Objective: Thin or damaged endometrium remains to be an unsolved problem in the treatment of patients with infertility. The empirical preference for endometrial thickness (EMT) among clinicians is >7 mm, and the refractory thin endometrium, which doesn't respond to standard medical therapies, can be the etiology of recurrent implantation failure (RIF). Autologous platelet-rich plasma (PRP) is known to help tissue regeneration and is widely used in various fields. In the present study, we conducted PRP treatment and investigated its effect on the refractory thin endometrium. Design: Prospective interventional study ( https://cris.nih.go.kr/cris , clinical trial registration number: KCT0003375). Methods: Women who had a history of two or more failed IVF cycles and refractory thin endometrium were enrolled in this study. The main inclusion criteria were EMT of <7 mm after more than 2 cycles of previous medical therapy for increasing the EMT. Twenty-four women were enrolled in this study. The subjects were treated with intrauterine infusion of autologous PRP 2 or 3 times from menstrual cycle day 10 of their frozen-thawed embryo transfer (FET) cycle, and ET was performed 3 days after the final autologous PRP infusion. 22 patients underwent FET, and 2 patients were lost to follow up. Results: The ongoing pregnancy rate and LBR were both 20%. The implantation and clinical pregnancy rates were 12.7 and 30%, respectively, and the difference was statistically significant. The average increase in the EMT was 0.6 mm compared with the EMT of their previous cycle. However, this difference was not statistically significant. Further, EMT of 12 patients increased (mean difference: 1.3 mm), while that of seven patients decreased (mean difference: 0.7 mm); the EMT of one patient did not change. There were no adverse effects reported by the patients who were treated with autologous PRP. Conclusions: The use of autologous PRP improved the implantation, pregnancy, and live birth rates (LBR) of the patients with refractory thin endometrium. We assume that the ability of autologous PRP to restore the endometrial receptivity of damaged endometrium has some aspects other than increasing the EMT. The molecular basis of the treatment needs to be revealed in future studies.

Intimate two-way interactions between the implantation-competent blastocyst and receptive uterus are prerequisite for successful embryo implantation. In humans, recurrent/repeated implantation failure (RIF) may occur due to altered uterine receptivity with aberrant gene expression in the endometrium as well as genetic defects in embryos. Several studies have been performed to understand dynamic changes of uterine transcriptome during menstrual cycles in humans. However, uterine transcriptome of the patients with RIF has not been clearly investigated yet. Here we show that several signaling pathways as well as many genes and microRNAs are dysregulated in the endometrium of patients with RIF (RIFE). Whereas unsupervised hierarchical clustering showed that overall mRNA and microRNA profiles of RIFE were similar to those of endometria of healthy women, many genes were significantly dysregulated in RIFE (cut off at 1.5 fold change). The majority (~75%) of differentially expressed genes in RIFE including S100 calcium binding protein P (S100P), Chemokine (C-X-C motif) ligand 13 (CXCL13) and SIX homeobox 1 (SIX1) were down-regulated, suggesting that reduced uterine expression of these genes is associated with RIF. Gene Set Enrichment analyses (GSEA) for mRNA microarrays revealed that various signaling pathways including Leukemia inhibitory factor (LIF) signaling and a P4 response were dysregulated in RIFE although expression levels of Estrogen receptor α (ERα) and Progesterone receptor (PR) were not significantly altered in RIFE. Furthermore, expression and phosphorylation of Signal transducer and activator of transcription 3 (STAT3) are reduced and a gene set associated with Janus kinase (JAK)-STAT signaling pathway is systemically down-regulated in these patients. Pairwise analyses of microRNA arrays with prediction of dysregulated microRNAs based on mRNA expression datasets demonstrated that 6 microRNAs are aberrantly regulated in RIFE. Collectively, we here suggest that dysregulation of several major signaling pathways and genes critical for uterine biology and embryo implantation may lead to uterine abnormalities in patients with RIF.

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