Pretreatment with long-acting gonadotropin-releasing hormone agonists improved pregnancy outcomes after hysteroscopic multiple polypectomies: A retrospective study of 660 frozen-thawed embryo transfer cycles.

OBJECTIVE: To compare the reproductive pregnancy outcomes of pretreatment with long-acting gonadotropin-releasing hormone agonist (GnRH-a) plus hormone replacement therapy (HRT) with HRT-only cycles, and investigate differences between single polypectomy and multiple polypectomies, and between one or two doses of GnRH-a. MATERIALS AND METHODS: This was a retrospective cohort study on patients undergoing polypectomy who underwent frozen-thawed embryo transfer (FET) from March 2018 to May 2019. They were divided into GnRH-a pretreatment and HRT-only groups. Each group was divided into single polypectomy or multiple polypectomies (in a single hysteroscopic session) subgroups. Clinical pregnancy rate and live birth rate (LBR) were the main outcomes. The effect of GnRH-a dosage was further analysed. RESULTS: There were 212 GnRH-a pretreatment cases (45 single and 167 multiple polyps) and 448 HRT-only cases (228 single and 220 multiple polyps). The LBR of the GnRH-a pretreatment group (53.3%) was significantly higher than the HRT group (43.3%; P = 0.016). Logistic regression analysis showed that GnRH-a pretreatment significantly affected the LBR (odds ratio, OR 1.470, 95% confidence interval, Cl 1.046-2.065; P = 0.026). In the multiple polypectomy subgroup, the LBR with GnRH-a pretreatment was higher than with HRT-only (54.5% vs 43.6%; P = 0.034). However, the LBR was not different between the respective single polypectomy subgroups (48.9% vs 43.0%; P = 0.466). For patients with multiple polyps, two GnRH-a pretreatments produced a higher LBR than a single GnRH-a pretreatment (62.7% vs 47.8%), but without significant difference (P = 0.055). CONCLUSION: GnRH-a pretreatment improved the LBR for FET cycles after hysteroscopic multiple polypectomies, independent of dose.

Unresponsive thin endometrium caused by Asherman syndrome treated with umbilical cord mesenchymal stem cells on collagen scaffolds: a pilot study.

BACKGROUND: Unresponsive thin endometrium caused by Asherman syndrome (AS) is the major cause of uterine infertility. However, current therapies are ineffective. This study is to evaluate the effect of transplantation with collagen scaffold/umbilical cord mesenchymal stem cells (CS/UC-MSCs) on this refractory disease. METHODS: Eighteen infertile women with unresponsive thin endometrium, whose frozen-thawed embryo transfers (FETs) were cancelled due to reduced endometrial thickness (ET ≤ 5.5 mm), were enrolled in this before and after self-control prospective study. Hysteroscopic examination was performed to confirm no intrauterine adhesions, then twenty million UC-MSCs loaded onto a CS were transplanted into the uterine cavity in two consecutive menstrual cycles. Then uterine cavity was assessed through hysteroscopy after two transplants. FETs were performed in the following cycle. Pregnancy outcomes were followed up. Endometrial thickness, uterine receptivity and endometrial angiogenesis, proliferation and hormone response were compared before and after treatment. RESULTS: Sixteen patients completed the study. No treatment-related serious adverse events occurred. Three months after transplantation, the average ET increased from 4.08 ± 0.26 mm to 5.87 ± 0.77 mm (P < 0.001). Three of 15 patients after FET got pregnant, of whom 2 gave birth successfully and 1 had a miscarriage at 25 weeks' gestation. One of 2 patients without FET had a natural pregnancy and gave birth normally after transplantation. Immunohistochemical analysis showed increased micro-vessel density, upregulated expression of Ki67, estrogen receptor alpha, and progesterone receptor, indicating an improvement in endometrial angiogenesis, proliferation, and response to hormones. CONCLUSION: CS/UC-MSCs is a promising and potential approach for treating women with unresponsive thin endometrium caused by AS. TRIAL REGISTRATION: ClinicalTrials.gov NCT03724617 . Registered on 26 October 2018-prospectively registered, https://register.clinicaltrials.gov/.

