Search

Background: Treatment of thin endometrium with granular leukocyte-colony stimulating factor (G-CSF) remains controversial., Aim: To investigate the effect of G-CSF on the outcome of frozen embryo transfer in patients with thin endometrium., Methods: A retrospective propensity score matching (PSM) study was performed to assess patients administered frozen embryo transfer at the Reproductive Medicine Center of the Affiliated Drum Tower Hospital of Nanjing University Medical School, in 2012-2018. The patients were divided into G-CSF intrauterine perfusion (G-CSF) and non-G-CSF groups, and clinical pregnancy, implantation, ectopic pregnancy, and early abortion rates between the two groups were compared., Results: Before PSM, 372 cycles were enrolled, including 242 and 130 cycles in the G-CSF and non-G-CSF groups, respectively. Age (34.23 ± 5.76 vs 32.99 ± 5.59 years; P = 0.047) and the blastula/cleavage stage embryo ratio (0.68 vs 0.37; P = 0.011) were significantly elevated in the G-CSF group compared with the non-G-CSF group; however, clinical pregnancy (46.28% vs 51.54%; P = 0.371) and embryo implantation (35.21% vs 35.65%; P = 0.910) rates were similar in both groups. After PSM by age and blastula/cleavage stage embryo ratio, 244 cycles were included (122 cases each in the G-CSF and non-G-CSF groups). The clinical pregnancy (50.82 % vs 48.36%; P = 0.701) and embryo implantation (37.38% vs 34.11%; P = 0.480) remained similar in both groups., Conclusion: Intrauterine infusion of G-CSF does not improve the clinical outcome of frozen embryo transfer in patients with thin endometrium., Competing Interests: Conflict-of-interest statement: All authors declare that there are no any conflicts of interest., (©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.)

The poor vascular development of an endometrium is the key cause of a thin endometrium due to the vascular endothelial growth factor (VEGF) decreasing in the glandular epithelium. Hence, inducing angiogenesis is an effective strategy for thin endometrium treatment in clinic. Herein, we developed a novel angiogenic hydrogel microsphere based on methacrylated hyaluronic acid (HAMA) loaded with VEGF for the treatment of a thin endometrium by a microfluidic electrospray technique. The generated HAMA microspheres with uniform size, porous structure, and satisfactory biocompatibility increased the drug-loading ability and controlled the drug-release rate by adjusting the hydrogel concentration. Besides, the HAMA microspheres loaded with VEGF showed satisfactory biocompatibility and promoted blood vessel formation in vitro. More importantly, the combination of HA and VEGF promoted new blood vessels and endometrial regeneration of a thin endometrium in vivo. Therefore, the combination of HA and VEGF would be conducive to the development of a drug-delivery microsphere with excellent biocompatibility and therapeutic effect for thin endometrium treatment and other biomedical applications.

Background: Human infertility is caused by many factors, among which thin endometrium is the main reason for poor embryo implantation. Currently, stem cell therapy could be a potential approach in treating human endometrial disorder like thin endometrium. In this study, we aimed to explore the influence of menstrual stem cells from non-thin endometrium (NTE-MenSCs) and thin endometrium (TE-MenSCs) on the phenotype of endometrial epithelial cells (EECs)., Methods: The MenSCs were isolated from women with and without thin endometria, characterized and co-cultured with the EECs. The expression of cytokeratin 7 (CK7) was verified by immunofluorescence while the detection stem cell markers was determined flow cytometry. Osteogenic and adipogenic differentiation were induced in appropriate media. The quantitative real-time PCR and western blotting were respectively used for detecting the mRNA and protein expression levels, respectively. The CCK-8 assay was used for cell viability analysis whereas ELISA was used for the detection of cytokine levels., Results: The results showed that the co-culture of NTE-MenSCs or TE-MenSCs and EECs promoted the proliferation, migration, and angiogenesis of endothelial progenitor cells differently. Furthermore, the TE-MenSCs promoted the expression of inflammation, vascularized adipose, and extracellular matrix related proteins. The epidermal growth factor (EGF)/Ras p21 pathway was found to mediate the influence of MenSCs on EECs., Conclusions: These findings are vital in that they may promote stem cell therapy of thin endometrium and enable embryo implantation in humans with thin endometrium., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/atm-21-4652). The authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Background: A thin endometrium has become a common reason for the repeated implantation failure. Growth hormone (GH) can regulate the proliferation and metabolism of endometrial cells. The aim of this study was to explore the effect of GH on thin endometrium., Methods: A total of 48 female Sprague-Dawley (SD) rats were randomly assigned to the following 4 groups with 12 rats in each group: blank control, model, subcutaneous, and GH groups. The blank control group was untreated and maintained in a routine manner. The model, subcutaneous, and GH groups were intrauterine perfused with 95% ethanol during estrus. After 6-8 h, the model group was intrauterine perfused with 0.2 mL normal saline, the subcutaneous group received subcutaneous injection of 0.12 mg/kg GH dissolved in 0.2 mL normal saline, and the GH group was intrauterine perfused with 0.12 mg/kg GH dissolved in 0.2 mL normal saline. Hematoxylin and eosin (HE) staining was used to examine the thickness of the endometrium. The expression of cytokeratin and vimentin was detected by western blotting and immunohistochemistry., Results: The intima thickness in the GH group and blank control group was increased compared with that in the model group (P<0.01). The intima thickness in the subcutaneous group was increased compared with that in the model group, but there was no significant difference. The expression of vimentin and cytokeratin was increased in the GH (P<0.01) and blank control (P<0.01) groups compared with that in the model group., Conclusions: Intrauterine perfusion of GH can promote the regeneration and repair of thin endometrium in rats. The therapeutic effect of uterine infusion of GH is better than that of subcutaneous injection of GH., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/atm-21-3583). The authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Endometrial injury and intrauterine adhesions are increasingly reported in recent years; however, treatment options remain limited. Intravenous injection of mesenchymal stem cells (MSCs) for endometrium regeneration has limited effectiveness as the retention rate of transplanted cells is low. Hydrogel-based tissue-engineered solutions, such as MSC-seeded bioscaffolds, are reported to increase retention rates; however, a less invasive alternative is still desirable. 560-µm homogeneous Matrigel microspheres are fabricated, loading them with about 1500 MSCs and injecting them into the injured endometria of rats' uteri. This minimally invasive procedure is proved to significantly increase endometrium thickness by over onefold after 21 d (p < 0.0001) and fertility rates from 25% to 75% in impaired and repaired uteri (p < 0.001), respectively. This study provides a minimally invasive alternative to endometrium repair with the promise to establish a broad-spectrum technique for MSC transplantation., (© 2021 Wiley-VCH GmbH.)

