Hypoxia-induced polarization of M2 macrophages and C-C motif chemokine ligand 5 secretion promotes the migration and invasion of trophoblasts†.

In the early stage of pregnancy, hypoxia in the placenta is of great significance to the migration and invasion of trophoblasts. In addition, changes to the polarity and activity of macrophages can affect embryo implantation, trophoblast migration and invasion, and vascular remodeling by affecting cytokine secretion. However, the mechanism of the effects of hypoxic conditions in the placenta on trophoblasts remains unknown. We used gene knockdown on macrophages, and drug treatment on trophoblasts, and cultured them under hypoxic and normoxic conditions. The cells were then subjected to wound-healing assays, Transwell cell invasion experiments, quantitative real-time reverse transcription Polymerase Chain Reaction (PCR), western blotting, and immunofluorescence. The polarization of macrophages in each group, the migration and invasion ability of trophoblasts, and changes to the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway were detected. Hypoxic conditions induce M2 polarization of macrophages. The conditioned medium from macrophages under hypoxic conditions increased the migration and invasion of trophoblasts and enhanced the levels of phosphorylated (p)-PI3K and p-AKT in trophoblasts. After C-C motif chemokine ligand 5 knockdown in macrophages, the ability of conditioned medium from macrophages cultured under hypoxic conditions to promote the migration and invasion of trophoblasts was weakened significantly. The use of PI3K/AKT signaling pathway agonists could reverse the attenuation effect caused by C-C motif chemokine ligand 5 knockdown.

Vaginal microbiome dysbiosis as a novel noninvasive biomarker for detection of chronic endometritis in infertile women.

OBJECTIVE: To identify the vaginal microbial signature in women with chronic endometritis (CE) and investigate the potential of vaginal microbiome characterization as a novel diagnostic tools for CE. METHODS: A cross-sectional study was conducted to compare the characteristics of the vaginal microbiome in 98 women who underwent endometrial biopsy for routine clinical inspection of infertility (49 women diagnosed with CE and 49 with non-CE). The vaginal microbiome was analyzed using 16S ribosomal RNA gene amplicon sequencing. The study included an analysis of diversity, bacterial abundance, and microbial function. In addition, microbial markers were identified, and a CE classifier was developed. RESULTS: The relative abundances of genera, including Bifidobacterium, Prevotella and Gardnerella, were found to be different between the two groups. Analysis of the Kyoto Encyclopedia of Genes and Genomes pathways reported differential expression in metabolism-related pathways in the two groups. We identified four microbial markers of CE (Enterobacter, Prevotella, Faecalibacterium, and Phascolarctobacterium) and developed a predictive classifier for diagnosing CE, achieving an area under the curve of 83.26%. CONCLUSION: The results of the current study revealed that, compared with the non-CE controls, patients with CE have a different vaginal microbiota, highlighting the diagnostic significance of the vaginal microbiome as a promising noninvasive biomarker in detecting CE.

[Luteal letrozole administration decreases serum estrogen level but not the risk of ovarian hyperstimulation syndrome].

OBJECTIVE: To explore the efficiency of using aromatase inhibitors during luteal phase in in vitro fertilization IVF stimulated cycles for patients at high risk for ovarian hyperstimulation syndrome (OHSS). METHODS: A total of 139 infertile women undergoing assisted reproductive technique with high risk for OHSS were enrolled in this clinical trial. In the treatment group 43 patients received five consecutive doses of aromatase inhibitors (letrozole) and support therapy combined with embryo cryopreservation. In the control group 96 patients received support therapy alone. All the patients were evaluated clinically, echographically, hematologically and tested for their steroid hormone. RESULTS: There was significantly lower estrogen level in the treatment group 2, 5 and 8 days after oocyte retrieval compared with the control group (P<0.001), There was no significant difference in luteinizing hormone and progesterone levels 2, 5 and 8 days after oocyte retrieval in the treatment group and control group (P>0.05). There were 7 cases of severe OHSS in the treatment group and 18 cases of severe OHSS in the control group. The rate of severe OHSS was not significantly different in the treatment group and control group (P=0.12). No side effect was reported in either group. CONCLUSION: Treatment with letrzolein luteal phase decreases serum estrogen levels of patients after oocyte retrieval,but it couldn't reduce the risk of severe OHSS.

