Hypoxia and the endometrium: An indispensable role for HIF-1α as therapeutic strategies.

Hypoxia-inducible factor 1 alpha (HIF-1α) is a major molecular mediator of the hypoxic response. In the endometrium, local hypoxic conditions induced by hormonal fluctuations and endometrial vascular remodeling contribute to the production of HIF-1α, which plays an indispensable role in a series of physiological activities, such as menstruation and metamorphosis. The sensitive regulation of HIF-1α maintains the cellular viability and regenerative capacity of the endometrium against cellular stresses induced by hypoxia and excess reactive oxygen species. In contrast, abnormal HIF-1α levels exacerbate the development of various endometrial pathologies. This knowledge opens important possibilities for the development of promising HIF-1α-centered strategies to ameliorate endometrial disease. Nonetheless, additional efforts are required to elucidate the regulatory network of endometrial HIF-1α and promote the applications of HIF-1α-centered strategies in the human endometrium. Here, we summarize the role of the HIF-1α-mediated pathway in endometrial physiology and pathology, highlight the latest HIF-1α-centered strategies for treating endometrial diseases, and improve endometrial receptivity.

The Endometrial Stem/Progenitor Cells and Their Niches.

Endometrial stem/progenitor cells are a type of stem cells with the ability to self-renew and differentiate into multiple cell types. They exist in the endometrium and form niches with their neighbor cells and extracellular matrix. The interaction between endometrial stem/progenitor cells and niches plays an important role in maintaining, repairing, and regenerating the endometrial structure and function. This review will discuss the characteristics and functions of endometrial stem/progenitor cells and their niches, the mechanisms of their interaction, and their roles in endometrial regeneration and diseases. Finally, the prospects for their applications will also be explored.

Bioinformatics Analysis Reveals Novel Differentially Expressed Genes Between Ectopic and Eutopic Endometrium in Women with Endometriosis.

Background: Endometriosis is one of the chronic and prevalent diseases among women. There is limited knowledge about its pathophysiology at the cellular and molecular levels, causing a lack of a definite cure for this disease. In this study, differentially expressed genes (DEGs) between ectopic and paired eutopic endometrium in women with endometriosis were analyzed through bioinformatics analysis for better understanding of the molecular pathogenesis of endometriosis. Methods: Gene expression data of ectopic and paired eutopic endometrium were taken from the Gene Expression Omnibus database. DEGs were screened by the Limma package in R with considering specific criteria. Then, the protein-protein interaction network was reconstructed between DEGs. The fast unfolding clustering algorithm was used to find sub-networks (modules). Finally, the three most relevant modules were selected and the functional and pathway enrichment analyses were performed for the selected modules. Results: A total of 380 DEGs (245 up-regulated and 135 down-regulated) were identified in the ectopic endometrium and compared with paired eutopic endometrium. The DEGs were predominantly enriched in an ensemble of genes encoding the extracellular matrix and associated proteins, metabolic pathways, cell adhesions and the innate immune system. Importantly, DPT, ASPN, CHRDL1, CSTA, HGD, MPZ, PED1A, and CLEC10A were identified as novel DEGs between the human ectopic tissue of endometrium and its paired eutopic endometrium. Conclusion: The results of this study can open up a new window to better understanding of the molecular pathogenesis of endometriosis and can be considered for designing new treatment modalities.

A serum lipidomics study for the identification of specific biomarkers for endometrial polyps to distinguish them from endometrial cancer or hyperplasia.

Endometrial diseases, including endometrial polyps (EP), endometrial cancer (EC) and endometrial hyperplasia (EH), are common gynecological diseases that affect women of childbearing and perimenopausal age. Clinically, biopsy or imaging methods are usually used to screen and diagnose these diseases; however, due to the invasiveness and heterogeneity of these tests, a noninvasive, convenient, objective and accurate biomarker is needed for the differential diagnosis of EP, EC or EH. In the present study, serum samples from 326 patients with endometrial diseases and 225 healthy volunteers were analyzed using nontargeted lipidomics. A combination of multivariate and univariate analyses was used to identify and qualify six, eight and seven potential biomarkers in the sera from patients with EP, EC and EH, respectively. Using a logistic regression algorithm and receiver operating characteristic (ROC) curve analysis, a biomarker panel including four specific EP biomarkers, 6-keto-PGF1α, PA(37:4), LysoPC(20:1) and PS(36:0), showed good classification and diagnostic ability in distinguishing EP from EC or EH. The biomarker panel for distinguishing EP from EC yielded an area under the curve (AUC) of 0.915, sensitivity of 100% and specificity of 72.41%, while that for distinguishing EP from EH yielded an AUC of 1.000, sensitivity of 100% and specificity of 100%. The two diagnostic models also showed good diagnostic abilities in the validation set. Therefore, this biomarker panel can be used as a rapid diagnostic method to assist in imaging examinations and provide a reference for clinicians in the identification and diagnosis of endometrial diseases.