Objective: This trial was designed to assess the treatment effects of granulocyte colony-stimulating factor (G-CSF) and transcutaneous electrical acupoint stimulation (TEAS) on thin endometrium in frozen-thawed embryo transfer (FET) cycles. Methods: Ninety-nine patients with previous cancellations of embryo transfer were included, 56 of whom were prospectively treated with intrauterine perfusion of G-CSF in subsequent FET cycles. The selected patients were randomized into the G-CSF perfusion only group and the G-CSF perfusion combined with TEAS group. The other 43 patients were retrospectively included as controls. Results: Compared to previous cycles, endometrial thickness was statistically significantly increased in the two treatment groups (5.97 ± 0.60, 7.52 ± 0.56, 6.14 ± 0.52, and 7.66 ± 0.44; P = 0.00 and 0.00, respectively). The increases in endometrial thickness suggested that no statistically significant difference was found between the two treatment groups. The G-CSF with TEAS group suggested a higher embryo implantation rate than the G-CSF perfusion only and control groups (33.33 and 29.1% and 33.33 and 17.39%; P = 0.412 and 0.091, respectively). The G-CSF combined with TEAS group demonstrated nominally higher clinical and ongoing pregnancy rates than the G-CSF perfusion-only group and controls, though, the difference was not statistically significant. Conclusion: G-CSF has a potential role in improving endometrium thickness in patients with thin unresponsive endometrium in FET treatment cycles. In addition, when combined with TEAS, G-CSF perfusion treatment also improves the embryo implantation rate; however, randomized controlled trials are highly demanded to provide high-grade evidence regarding clinical pregnancy rate after G-CSF perfusion treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Song, Zhang, Zhu and Shan.)

An adequate thickness and pattern of the pre-ovulatory endometrium is considered one of the essential requirements for a successful pregnancy. Although various methods for increasing endometrial thickness have been proposed, the real value of these interventions remains controversial. Here, we present a case of successful administration of extended estrogen supplementation before conventional controlled ovarian hyperstimulation in a woman who had experienced repeated implantation failure because of an unresponsive thin endometrium. After the estrogen supplement was administrated for an extended period, the in vitro fertilization/embryo transfer in this patient led to an uneventful twin pregnancy and delivery at term. [ABSTRACT FROM AUTHOR]

Infertile women undergoing ovulation induction (OI) with clomiphene citrate (CC) who have adequate follicular recruitment and an endometrial thickness of <7 mm as determined by transvaginal sonography in the late follicular phase were switched to tamoxifen for OI in a subsequent cycle. A comparison between the endometrial thickness on CC and tamoxifen was made with by paired analysis. For women undergoing OI with CC who have adequate follicular recruitment and thin endometrium (<7 mm), switching to tamoxifen in subsequent cycles improves endometrial thickness. [Copyright &y& Elsevier]

This study aims to investigate the effects of intrauterine perfusion of granulocyte colony-stimulating factor (G-CSF) on a thin-endometrium rat model. Twenty rats in two groups of 10 were used. Group I was perfused with normal saline (NS) in the right uterine horn and 95% ethanol in the left one. Group II was bilaterally perfused with 95% ethanol into the uterine horns. After three estrous cycles, Group II was perfused with NS in the right uterine horn and G-CSF (30 μg/kg) in the left one. Hematoxylin–eosin (HE) and immunohistochemistry (IHC) staining were used to detect changes in endometrial thickness and expression of cytokeratin 19 (CK19) and vimentin (Vim). The relative expression levels of vascular endothelial growth factor (Vegf) and leukemia inhibitory factor (Lif) were also tested via reverse transcription-quantitative real-time polymerase chain reaction (RT-qPCR) and Western-blot analyses. G-CSF treatment significantly increased the thickness of the endometrium in the 95% ethanol-induced thin-endometrium rat model. The expression levels of endometrial glandular epithelial cell marker for CK19 and stromal cell marker Vim were augmented in the G-CSF-treated group compared with the control group. Moreover, G-CSF treatment stimulated the expression of VEGF and LIF in the 95% ethanol-induced thin-endometrium rat model. G-CSF intrauterine perfusion improved endometrial receptivity in the thin-endometrium rat model by stimulating endometrial proliferation and angiogenesis. • Intrauterine perfusion of G-CSF could significantly increase the thickness of endometrium in thin-endometrium rat model. • Cytokeratin 19 and Vimentin were augmented in G-CSF treatment group when compared to control group. • G-CSF treatment could stimulate the expression of VEGF and LIF in thin-endometrium rat model. • G-CSF might improve endometrial receptivity through stimulating endometrial proliferation and angiogenesis. [ABSTRACT FROM AUTHOR]

In patients whose embryo transfer has been previously canceled due to a thin endometrium, the injection of platelet-rich plasma (PRP) guided by hysteroscopy into the endomyometrial junction improves endometrial thickness and vascularity. This may well serve as a novel approach for the management of these patients. In this study, 32 patients aged between 27 and 39 years, suffering from primary or secondary infertility, were selected for hysteroscopic instillation of PRP. This cross-sectional study included a retrospective assessment of the improvement of endometrial thickness (>7 mm) on the commencement of progesterone treatment in 24 of 32 patients (75%) after hysteroscopy-guided injections of PRP into the subendometrial zone. After PRP instillation, the endometrium was 7 mm or thicker in 24 of 32 patients, and all 24 patients underwent frozen embryo transfer. Moreover, 12 of 24 patients who underwent embryo transfer conceived, whereas 10 had a clinical pregnancy with visualization of cardiac activity at 6 weeks and two had a biochemical pregnancy. Our approach of PRP injection into the subendometrial region is consistent with the histologically proven regeneration of the endometrium from the endomyometrial junction. We observed an improvement of endometrial thickness and higher pregnancy rates in cases of previously canceled embryo transfer due to a thin endometrium. [ABSTRACT FROM AUTHOR]