Deletion of ACLY Disrupts Histone Acetylation and IL-10 Secretion in Trophoblasts, Which Inhibits M2 Polarization of Macrophages: A Possible Role in Recurrent Spontaneous Abortion.

Changes to macrophage polarization affect the local microenvironment of the placenta, resulting in pathological pregnancy diseases such as recurrent spontaneous abortion (RSA). Macrophages are in close contact with trophoblasts during placental development, and trophoblast-derived cytokines are important regulators of macrophage polarization and function. Histone acetylation can affect the expression and secretion of cytokines, and ATP citrate lyase (ACLY) is an important factor that regulates histone acetylation. The aim of this study was to investigate the effect of ACLY expression differences in trophoblast on macrophage polarization and its mechanism. Our data demonstrate that ACLY level in placental villi of patients with RSA is decreased, which may lead to the inhibition of histone acetylation in trophoblasts, thereby reducing the secretion of IL-10. Reduced IL-10 secretion activates endoplasmic reticulum stress in macrophages, thus inhibiting their M2 polarization.

Flexible GnRH Antagonist Protocol versus Progestin-primed Ovarian Stimulation (PPOS) Protocol in Patients with Polycystic Ovary Syndrome: Comparison of Clinical Outcomes and Ovarian Response.

Polycystic ovary syndrome (PCOS) is one of the most common causes of infertility in women. Progestin-primed ovarian stimulation (PPOS) protocol, which used oral progestin to prevent premature luteinizing hormone (LH) surges in ovarian stimulation, has been proved to be effective and safe in patients with PCOS. The aim of the present study was to compare the efficacy of PPOS protocol with that of the traditional gonadotropin-releasing hormone (GnRH) antagonist protocol in patients with PCOS. A total of 157 patients undergoing in-vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) were recruited into this study. The patients were divided into two groups by the stimulation protocols: the GnRH antagonist protocol group and the PPOS protocol group. There was no significant difference in the clinical characteristics between the two groups. Dose and duration of gonadotropin were higher in the PPOS protocol group. Estradiol levels on the day of human chorionic gonadotropin (hCG) administration were significantly lower in the PPOS protocol group. Fertilization rates and the number of good quality embryos were similar between the two groups. Remarkably, we found 6 patients with moderate ovarian hyperstimulation syndrome (OHSS) in the GnRH antagonist protocol group but 0 in the PPOS protocol group. A total of 127 women completed their frozen embryo transfer (FET) cycles. There were no significant differences between the two groups in terms of clinical pregnancy rate per transfer, implantation rate, first-trimester miscarriage rate and on-going pregnancy rate per transfer. To conclude, PPOS protocol decreased the incidence of OHSS without adversely affecting clinical outcomes in patients with PCOS.

IL-17 Induces Fetal Loss in a CBA/J×BALB/c Mouse Model, and an Anti-IL-17 Antibody Prevents Fetal Loss in a CBA/J×DBA/2 Mouse Model.

PROBLEM: Many researchers have demonstrated that the expression of interleukin-17(IL-17) is higher in spontaneous abortion. However, whether Th17 cells are an independent factor in inducing abortion is not known. METHOD OF STUDY: This study investigated the effect of exogenous recombinant IL-17 and an anti-IL-17 antibody in a normal and an abortion mouse model using flow cytometry, enzyme-linked immunosorbent assay, real-time PCR, and Western blot. RESULTS: Th17 cells and the related factors, IL-17 and RORγt, were significantly upregulated in abortion mice, and Treg cells and the related factor, Foxp3, were downregulated. Intraperitoneal injection of recombinant IL (rIL)-17 induced fetal loss in a normal mouse model, and an anti-IL-17 antibody prevented fetal loss in an abortion mouse model. CONCLUSION: This study confirmed an imbalance of the Th17/Treg paradigm in abortion mice and IL-17 as a risk factor of fetal loss. An anti-IL-17 antibody may prevent abortion.