PPOS Protocol Effectively Improves the IVF Outcome Without Increasing the Recurrence Rate in Early Endometrioid Endometrial Cancer and Atypical Endometrial Hyperplasia Patients After Fertility Preserving Treatment.

Objective: To investigate the effectiveness and recurrence risk of different ovulation stimulation protocols in early-stage endometrioid endometrial cancer (EEC) and atypical endometrial hyperplasia (AEH) patients after successful fertility preserving treatment. Design: A retrospective review of clinical files between June 2012 and July 2018. Setting: University hospital. Patients: Ninety seven women (74 AEH and 23 early-stage EEC patients) underwent in vitro fertilization (IVF) and frozen-thawed embryo transfer (FET) after successful fertility preserving treatment. All patients received megestrol acetate which was initiated immediately after AEH or EEC diagnosis by hysteroscopy. Fertility treatment was initiated after confirmation of complete response by two consecutive hysteroscopic evaluations and endometrium biopsy in a 3-month interval. Women with tubal factors underwent IVF treatment directly. Women who failed to conceive spontaneously within 12 months or after other infertility treatments like ovulation induction for 6 consecutive months or 2 consecutive artificial insemination failures were also offered IVF treatment. Main Outcome Measure (s): The clinical and laboratory embryo data, clinical pregnancy outcomes and endometrial disease recurrence rates. Results: Compared with the standard regimen group, the good-quality embryo rate was higher in progestin primed ovarian stimulation (PPOS) regimen group (P = 0.034). Univariate analysis showed significant differences in age (P = 0.033), treatment time of endometrial lesions (P < 0.001), and duration of Gn treatment (P = 0.018) between the recurrent and non-recurrent groups. In the adjusted model of multivariate logistic regression analysis, the age (P = 0.014) at ovulation induction and treatment time of endometrial lesions (P < 0.001) were significantly correlated with the recurrence of endometrial disease. Conclusions: The PPOS protocol is a feasible and safe strategy to stimulate ovulation during IVF after fertility preservation therapy, and the age at ovulation induction and treatment time of endometrial lesions are two stable predictors of recurrence in endometrial diseases.

Possible roles of HLA-G regulating immune cells in pregnancy and endometrial diseases via KIR2DL4.

Major histocompatibility complex (MHC) molecules bind peptides originated from cellular synthesis and present them at the cell surface for recognition by receptors on immune cells like T lymphocytes, natural killer (NK) cells or mast cells. Such recognition plays a crucial part in autoimmunity, anti-bacterial, anti-viral and anti-tumor responses. Human leukocyte antigen G (HLA-G) is a member of non-classical HLA class I molecules which has been studied deeply in recent years into its role in pregnancy and endometrial diseases, including endometrial tumor, endometriosis and adenomyosis, etc. Understanding the mechanism of the maintenance of pregnancy and immune escape of endometrial diseases in a HLA-G dependent way is of current interest. Perception from studies in the expression of HLA-G and possible pathways is a vital part of understanding mechanisms related to immune escape.

Unexpected endometrial malacoplakia related to abortion and placental rests retention: a case report.

BACKGROUND: Malacoplakia is a rare chronic inflammatory disease. The name derives from the Greek "µαλακός" meaning "soft" and "πλάξ" meaning "plaque", describing its usual macroscopic presentation as a friable yellow soft plaque. It was first described by von Hansemann in 1901 and by Michaelis and Gutmann in 1902. The urinary system is the most commonly involved site. Female genital tract involvement is extremely rare. Treatment is prevalently based on antibiotics with surgical intervention sometimes necessary. Prognosis is usually good, but relapse may frequently occur. CASE PRESENTATION: This report illustrates the first case of endometrial malacoplakia in a 40 years-old patient who received endometrial curettage due to the retention of placental rests following an abortion. After conspicuous vaginal sero-hematic secretions, the patient received a further curettage. The histological examination did not show any retention of chorionic rests, but an endometrial and myometrial infiltration of histiocytes with large granular cytoplasm within a chronic inflammatory background. Immunoreactivity for CK-pool was negative, while CD68 immunostaining was strongly positive. CONCLUSIONS: Malacoplakia of endometrium is an extremely rare condition, with few cases reported in the whole international literature. In this paper, we present the first case associated to an abortion followed by endometrial curettage procedures. This rare disease should always be attentively examined, considering, among differential diagnoses, uterine neoplasms or physiological conditions such as cumulus of foamy macrophages in the endometrium.