• GM-CSF improves regeneration of injured endometrium in mice. • GM-CSF increases the proliferation of primary human endometrial glandular cell and the migration of stromal cell. • GM-CSF has potential application in clinical treatment for thin endometrium. Endometrial injury can result in thin endometrium and subfertility. Granulocyte macrophage colony stimulating factor (GM-CSF) contributes to tissue repair, but its role in endometrial regeneration has not been investigated. To determine the effect of GM-CSF on endometrial regeneration, we established a mouse model of thin endometrium by uterine perfusion with 20 μL 90% ethanol. Thin endometrium in mice was featured by lowered endometrial thickness, decreased expression of Ki67 in glandular cells, and a reduced number of implantation sites. To explore the mechanism of GM-CSF on endometrial regeneration, endometrium was obtained from patients undergoing hysterectomy or hysteroscopy and endometrial biopsy. Effects of GM-CSF on primary cultured human endometrial glandular and stromal cells were examined by the 5-bromo-2′-deoxyuridine (BrdU) proliferation assay and transwell migration assay, followed by exploration of the potential signaling pathway. GM-CSF intraperitoneal (i.p.) injection significantly increased endometrial thickness, expression of Ki67 in endometrial glandular cells, and the number of implantation sites. GM-CSF significantly promoted proliferation of primary human endometrial glandular cells and migration of stromal cells. GM-CSF activated p-Akt and increased expressions of p70S6K and c-Jun, which were blocked by LY294002. We found that GM-CSF could improve endometrial regeneration, possibly through activating PI3K/Akt signaling pathway. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of joint administration of electroacupuncture (EA) and bone marrow mesenchymal stem cells (BMMSC) on the expression of estrogen receptor (ER) and progesterone receptor (PR) in thin endometrium rats, so as to explore its mechanisms underlying improvement of conception rate., Methods: Forty female SD rats were divided into control, model, BMMSC and EA+BMMSC groups. The thin endometrium model was established by intrauterine infusion of 95% ethanol and saline. EA (1 mA, 2 Hz/15 Hz) was applied to "Guanyuan"(CV4), unilateral "Zigong" (EX-CA1) and unila-teral "Sanyinjiao" (SP6) for 15 min, once daily for 10 d. Rats of the BMMSC and EA+BMMSC groups received injection of BMMSC suspension through caudal vein on the day of modeling, the 3 rd day after surgery, and the 2 nd and the 3 rd estrus phases, respectively. Changes of body weight and estrus phase were continuously recorded. After three estrus cycles, uterine specimens were taken and the uterine coefficient was calculated. The immunoactivity of KI67(an antigen for cell proliferation) was detected by immunohistochemistry, and the expression of ER and PR was detected by Western blot., Results: Compared with the control group, the uterine coefficient, and expression of endometrium ER and PR proteins were significantly decreased in the model group ( P <0.001, P <0.01). In Comparison with the model group, the uterine coefficient, immunoactivity of KI67, and expression of ER and PR proteins were significantly increased in both BMMSC and EA+BMMSC groups ( P <0.000 1, P <0.001, P <0.01). The expression level of PR in the EA+BMMSC group was notably higher than that in the BMMSC group ( P <0.05), but no significant difference was found between the BMMSC and EA+BMMSC groups in the levels of uterine coefficient and ER expression ( P >0.05)., Conclusion: EA combined with BMMSC injection has a positive effect in promoting the proliferation of endometrium cells in rats with thin endometrium, which may be related to its effect in up-regulating the expression of ER and PR proteins.

Objective: To explore the influence for combination of Dingkun Dan with estradiol valerateon in treating rats with thin endometrium with Kidney-Yang deficiency based on Wnt/β-catenin signaling pathway., Methods: The estrous period 40 rats were randomly divided into the normal control group, the model group, the Dingkun Dan group, the estradiol valerateon group and the combination group, with 8 rats in each group. In addition to the normal control group, the rat model of thin endometrium with Kidney-Yang deficiency was established in other groups. The control group used free diet, the model group was given distilled water, the estradiol valerateon group was treated with progynova by gavage at 0.3 mg/(kg·d) , Dingkun Dan group was treated with Dingkun Dan by gavage at 2.26 g/(kg·d), and the combined group was given Dingkun Dan at 2.26 g/(kg·d) on the basis of progynova at 0.3 mg/(kg·d). After 3 estrous cycles, the rats were killed and harvested. HE staining was used to observe histopathologic changes in endometrium. The expression of VEGF in rats endometrium were detected by immunohistochemistry. The expression of β-catenin, E-cadherin and MMP-9 protein in rat endometrium was detected by Western blot., Results: Compared with the control group, the uterine cavity was narrowed or enlarged, the endometrium glands and blood vessels were sparse, and the endometrium was thinner significantly in the model group ( P <0.01); the levels of VEGF was decreased significantly ( P <0.01), while β-catenin, E-cadherin and MMP-9 were increased significantly ( P <0.01). Compared with the model group, more endometrial glands, rich intimal vessels, the endometrium were thickened significantly in the 3 treatment groups ( P <0.01 or P <0.05); the levels of VEGF was increased differently. The protein levels of β-catenin and E-cadherin were significantly decreased in each treatment group ( P <0.01), and MMP-9 were significantly decreased in the Dingkun Dan group and in the combination group ( P <0.01). Compared with the estradiol valerateon group, the level of β-catenin in Dingkun Dan group was higher, and MMP-9 was lower ( P <0.05 or P <0.01). The levels of β-catenin and MMP-9 in the combination group were significantly decreased ( P <0.01). Compared with the combination group, the levels of β-catenin was increased significantly, while decreased signicantly in Dingkun Dan group ( P <0.01 or P <0.05)., Conclusion: Dingkun Dan combined with estradiol valerateon can increase the thicken of the endometrium by up-regulation of VEGF, while down-regulate of β-catenin, E-cadherin and MMP-9 in rats with Shen-Yang deficiency and thin endometrium., (Copyright© by Editorial Board of Journal of Sichuan University (Medical Sciences).)

