A series of recent studies has confirmed that the adverse effects of GnRH-ant on endometrial receptivity were the main reason for this difference in pregnancy rate (4). Furthermore, in our previous studies we demonstrated the dose-related harmful effects of GnRH-ant on endometrial receptivity (6, 7).…”

“…Furthermore, Group 1 had a notable reduction in GnRH-ant consumption and reduced duration of stimulation compared with Group 2; this might result in improved pregnancy outcomes in Group 1. Many studies have reported that GnRH-ant is unfavorable for endometrial receptivity (4, 22), and our previous studies also found that antagonists caused uterine natural killer (uNK) cells and inflammatory factors such as perforin and tumor necrosis factor α (TNFα) to increase in a dose-dependent manner (6, 7). Furthermore, prolonged ovarian stimulation was associated with a decreased rate of superior-quality embryos and lower implantation, and live birth rates (23–25).…”

An insight into the role of the death receptor CD95 throughout pregnancy: Guardian, facilitator, or foe

“…However, it has been also associated with less successful embryo implantation and live birth rates, mainly caused by lower endometrial receptivity (Kdous, Chaker, Bouyahia, Zhioua, & Zhioua, ). A possible cause for this failure could be the fact that CD95L protein expression is increased in the endometrium of patients treated with GnRH antagonists, concomitant with higher levels of 17β‐estradiol, responsible for up‐regulation of CD95L mRNA and cytotoxicity of NK cells (Hao et al, ; Xu et al, ). Melatonin has also been used to improve the ratio of successful implantations in IVF procedures.…”