Objectives: To evaluate the effect of intrauterine infusion and hysteroscopic injection of autologous platelet-rich plasma (PRP) in patients with a persistent thin endometrium (EM) undergoing euploid frozen embryo transfer (EFET) cycles. Methods: This prospective case-control study enrolled 116 infertile women with thin EM (<7 mm) who underwent hormone replacement therapy (HRT) for EFET. These women had experienced at least one previous unsuccessful EFET cycle, which either resulted in the cancellation of the cycle or failure of pregnancy. A total of 55 women received an intrauterine infusion of PRP before FET, 38 received a hysteroscopic injection of PRP, and 23 received standard HRT treatment without PRP (control group). Only euploid embryos were transferred in these cycles. The primary outcomes were the implantation rate (IR) and clinical pregnancy rate (CPR) after EFET. Results: After receiving intrauterine infusion and hysteroscopic injection of PRP, 78.2% and 55.3% of patients, respectively, showed an EM thickness exceeding 7 mm, followed by embryo transfer. The hysteroscopic injection group demonstrated significantly higher IR (52%), a higher trend of CPR (52%), and a higher live birth rate (38%) than the control group (18%, 22%, and 4%). Conclusions: Intrauterine infusion and hysteroscopic injection of autologous PRP may be effective methods to increase EM thickness in HRT cycles. According to our results, both methods could increase EM thickness, while hysteroscopic injection appeared to provide more significant assistance in increasing IR, CPR, and live birth rate after EFET in patients with persistent thin EM.

Although both subcutaneous injection and intrauterine infusion of granulocyte colony-stimulating factor (G-CSF) have been reported to improve pregnancy outcomes in patients with recurrent implantation failure (RIF), how to administer it is still no consensus. The study aimed to investigate which administration route is optimal. We searched PubMed, Embase, the Cochrane Library (CENTRAL), Web of Science, and China National Knowledge Internet (CNKI) from inception to April 10, 2023, with language in both English and Chinese. The randomized controlled trials (RCTs) compared the effectiveness of G-CSF to treat patients with RIF were included in this network meta-analysis (NMA). The odds ratio (OR) and 95% confidence interval (CI) in pregnancy outcomes (implantation rate, IR; clinical pregnancy rate, CPR; live birth rate, LBR; miscarriage rate, MR; ectopic pregnancy rate, EPR) were summarized by NMA with a random-effects model. A total of 1360 RIF patients from 14 RCTs were included in this NMA, with no publication bias and small sample effects. No direct evidence compared the effectiveness of different administration routes of G-CSF on IR, LBR and MR. Both subcutaneous injection and intrauterine infusion of G-CSF increased the IR (OR = 2.81, 95% CI: 1.10-7.24; OR = 2.15, 95% CI: 1.50-3.07, respectively) and CPR (OR = 2.79, 95% CI: 1.86-4.17; OR = 1.74, 95% CI: 1.30-2.33, respectively) in patients with RIF. According to SUCRA, subcutaneous injection is more likely to be the optimal medication administration route. However, more high-quality studies were also needed to support these, especially IR and LBR.