Objective: Endometrial thickness is a prognostic factor for successful pregnancy. This meta-analysis aimed to examine the role of sildenafil citrate on infertile women with a thin endometrium., Methods: Two investigators independently searched the literature on sildenafil citrate and infertile women with a thin endometrium from PubMed, EMBASE, and the Cochrane Controlled Trials Register Database from inception to January 2019., Results: Nine studies involving 1452 patients were included for analysis in our study. We found that endometrial thickness in patients who received sildenafil citrate was significantly higher than that in the control group (placebo or no treatment) (weighted mean difference: 1.22; 95% confidence interval [CI]: 1.07-1.38). The radial artery resistance index was significantly lower (weighted mean difference: -0.12; 95% CI: -0.17 to -0.06), and the clinical pregnancy rate (risk ratio: 1.31; 95% CI: 1.11-1.53) and biochemical pregnancy rate (risk ratio: 1.45; 95% CI: 1.11-1.89) were significantly higher in the sildenafil citrate group compared with the control group., Conclusion: Sildenafil citrate is effective in improving endometrial thickness, the clinical pregnancy rate, and the biochemical pregnancy rate in women who have a thin endometrium. This treatment is a potential therapeutic intervention for a thin endometrium.

The aim of this paper was to investigate the effect of Dingkun Dan on endometrial receptivity in rats with multiple lesions. Forty SD female rats with regular sexual cycle were randomly divided into 5 groups, control group, model group, progynova group, Dingkun Dan group and combination group. The thin endometrium model of kidney-yang deficiency was established in all the other rats except normal control group. The rats in normal control group were free to drink and eat; the rats in the model group were administered with distilled water; the rats in the progynova group were treated with progynova; rats in Dingkun Dan group were treated with Dingkun Dan, and the rats in combination group were treated with Dingkun Dan and progynova. After 15 days, serum levels of OPN, VEGF and MMP-9 were measured by ELISA. HE staining, immunohistochemistry and RT-PCR were used to analyze endome-trial morphology, endometrial thickness and the treatment mechanism of Dingkun Dan. As compared with the control group, the serum levels of OPN, VEGF and MMP-9 in the model group were significantly increased(P&lt;0.01). As compared with the model group, the serum levels of OPN and MMP-9 were decreased in Dingkun Dan group(P&lt;0.05, P&lt;0.01). As compared with the control group, endometrial stromal cells were fewer, the endometrium glands and blood vessels were sparse, and the endometrium was thinner significantly in the model group(P&lt;0.01). As compared with the model group, there were more endometrial glands, rich intimal vessels, and dense stromal cells in various treatment groups, and the endometrium were thickened significantly in the treatment groups(P&lt;0.01). As compared with the control group, the expression area of CK19 in the model group was decreased significantly(P&lt;0.01). As compared with the model group, the expression area of CK19 in each treatment group was increased significantly(P&lt;0.05). As compared with the control group, endometrial β-catenin and MMP-9 mRNA expression levels were increased significantly in the model group(P&lt;0.05), while VEGF mRNA expression was decreased(P&lt;0.05). As compared with the model group, MMP-9 mRNA expression was decreased significantly in the progynova group and the combination group(P&lt;0.05). Dingkun Dan combined with progynova can improve endometrial receptivity by up-regulating expression of β-catenin, VEGF mRNA and down-regulating the expression of MMP-9 mRNA in the injury rats.

Objective: Our primary objective was to evaluate the endometrial changes before and after the transfer of endometrial mesenchymal stem cells (enMSCs) in a population of thinned endometrium women, with absence or hypo-responsiveness to estrogen and repeated implantation failure (RIF). The secondary objective was to evaluate the clinical outcomes of the intervention in terms of clinical pregnancy (CP), early abortions, ongoing pregnancy and live birth delivery rate (LBDR) per in vitro fertilization (IVF) cycle., Methods: A longitudinal and experimental study. The intervention was defined as "subendometrial inoculation of enMSCs," and the post-intervention changes were evaluated by the following variables: endometrial thickness (Eth), endometrial flow cytometry (enFC), endometrial histopathology (enHP) and endometrial immunohistochemistry (enIHQ). The variables were analyzed after the intervention (Post-treatment) regarding previous values (Pretreatment)., Results: Eth values before and after treatment with enMSCs were 5.24±1.24 mm vs. 9.93±0.77 (p=0.000), respectively. Endometrial Flow Cytometry showed significant differences in favor of Normalized variables in the post-treatment assessment, associated with the pretreatment, LT/Li, LB/Li, NK/Li, CD8/CD3+ and CD4/CD8 (p≤0.015), respectively. Only two variables Li/PC and CD4/CD3 had NS (p=0.167 and 0.118). A similar analysis was performed on enHP with an HP increase post-treatment (p=0.007). The CP rate was 79.31% (23/29), a live birth delivery rate per embryo transfer was 45.45% (10/22) and ongoing pregnancy 7/29 (24.14%)., Conclusion: Subendometrial enMSCs inoculation produces a significant increase in endometrial thickness; normalize the enHP, enIHQ and enFC. As a result, IVF after treatment with enMSCs yields a higher rate of CP and LBDR.

Zinc (Zn) has antioxidant effect in different types of organs and is closely associated with human health. Endometrial receptivity is one of the most important factors in the embryo implantation and development. However, the regulatory mechanism of Zn in endometrium tissue is still unclear. In the study, we found that plasma Zn level is significantly associated with female infertility, which severely affects female reproductive health. Primary endometrial stromal cells were isolated from female endometrium and cultured in the laboratory. Zn chelator TPEN treatment reduced the expression of stem cell markers CD73, CD90, and CD105 and generated reactive oxygen species in endometrial stromal cells. However, pretreatment of Zn (zinc sulfate) is able to prevent TPEN-induced oxidative stress in vitro. By transcriptional profiling and gene ontology analysis, we found that Zn increased the cellular pluripotency signaling and extracellular matrix-receptor interaction, but reduced autophagy, endocytosis, and the nitrogen metabolism pathway. We further discovered the antioxidant function of Zn through the peroxisome proliferator-activated receptor gamma coactivator 1α/nuclear factor erythroid-2-related factor signaling pathway in endometrial stromal cells. Zn supplementation may open up an effective therapeutic approach for patients with oxidative stress-related endometrial diseases.