A scaffold laden with mesenchymal stem cell-derived exosomes for promoting endometrium regeneration and fertility restoration through macrophage immunomodulation.

Endometrial traumas may cause intrauterine adhesions (IUAs), leading to infertility. Conventional methods in clinic have not solved the problem of endometrial regeneration in severe cases. Umbilical cord-derived mesenchymal stem cell (UC-MSC)-based therapies have shown some promising achievements in the treatment of IUAs. However, the limitations of potential tumorigenicity, low infusion and low retention are still controversial and restricted the clinical application of MSCs. In contrast, UC-MSC-derived exosomes exhibit a similar function to their source cells and are expected to overcome these limitations. Therefore, a novel and viable cell-free therapeutic strategy by UC-MSC-derived exosomes was proposed in this study. Here, we designed a construct of exosomes and collagen scaffold (CS/Exos) for endometrial regeneration in a rat endometrium-damage model, and investigated the regeneration mechanism through macrophage immunomodulation. The CS/Exos transplantation potently induced (i) endometrium regeneration, (ii) collagen remodeling, (iii) increased the expression of the estrogen receptor α/progesterone receptor, and (iv) restored fertility. Mechanistically, CS/Exos facilitated CD163+ M2 macrophage polarization, reduced inflammation, and increased anti-inflammatory responses in vivo and in vitro. By RNA-seq, miRNAs enriched in exosomes were the main mediator for exosomes-induced macrophage polarization. Overall, we demonstrated that CS/Exos treatment facilitated endometrium regeneration and fertility restoration by immunomodulatory functions of miRNAs. Our research highlights the therapeutic prospects of CS/Exos for the management of IUAs. STATEMENT OF SIGNIFICANCE: Severe endometrial traumas always result in intrauterine adhesions (IUAs) and infertility. The limited outcomes by conventional methods in the clinic make it very important to develop new strategies for endometrium regeneration and fertility restoration. In this study, an exosome-laden scaffold (CS/Exos) was designed and the transplantation of CS/Exos potently induced (i) endometrium regeneration, (ii) collagen remodeling, (iii) increased the expression of the estrogen receptor α/progesterone receptor, and (iv) restored fertility. In mechanism, the construct of CS/Exos facilitated M2 macrophage polarization, reduced inflammation, and increased anti-inflammatory responses. Furthermore, miRNAs enriched in exosomes were the main mediator for exosome-induced macrophage polarization. This study highlights the therapeutic prospects of CS/Exos and the translational application for the management of severe IUAs.

Combination of noninvasive methods in diagnosis of infertile women with minimal or mild endometriosis, a retrospective study in China.

This study means to investigate a combination of noninvasive methods in diagnosis of minimal or mild endometriosis expecting to narrow down the range of laparoscopic exploration for female infertility.It is a retrospective case control study of totally 447 patients suspected unexplained infertility before surgery were eligible from May 2012 to February 2017. Of these, 299 patients were laparoscopy-proved minimal or mild endometriosis group, the remaining 148 patients served as control group (normal pelvis). Preoperative age, duration of infertility, type of infertility, body mass index, baseline follicle-stimulating hormone, anti-Müllerian hormone, serum CA125, clinical symptoms, findings on vagino-recto-abdominal examinations and pregnancy prognosis had been recorded. Every variable and their combinations were evaluated.Any single factor had limited diagnostic value. The cut-off value for CA125 was 19.25 IU/L. Parallel testing had a higher sensitivity at 81.3%. Serial tests of vagino-recto-abdominal examination combined with dysmenorrhea or positive CA125 got reasonable sensitivity (51.4% and 49%), remarkable high specificities (95.7% and100%) and Positive Predictive Value (96.4% and 100%). Multivariate logistic regression identified the following factors in decreasing order of importance: (1) vagino-recto-abdominal examinations, (2) CA125, (3) dysmenorrhea, their ORs being 16.148, 3.796, and 2.809, respectively. The spontaneous pregnancy rate (50.8%) in minimal or mild endometriosis was higher than control (35.6%, P = .043).A combination of noninvasive diagnostic methods had certain preoperative diagnostic value of minimal or mild endometriosis, which might benefit some patients from avoiding laparoscopic surgery.