BACKGROUND: Endometritis is an inflammatory reaction of the lining of uterus, leading to the occurrence of infertility. Platelet rich plasma (PRP) has been proven to exhibit extremely effective for the treatment of endometrium-associated infertility, but the mechanism of its prevention for endometritis remains unclear.
OBJECTIVE: The present study aimed to investigate the protective effect of PRP against endometritis induced by lipopolysaccharide (LPS) and elucidate the mechanism underlying these effects.
METHODS: Mouse model of endometritis was established by intrauterine perfusion of LPS. PRP intrauterine infusion was administered at 24 h after LPS induction. After another 24 h, the uterine tissues were harvested to observe histopathological changes, production of proinflammatory cytokines, variation of the Toll-like receptor 4/nuclear factor κB (TLR4/NF-κB) signaling pathways, and validated the anti-inflammatory effect of PRP. The myeloperoxidase (MPO) activity and concentration of nitric oxide (NO) were determined using assay kit. Proinflammatory chemokines (tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6)) were measured by ELISA and Real-Time PCR. The activity of TLR4/NF-κB pathway in uterine tissues was measured by Western blotting.
RESULTS: Hematoxylin-eosin staining (H&E) appeared that PRP remarkably relieved the impairment of uterine tissues. Detection of MPO activity and concentration of NO revealed that PRP treatment distinctly mitigated infiltration of inflammatory cells in mice with endometritis induced by LPS. PRP treatment significantly affected the expression of TNF-α, IL-1β, and IL-6. PRP was also found to suppress LPS-induced activation of TLR4/NF-κB pathway.
CONCLUSIONS: PRP effectively alleviates LPS-induced endometritis via restraining the signal pathway of TLR4/NF-κB. These findings provide a solid foundation for PRP as a potential therapeutic agent for endometritis.

Gestational diabetes mellitus (GDM) is a gestational disorder characterized by hyperglycemia, that can lead to dysfunction of diverse cells in the body, especially the immune cells. It has been reported that immune cells, specifically natural killer (NK) cells, play a crucial role in normal pregnancy. However, it remains unknown how hyperglycemia affects NK cell dysfunction thus participates in the development of GDM. In this experiment, GDM mice were induced by an intraperitoneal injection of streptozotocin (STZ) after pregnancy and it has been found that the intrauterine growth restriction occurred in mice with STZ-induced GDM, accompanied by the changed proportion and function of NK cells. The percentage of cytotoxic CD27-CD11b+ NK cells was significantly increased, while the proportion of nourished CD27-CD11b- NK cells was significantly reduced in the decidua of GDM mice. Likewise, the same trend appeared in the peripheral blood NK cell subsets of GDM patients. What\'s more, after intrauterine reinfusion of NK cells to GDM mice, the fetal growth restriction was alleviated and the proportion of NK cells was restored. Our findings provide a theoretical and experimental basis for further exploring the pathogenesis of GDM.

Regulatory T cells (Tregs) are a specialized type of T cells that help maintain immune tolerance and homeostasis. The potential of Tregs cell-based therapies in treating diseases has been demonstrated in several clinical trials, which have shown promising outcomes and high safety in autoimmune diseases, transplant rejection, and graft-versus-host disease. However, their effectiveness and safety in improving endometrial receptivity and reducing pregnancy loss in human reproduction are unknown.
The study used a retrospective design and included patients with recurrent pregnancy loss (RPL) and lower levels of endometrial FoxP3+ Tregs. Patients in the Tregs group (n = 33) received intrauterine Tregs infusion three times during the follicular phase, while the control group (n = 28) did not receive any intrauterine infusion.
The intrauterine infusion of autologous Tregs increased the levels of FoxP3+ Tregs and CD56+ NK cells. Patients in the Treg group had higher live birth rates and lower miscarriage rates, especially early miscarriage rates. However, the two groups had no differences in the implantation rate, clinical pregnancy rate, and percentage of preterm delivery.
The findings suggest that intrauterine Tregs infusion may be a potential therapeutic approach for RPL. Further research in larger clinical trials is needed to confirm these findings.

Previous studies of intrauterine infusion therapy in recurrent implantation failure (RIF) patients have shown conflicting results, and there is a lack of head-to-head horizontal comparisons between different drugs. This study aimed to assess the effectiveness of four intrauterine infusion drugs, including human chorionic gonadotropin (HCG), granulocyte colony-stimulating factor (G-CSF), peripheral blood mononuclear cells (PBMCs) and autologous platelet-rich plasma (PRP), in improving pregnancy outcomes in RIF patients through the network meta-analysis. Randomized controlled trials (RCTs) of preimplantation intrauterine infusion for RIF were searched in the Cochrane Library, Embase, Medline and CINAHL. Meanwhile, relevant data were extracted and Stata 15.0 software was applied to statistical analysis. A total of 21 studies with a sample size of 2917 cases were included in this study. Clinical pregnancy rate network meta-analysis showed that, intrauterine infusion of all four drugs is significantly better than the blank and placebo groups, while only PRP could significantly increase live birth rate compared with the blank and placebo groups. The SUCRA plots of clinical pregnancy and live birth rates showed a higher ranking of PRP and PBMCs. Early abortion intervention analysis found that only G-CSF is significantly better than the blank and placebo groups, and the SUCRA plot of G-CSF showed the highest ranking. All these findings confirmed that all four intrauterine infusion drugs can improve pregnancy outcomes in RIF patients to varying degrees, with PRP being the most effective. Further prospective, large-scale and high-quality RCTs are still necessary to determine the exact subgroups of benefit for the different drugs.