Successful implantation requires a receptive endometrium and a good quality egg. The challenges a physician encounters with regard to this in assisted reproductive technology are obtaining good quality embryo, achieving optimal endometrial thickness (EMT), and subsequently implantation, which is denotive of a receptive endometrium. Granulocyte colony-stimulating factor (G-CSF) has been observed to be a biomarker of oocyte quality and has been shown to enhance EMT and implantation because of its immunological effects. A systematic search for all relevant articles on G-CSF in follicular fluid and its therapeutic benefit in thin endometrium and recurrent implantation failure was performed, and peer-reviewed, full-text articles related to humans were included in the study. As a tool to determine the potentiality of oocyte, G-CSF shows promise with its predictability increasing in combination with morphological embryo scoring or interleukin 15. For the thin endometrium, G-CSF is especially useful in patients who are refractory to other treatment modalities. In recurrent implantation failure (RIF), G-CSF showed potential in a subset of patients with immunological deficiency lacking killer cell immunoglobulin-like receptor genes. This review highlights the various forms of usage of G-CSF and the effectiveness of G-CSF in infertility. G-CSF equips embryologists with a tool to determine the potentiality of oocyte and physicians with therapy for thin endometrium and RIF, especially since the available treatment options are ineffective., Competing Interests: The authors have declared that no competing interests exist.

Background: Platelet-rich plasma (PRP) contains abundant growth factors and is gradually used in the field of reproduction. A thin endometrium is recognized as a critical factor in embryo implantation failure. Endometrial mesenchymal stem cells (EnMSCs), which were isolated from human menstrual blood, are highly proliferative and show multiple differentiation capacity. The current study was to investigate the effect of PRP on the proliferation and migration of EnMSCs, and the effectiveness of PRP in the treatment of patients with thin endometrium., Materials and Methods: EnMSCs were treated with PRP in vitro, followed by measuring cell proliferation, migration, and adhesion by using CCK8, scratch, and adhesion test, respectively. Twenty patients undergoing in vitro fertilization (IVF) with refractory thin endometrium history were given PRP by infusion into the uterine cavity after the treatment of hormone replacement therapy (HRT)., Results: All components of PRP significantly stimulated the growth, migration, and adhesion of EnMSCs when compared with the negative control. Cell proliferation and migration were induced by PRP in a dose-dependent manner with maximum proliferation at a 2% PRP dose. The clinical data showed that successful endometrial expansion and pregnancy were discovered in 12 patients after PRP infusion, and the pregnancy rate increased to 60%., Conclusion: Intrauterine PRP infusion represents a new way for female patients with thin endometrium with poor response. This study lays the foundations for the potential treatment of thin endometrium with PRP in vivo., (© 2018 Wiley Periodicals, Inc.)

Endometrial thickness is a key factor involved in achieving desired outcomes in assisted reproductive technology (ART). Various therapeutic modalities have been proposed to patients with thin endometrium. This study aimed to summarize the available findings regarding the effect of Pentoxifylline (PTX) and Tocopherol combination on improving endometrial thickness. The review included interventional studies, including randomized controlled trials (RCTs) and quasi‐experimental studies, assessing PTX and vitamin E (Tocopherol) combination in women with thin endometrium. Electronic searches using the MeSH terms were conducted in the following databases: Medline, Embase, Scopus, Web of Science, and The Cochrane Library. The effect was measured as weighted mean difference (MD) and 95% confidence intervals (CI) by the random‐effects model. The initial search yielded 66 potentially relevant articles. After studying these publications, 4 were potentially eligible and retrieved in full text (three before–after studies and one RCT). A meta‐analysis of three quasi‐experimental studies showed a significant difference in endometrial thickness after treatment (MD: 1.96 mm; 95% CI: 0.94–2.98, p < .001) but there was no difference in the mean of endometrial thickness between case and control groups (10.8 vs. 10.48 mm, p = .467) in aforementioned RCT. Although the effect of intervention was seen in quasi experimental studies but this finding was not confirmed in the only retrieved RCT. Due to the methodological weakness of the retrieved studies as well as the lack of appropriate clinical trial studies, there is no certainty about the effectiveness of the PTX and Tocopherol combination. Future trials with desirable design and larger sample size that address the limitations in the current evidence are needed before definitive claims can be made about the effect of PTX and Tocopherol combination. Practical applications: Endometrial thickness is affected by many factors including age, genetic, estradiol levels, and previous injuries to endometrium. Many drugs and nutritional supplements have been studied on endometrial thickness in which PTX and Tocopherol in combination have been shown to have restoring effects on endometrium. It seems that the properties of PTX and Tocopherol could be favorable for endometrium restoration. [ABSTRACT FROM AUTHOR]

Objective: One of the important aspects involved in achieving optimal outcomes after assisted reproductive treatment (ART) is the endometrium. Some cycles are cancelled due to inadequate endometrial growth in ART. In this clinical trial, we evaluated the effectiveness of platelet-rich plasma (PRP) in the treatment of thin endometrium., Materials and Methods: In this randomized clinical trial, 83 women with poor endometrial response to standard hormone replacement therapy (HRT) (endometrium thickness < 7 mm) in the 13th day of the cycle in a frozen-thawed embryo transfer (FET) were entered in two groups. In the PRP group (n = 40), in addition to HRT, 0.5-1 cc of PRP was infused into the uterine cavity on the 13th day of HRT cycle. The control group (n = 43) was only received HRT. If endometrial thickness failed to increase after 48 h, PRP infusion was repeated in the same cycle. When the endometrium thickness reached ≥7 mm, embryo transfer was done. Finally, endometrial thickness, chemical, clinical, and ongoing pregnancy rates were compared between two groups., Results: Endometrial thickness increased significantly to 8.67 ± 0.64 in PRP group than in controls (p = 0.001). This increase was higher in women who conceived in PRP group (p value: 0.031). The implantation rate and per-cycle clinical pregnancy rate were significantly higher in PRP group (p = 0.002 and 0.044, respectively (p = 0.002)., Conclusion: PRP may be effective in improving the endometrial growth, and possibly pregnancy outcomes in women with a thin endometrium., (Copyright © 2018. Published by Elsevier B.V.)

Introduction: We often see patients with a thin endometrium in ART cycles, in spite of standard and adjuvant treatments. Improving endometrial growth in patients with a thin endometrium is very difficult. Without adequate endometrial thickness these patients, likely, would not have reached embryo transfer. We planned this study to investigate the efficacy of intrauterine granulocyte colony stimulating factor (GCSF) perfusion in improving endometrium, and possibly pregnancy rates in frozen-thawed embryo transfer cycles. Materials and Methods: This is a non-randomized intervention clinical trial. Among 68 infertile patients with thin endometrium (-7 mm) at the 12th-13th cycle day, 34 patients received GCSF (300 microgram/lmL) to improve endometrial thickness by direct administration by slow intrauterine infusion using IUI catheter. If the endometrium had not reached at least to 7-mm within 48-72 hr, a second infusion was given. Endometrial thickness was assessed by serial vaginal ultrasound at the most expanded area of the endometrial stripe. Results: The cycle was cancelled in the patients with thin endometrium (endometrial thickness below 7mm) until 19th cycle day ultimately. The cycle cancelation rate owing to thin endometrium was similar in GCSF group (15.20%), followed by (15.20%) in the control group (p=1.00). The endometrial growth was not different within 2 groups, an improvement was shown between controlled and GCSF co-treated groups, with chemical (39.30% vs. 14.30%) and clinical pregnancy rates (32.10% vs. 12.00%) although the differences were not significant. Conclusion: Our study fails to demonstrate that GCSF has the potential to improve endometrial thickness but it shows that GCSF has the potential to improve chemical and clinical pregnancy rate of the infertile women with thin endometrium in frozen-thawed embryo transfer cycle. [ABSTRACT FROM AUTHOR]

Objective: To explore the relationship between endometrial thickness and clinical pregnancy outcomes in frozen-thawed embryo transfer cycles. Methods: A prospective study was performed for 1 475 frozen-thawed embryo transfer cycles at Peking University People's Hospital from January 2014 to December 2015. The patients were divided into different groups according to endometrial thickness of ovulation day in natural menstrual cycles or endometrial transformation day in hormone replacement cycles;patients with thin endometrium were enndometrial thickness ≤6 mm. Then the clinical pregnancy outcomes including clinical pregnancy rate, embryo implantation rate, abortion rate, multiple birth rate and live birth rate were analyzed. Results: In all, 1 475 frozen-thawed embryo transfer cycles were analyzed. The mean age of patients was (32.5±3.9) years old and mean endometrial thickness was (9.2±1.9) mm, and mean number of embryos was 2.03±0.37. The study included 518 (35.1%) natural menstrual cycles and 957 (64.9%) hormone replacement cycles. The number of embryo-transfer cycles and blastocyst-transfer cycles were respectively 700 (47.5%) and 775 (52.5%) . The overall clinical pregnancy rate, embryo implantation rate, abortion rate, multiple birth rate and live birth rate were 54.4%, 35.7%, 23.3%, 24.1%, 43.9%, respectively. The ectopic pregnancy rate in the study was 0.6%. In patients with thin endometrium,there were significant differences in 2 pronucleus count ( P= 0.016) and available embryo count ( P= 0.024) between cycles that resulted in pregnancy and those that did not;besides, the use of sildenafil and growth hormone did not improve pregnancy outcomes in patients with thin endometrium ( P= 0.183, P= 0.400) . The clinical pregnancy rate, embryo implantation rate and live birth rate of embryo-transfer and blastocyst-transfer were similar in patients with thin endometrium (all P> 0.05) . Conclusions: Patients with thin endometrium have poor pregnancy outcomes. The clinical pregnancy rate, embryo implantation rate and live birth rate of embryo-transfer and blastocyst-transfer are similar in patients with thin endometrium. Compared thin endometrium and non-thin endometrium patients, the clinical pregnancy rate and live birth rate of blastocysts have more substantial decline than those of embryos. Improving the quality of embryo could improve the pregnancy outcome of patients with thin endometrium. Sildenafil and growth hormone could not improve pregnancy outcome in patients with thin endometrium.

Study Question: What is the independent contribution of endometrial thickness (EMT) on day of embryo transfer to achieving an ongoing pregnancy and live birth after IVF treatment?, Summary Answer: EMT is a poor predictor of IVF success and has only little independent prognostic value., What Is Known Already: In a number of previous studies, pregnancy rates have been found to be lower in patients with thin endometrium., Study Design Size Duaration: This is a retrospective analysis of data from two large, randomized phase III studies (conducted in Europe and the USA) comparing s.c. progesterone with vaginal progesterone for luteal phase support. The studies were very similar in design, patient population and outcome, and the study data were combined and analysed on an individual patient level., Participants/materials Setting Method: Subjects were infertile patients with an indication for IVF/ICSI, aged between 18 and 42 years, BMI <30 kg/m 2 , <3 prior ART cycles and ≥ 3 oocytes after controlled ovarian stimulation with GnRH-agonist or GnRH-antagonist. EMT was assessed on day of embryo transfer ( n = 1401). The association of EMT and ongoing pregnancy rate was determined by comparison of outcomes by quantiles of EMT. The predictive capacity of EMT for ongoing pregnancy achievement was assessed at each millimeter cut-off. Finally, a regression model was built to determine the contribution of EMT among other confounders, such as age and oocyte numbers, on the likelihood of ongoing pregnancy and live birth., Main Results and the Role of Chance: In univariate analysis, ongoing pregnancy rates correlate to EMT. In patients above a cut-off of ≥9 mm EMT, the chance of pregnancy was higher as compared to patients with an EMT of 3-8 mm (odds ratio (OR) = 1.69, 95% CI: 1.23-2.35, P = 0.001; sensitivity 88.89%, specificity 17.52%, positive predictive value 39.02%, negative predictive value 72.64% and likelihood ratio 1.08). In multivariate regression analysis, after controlling for trial, female age and oocyte numbers, EMT was a statistically significant predictor of live birth (OR = 1.05, 95% CI: 1.00-1.10; P = 0.0351). If EMT indeed is an independent factor affecting outcome, this finding implies that at a baseline live birth rate of 20% an increase of 2 mm in EMT should result in an increase of the live birth rate of ~1.6%., Limitations Reasons for Caution: The independent contribution of EMT to live birth likelihood is small and may result from (undetermined) confounding. The EMT on day of embryo transfer is usually higher as compared to the EMT on day of triggering final oocyte maturation when it is conventionally assessed during routine cycle monitoring. Furthermore, endometrial lining pattern and/or subendometrial Doppler flow have not been assessed and, accordingly, the conclusions of this work are limited to only the thickness of the endometrium., Wider Implications of the Findings: EMT can be ignored during cycle monitoring of the majority of IVF patients and only the extremes of EMT deserve further diagnostic work-up., Study Funding/competing Interests: The study was supported by IBSA. G.G. has received personal fees and non-financial support from MSD, Ferring, Merck-Serono, Finox, TEVA, IBSA, Glycotope, Abbott, Gedeon-Richter as well as personal fees from VitroLife, NMC Healthcare, ReprodWissen, BioSilu and ZIVA. S.T. and B.C. are employees of IBSA., Trial Registration Number: NCT00827983 and NCT00828191 (clinicaltrials.gov)., Trial Registration Date: 23 January 2009 (NCT00827983 and NCT00828191)., Date of First Patient’s Enrolment: January 2009 (NCT00827983 and NCT00828191).