OBJECTIVE: To analyze the effect of intrauterine infusion on platelet-rich plasma on hormone levels and endometrial receptivity of patients with repeated embryo implantation failure (RIF).
METHODS: A total of 64 patients with repeated implantation failure and re-fertilization-embryo transfer who were admitted to our hospital from January 2019 to December 2021 were analyzed retrospectively. Among them were 30 patients who did not receive the platelet-rich plasma perfusion therapy. This became the control group (CG). The 34 patients who received the therapy were regarded as the research group (RG). The changes of hormone levels before and after the treatment and endometrial receptivity after the treatment were evaluated. The outcomes of IVF assisted pregnancy, including rates of embryo implantation, clinical pregnancy, and early miscarriage, were compared after the treatment. Risk factors for clinical pregnancy were analyzed by logistic regression.
RESULTS: After treatment, the estradiol (E2) level increased and the follicle stimulating hormone (FSH) level decreased (P<0.05), but there was no marked difference in luteinizing hormone (LH) before or after the treatment (P>0.05). The E2 level in the RG was higher than that in the CG, and FSH in the RG was lower (P<0.05). In comparison to CG, the endometrial thickness on the day of human chorionic gonadotropin (hCG) injection and embryo transfer in the RG increased dramatically (P<0.05). The uterine artery pulsation index (PI) and uterine artery resistance index (RI) decreased (P<0.05). The embryo implantation and clinical pregnancy rates in the RG increased markedly (P<0.01), and the early abortion rate decreased significantly (P<0.05). The logistic regression analysis identified that age, number of transplant failures, treatment regimens, and FSH were risk factors for clinical pregnancy outcomes in patients.
CONCLUSIONS: Intrauterine infusion of platelet-rich plasma can improve the hormone levels in RIF patients, increase endometrial thickness, and enhance endometrial blood flow, increasing the pregnancy rate of patients and improving clinical pregnancy.

The occurrence of metritis during the postpartum period causes serious economic losses in dairy cattle. The Micronised Purified Flavonoid Fraction (MPFF) is a polyphenolic flavonoid compound which is considered to have many health-related properties such as antibiotic, anti-inflammatory, phlebotonic, and several vascular-protecting activities. The aim was to evaluate the effects of a new strategic therapy for metritis based on MPFF intrauterine infusions during the early postpartum in dairy cows naturally infected by Escherichia coli. The clinical effects on reproductive anatomical structures and chronological involution dynamics were monitored until day 24 postpartum by ultrasonography. Moreover, uterine bacteriological and cytological (polymorphonuclear neutrophils; PMNs) profiles were analysed before and after MPFF infusion. The results showed that the success rate (% cure) at day 24 postpartum was improved significantly when using higher MPFF doses (p < 0.05). Moreover, MPFF treatment acutely diminished the size of the cervix and uterus and improved the involution process during the first 24 days (p < 0.05). The prevalence of pathogenic bacteria found in in vitro cultures was significantly variable (p < 0.01), as were the antibiotic sensitivity patterns. Pathogenic bacteria isolates decreased after MPFF applications in a dose−response fashion (p < 0.01), while isolates obtained from controls and low-dose-MPFF-treated animals were stable and similar (p > 0.05). The sensitivity patterns of pathogenic bacteria isolated in in vitro cultures from MPFF-treated animals were variable, although resistance to E. coli, Staphylococcus aureus, Bacillus spp., and coliforms was shown irrespective of the MPFF doses used. However, MPFF-treated cows showed a dose−response effect regarding PMN rates (p < 0.05). The calving-first service, calving−conception interval, and conception rate improved significantly from using higher MPFF doses (p < 0.05). In conclusion, this study shows that MPFF treatment differentially affects uterine involution, bacteriological profiles, cytological traits, and reproductive performance in metritis-positive dairy cows naturally infected by E. coli.