Purpose: To investigate whether autologous platelet-rich plasma (PRP) treatment can improve regeneration of the endometrium in an experimental model of ethanol-induced damage., Materials and Methods: Sixty female Sprague-Dawley rats were randomly assigned into three groups: control group, ethanol group, and PRP-treated group (administration of 0.25 mL of PRP into both uterine cavities 72 hours after ethanol injection). After 15 days of endometrial damage, all the animals were sacrificed during the estrous cycle, and samples were taken from the mid-uterine horn. Functional and structural recovery of the endometrium was analyzed by hematoxylin-eosin (H&E) and Masson trichrome (MT) staining, real-time polymerase chain reaction (PCR) assay, and immuno-histochemical (IHC) analyses., Results: H&E and MT staining confirmed significantly decreased fibrosis and increased cellular proliferation in the PRP-treated group, compared to the ethanol group. The endometrial areas in the ethanol and PRP-treated groups were 212.83±15.84 μm² and 262.34±12.33 μm² (p=0.065). Significantly stronger IHC expression of cytokeratin, homeobox A10 (HOXA10), vascular endothelial growth factor (VEGF), and Ki-67 was found in the PRP-treated group, compared to the ethanol group. In real-time PCR analyses, interleukin-1β mRNA was down-regulated, while c-Kit mRNA was up-regulated, in the PRP-treated group, compared to the ethanol group., Conclusion: Intrauterine administration of autologous PRP stimulated and accelerated regeneration of the endometrium and also decreased fibrosis in a murine model of damaged endometrium., Competing Interests: The authors have no financial conflicts of interest., (© Copyright: Yonsei University College of Medicine 2017)

Introduction: This study investigated subfertile patients with abnormally thin endometrium after infertility treatment. As they had adequate serum concentrations of hormones, an endometrial factor for subfertility was suspected., Methods: To elucidate the cause of subfertility, endometrial biopsies were taken in each patient in the late proliferative and mid-secretory phases of one menstrual cycle. Endometrial biopsies from women with normal menstrual cycles and confirmed fertility who were undergoing hysterectomy for benign uterine disease were used as positive controls. The tissue samples were investigated for steroid hormone receptor expression and for the proliferation marker Ki-67. Immunohistochemistry was performed with antibodies against the marker molecules for endometrial receptivity - β 3 integrin, VEGF, LIF, and CD56 (large granular lymphocytes, LGLs)., Results: The steroid hormone receptors for estrogen (E2) and progesterone (P) were expressed normally (at the first biopsy) and were down-regulated (at the second biopsy) within the cycle. Strikingly, all of the marker molecules investigated showed negative or weak and inadequate expression in the mid-secretory phase. Numbers of LGLs remained as low as in the proliferative phase. In contrast, fertile patients were found to express these marker molecules distinctly in the mid-secretory phase., Conclusions: It may be hypothesized that a severe deficiency of these angiogenesis-related marker molecules leads to defective development of the endometrium, which remains thin. Deficient angiogenetic development may thus provide an explanation for the endometrial factor that causes infertility. Further investigations will need to focus on identifying the regulating factors that act between steroid receptor activation and the expression of these marker molecules.

Introduction: Embryo implantation process is a complex phenomenon and depends on fetal and maternal factors interaction. Endometrial thickness is needed for successful implantation. Increasing endometrial thickness, raise the chance of clinical pregnancy. The triple line pattern, with thickening more than 7mm, is indicating the greater chance of successful implantation. We designed this study to assess adding HCG to the conventional protocol in endometrial preparation in women with thin endometrium and history oflVF-ET failure. Materials and Methods: This non-randomized clinical trial study (quasi experimental design) was performed in Yazd Research and Clinical Center for Infertility on 28 patients. Participants were women who candidate for frozen thawed embryo transfer and had 2 previous failed ET cycle because of thin endometrium. All patients received 8 mg estradiol valterate on second day of menstrual cycle and continued during the study. HCG was administrated (150 IU, IM) from 8th days of cycle. In 12th-13th day Trans-vaginal sonography was done, when endometrial thickness reached at least 7mm, HCG was discontinued and frozen thawed embryo transfer was done. Results: Totally 28 patients were included. The mean age of participants was 30.39±4.7 years. The mean of endometrial thickness before and after HCG were 5.07±0.43 and 7.85±0.52 mm which were significantly different (p=0.00). After HCG administration 100% patient's endometrial thickness reached more than 7mm. The frequency of 20% improvement after HCG was 89.3% (25 patients). Also there were 5 (17.8%) clinical and chemical pregnant women after HCG. Conclusion: Our study findings suggest that adding HCG to the conventional preparation method is an effective protocol and significantly improved endometrial thickness and pregnancy outcomes in women with previous embryo transfer failure because of thin endometrium. [ABSTRACT FROM AUTHOR]

Introduction: We often see patients with a thin endometrium in ART cycles, in spite of standard and adjuvant treatments. Improving endometrial growth in patients with a thin endometrium is very difficult. Without adequate endometrial thickness these patients, likely, would not have reached embryo transfer. Materials and Methods: This is a non randomized intervential clinical trial. Among 68 infertile patients with thin endometrium (7 mm) at the 12th-13th cycle day, 34 patients received G-CSF (300 microgram/lmL) to improve endometrial thickness. It was directly administered by slow intrauterine infusion using IUI catheter. If the endometrium had not reached at least a 7-mm within 48-72 h, a second infusion was given. Endometrial thickness was assessed by serial vaginal ultrasound at the most expanded area of the endometrial stripe. The cycle was cancelled in the patients with thin endometrium (endometrial thickness 7mm) until 19th cycle day ultimately. Results: The cycle cancelation rate owing to thin endometrium was similar in G-CSF group (15.20%), followed by (15.20%) in the control group (p=1.00). The endometrial growth was not different within 2 groups, an improvement was shown between controlled and G-CSF cotreated groups, with chemical (39.30% vs. 14.30%) and clinical pregnancy rates (32.10% vs. 12.00%) although were not significant. Conclusion: Our study fails to demonstrate that G-CSF has the potential to improve endometrial thickness but has the potential to improve chemical and clinical pregnancy rate of the infertile women with thin endometrium in frozen-thawed embryo transfer cycle. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether bone marrow mesenchymal stem cell (BMSC) treatment could improve the regeneration of endometrium and improve the endometrial receptivity in an experimental model of thin endometrium. Design: Randomized, control trial, animal research. Setting: National key laboratory. Animal(s): Sprague-Dawley rats. Intervention(s): Bone marrow mesenchymal stem cell transplantation by tail vein IV injection. Main Outcome Measure(s): Endometrial thickness, the expression of mark proteins for endometrial cell, and endometrial receptivity. Result(s): The endometrium was significantly thicker and the expression of cytokeratin, vimentin, integrin αγβ3, and leukemia inhibitor factor were significantly stronger compared with the control group. Some proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α) messenger RNA (mRNA) and interleukin-1β mRNA, were significantly down-regulated, and anti-inflammatory cytokines, such as fibroblast growth factor-β (bFGF) mRNA and interleukin-6 mRNA, were significantly up-regulated in the experimental group compared with the control group. Conclusion(s): The BMSCs have beneficial effect on thin endometrium, and may play a role through migration and immunomodulatory of BMSCs. [Copyright &y& Elsevier]

Introduction: This study was to evaluate the effectiveness of PRP in the therapy of infertile women with thin endometrium (≤ 7 mm)., Material and Methods: Five women undergoing in vitro fertilization (IVF) with poor endometrial response still had thin endometrium (< 7 mm) after standard hormone replacement therapy (HRT) and had to cancel embryo transfer cycle. In addition to HRT, intrauterine infusion of PRP was performed. PRP was prepared from autologous blood by centrifugation, and 0.5-1 ml of PRP was infused into the uterine cavity on the 10(th) day of HRT cycle. If endometrial thickness failed to increase 72 h later, PRP infusion was done 1-2 times in each cycle. Embryos were transferred when the endometrium thickness reached > 7 mm., Results: Successful endometrial expansion and pregnancy were observed in all the patients after PRP infusion. Intrauterine PRP infusion represent a new method for the thin endometrium with poor response., Conclusion: This article reported that platelet-rich plasma (PRP) was able to promote the endometrial growth and improve pregnancy outcome of patients with thin endometrium.

Background: We often see patients with a thin endometrium in ART cycles, in spite of standard and adjuvant treatments. Improving endometrial growth in patients with a thin endometrium is very difficult. Without adequate endometrial thickness these patients, likely, would not have reached embryo transfer., Objective: We planned this study to investigate the efficacy of intrauterine granulocyte colony-stimulating factor (G-CSF) perfusion in improving endometrium, and possibly pregnancy rates in frozen-thawed embryo transfer cycles., Materials and Methods: This is a non-randomized intervention clinical trial. Among 68 infertile patients with thin endometrium (-7 mm) at the 12(th)-13(th) cycle day, 34 patients received G-CSF. G-CSF (300 microgram/1mL) to improve endometrial thickness was direct administered by slow intrauterine infusion using IUI catheter. If the endometrium had not reached at least a 7-mm within 48-72 h, a second infusion was given. Endometrial thickness was assessed by serial vaginal ultrasound at the most expanded area of the endometrial stripe., Results: The cycle was cancelled in the patients with thin endometrium (endometrial thickness below 7mm) until 19(th) cycle day ultimately The cycle cancelation rate owing to thin endometrium was similar in G-CSF group (15.20%), followed by (15.20%) in the control group (p=1.00). The endometrial growth was not different within 2 groups, an improvement was shown between controlled and G-CSF cotreated groups, with chemical (39.30% vs. 14.30%) and clinical pregnancy rates (32.10% vs. 12.00%) although were not significant., Conclusion: Our study fails to demonstrate that G-CSF has the potential to improve endometrial thickness but has the potential to improve chemical and clinical pregnancy rate of the infertile women with thin endometrium in frozen-thawed embryo transfer cycle.

Study Objective: To investigate the efficacy of administration of dienogest to thin the endometrium before hysteroscopic surgery and to evaluate the surgical outcome., Design: Retrospective clinical study (Canadian Task Force classification III)., Setting: Community hospital., Patients: Twenty-six patients who underwent hysteroscopic surgery for treatment of endometrial polyps or submucous myomas <25 mm., Interventions: Before hysteroscopic surgery, 13 patients (dienogest group) received 2 mg dienogest orally for 2 weeks, and 13 patients (GnRH group) received a gonadotropin-releasing hormone agonist subcutaneously 1 to 3 times every 4 weeks, and 4 of those received hormone therapy after surgery. Endometrial thickness, serum estradiol and progesterone concentrations, duration of surgery, weight of tissue removed, surgical field visualization, and time to resumption of spontaneous menstruation were recorded., Measurements and Main Results: Endometrial thickness decreased from approximately 7.0 mm to 3.9 mm in the dienogest group. Duration of surgery and weight of tissue removed were similar between groups. The surgical field was clearly visualized in 12 patients in each group. Spontaneous menstruation resumed at approximately 22.0 days after hysteroscopic surgery in the dienogest group; in contrast, no resumption of spontaneous menstruation was observed within the first postoperative month in the GnRH group. No patients had perioperative complications, and none exhibited any residual tumor., Conclusion: Administration of dienogest for 2 weeks thinned the endometrium and yielded favorable surgical outcomes, similar to those with GnRH agonists. Administration of dienogest may be an effective and convenient treatment before hysteroscopy., (Copyright © 2013 AAGL. Published by Elsevier Inc. All rights reserved.)