BACKGROUND: Among recurrent implantation failure (RIF) patients, the rate of successful implantation remains relatively low due to the complex etiology of the condition, including maternal, embryo and immune factors. Effective treatments are urgently needed to improve the outcomes of embryo transfer for RIF patients. In recent years, many researchers have focused on immunotherapy using granulocyte colony-stimulating factor (G-CSF) to regulate the immune environment. However, the study of the G-CSF for RIF patients has reached conflicting conclusions. The aim of this systematic review and meta-analysis was performed to further explore the effects of G-CSF according to embryo transfer cycle (fresh or frozen) and administration route (subcutaneous injection or intrauterine infusion) among RIF patients.
METHODS: The PubMed, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) databases were searched for literature published from the initial to October 2020. The meta-analysis, random-effects model and heterogeneity of the studies with I2 index were analyzed. Stata 15 was used for statistical analysis.
RESULTS: A total of 684 studies were obtained through the databases mentioned above. Nine RCTs included 976 RIF patients were enrolled in this meta-analysis. Subgroup analysis indicated that G-CSF improved the clinical pregnancy rate for both the fresh and frozen embryo transfer cycles (fresh RR: 1.74, 95% CI: 1.27-2.37, I2 = 0.0%, n = 410; frozen RR: 1.44, 95% CI: 1.14-1.81, I2 = 0.0.%, n = 366), and for both subcutaneous injection and intrauterine infusion (subcutaneous RR: 1.73, 95% CI: 1.33-2.23, I2 = 0.0%, n = 497; intrauterine RR: 1.39, 95% CI: 1.09-1.78, I2 = 0.0%, n = 479), but the biochemical pregnancy rate of the RIF group was also higher than that of the control group (RR: 1.85, 95% CI: 1.28-2.68; I2 = 20.1%, n = 469). There were no significant differences in the miscarriage rate (RR: 1.13, 95% CI: 0.25-5.21: I2 = 63.2%, n = 472) and live birth rate (RR: 1.43, 95% CI: 0.86-2.36; I2 = 52.5%; n = 372) when a random-effects model was employed.
CONCLUSIONS: The administration of G-CSF via either subcutaneous injection or intrauterine infusion and during both the fresh and frozen embryo transfer cycles for RIF patients can improve the clinical pregnancy rate. However, whether G-CSF is effective in improving livebirth rates of RIF patients is still uncertain, continued research on the utilization and effectiveness of G-CSF is recommended before G-CSF can be considered mainstream treatment for RIF patients.

The objective of this study was to investigate the clinical benefits of intrauterine perfusion with G-CSF in patients undergoing a frozen-thawed embryo transfer (FET) after at least two previous implantation failures. This was a prospective, randomized, single-blind study. The intervention group received an intrauterine infusion of G-CSF whereas the placebo group was given an intrauterine infusion of physiological saline before embryo transfer. A third (control) group did not receive an intrauterine infusion prior to embryo transfer. The clinical pregnancy rates of both the intervention and placebo group were significantly higher than that in the control group (p < 0.05). But the miscarriage rates of the G-CSF were significantly lower than those of the other two groups (p < 0.05). The intrauterine infusion of G-CSF before frozen-thawed embryo transfer significantly reduced miscarriage rates and improve the live birth rates. While intrauterine perfusion with physiological saline did not reduce miscarriage rates.