The Healthy and Diseased Equine Endometrium: A Review of Morphological Features and Molecular Analyses.

Mares are seasonally polyestric. The breeding season in spring and summer and the winter anestrus are flanked by transitional periods. Endometrial diseases are a frequent cause of subfertility and have an economic impact on the horse breeding industry. They include different forms of endometrosis, endometritis, glandular maldifferentiation, and angiosis. Except for suppurative endometritis, these are subclinical and can only be diagnosed by the microscopic examination of an endometrial biopsy. Endometrosis is characterized by periglandular fibrosis and nonsuppurative endometritis by stromal infiltration with lymphocytes and plasma cells. The pathogenesis of endometrosis and nonsuppurative endometritis is still undetermined. Some mares are predisposed to persistent endometritis; this has likely a multifactorial etiology. Glandular differentiation has to be interpreted under consideration of the season. The presence of endometrial diseases is associated with alterations in the expression of several intra- and extracellular molecular markers. Some of them may have potential to be used as diagnostic biomarkers for equine endometrial health and disease. The aim of this review is to provide an overview on pathomorphological findings of equine endometrial diseases, to outline data on analyses of cellular and molecular mechanisms, and to discuss the impact of these data on reproduction and treatment.

The incidence rate of unresponsive thin endometrium in frozen embryo transfer cycles: A case-series of therapy with granulocyte colony stimulating factor.

BACKGROUND: Treatment-resistant thin endometrium (TTE) during in-vitro fertilization is a relatively uncommon and challenging problem. OBJECTIVE: The primary aim of the study was to assess the TTE rate during frozen embryo transfer (FET) cycles and the secondary aim was to evaluate the effect of intrauterine instillation of granulocyte colony stimulating factor (G-CSF) in these cases. MATERIALS AND METHODS: In this cross-sectional study, all of the women who underwent FET cycles with hormonal endometrial preparation in Royan Institute from June 2015 to March 2018 were evaluated and all of the cases with TTE diagnosis (endometrial thickness < 7 mm after using high doses of estradiol) were included. In the eligible cases, 300 µgr of G-CSF was infused intrauterine. If the endometrium had not reached at least a 7-mm, a second infusion was prescribed within 48 hr later. RESULTS: During the study, 8,363 of FET cycles were evaluated and a total of 30 infertile patients (0.35%) with TTE diagnosis were detected. Finally, 20 eligible patients were included. The changes of endometrial thickness after G-CSF therapy were significant (p < 0.001); however, the endometrial thickness did not reach 7 mm in nine patients (45%) and the embryo transfer was canceled. CONCLUSION: It was found that the rate of TTE during the FET cycle is very low and intrauterine perfusion of G-CSF has a potential effect to increase the endometrial thickness in these patients; however, the rate of cancellation was still high and poor pregnancy outcomes were observed.

Clinical Significance of Endometrial Abnormalities in Patients with Breast Cancer after Oral Administration of Tamoxifen / 中国医科大学学报

Objective To analyze the clinical significance of endometrial abnormalities in patients with breast cancer after oral administration of tamoxifen, and to determine the risk factors for endometrial malignancy. Methods We collected data from 135 patients with breast cancer who underwent surgery for endometrial abnormalities after oral administration of tamoxifen at the Department of Gynecology from September 2011 to December 2017. According to the pathological results obtained, the patients were divided into groups A (benign endometrial lesion) and B (precancerous and malignant endometrial lesion). The relationships between endometrial malignancy and factors including age, menopausal status, body mass index, endometrial thickness, abnormal uterine bleeding, oral dose of tamoxifen, duration of oral medication, and complications (hypertension and diabetes) were compared between the groups. Results There were 124 patients in group A and 11 patients in group B. The difference in the incidence of abnormal uterine bleeding, which was a risk factor for endometrial malignancy, was significant different between the groups (P ＜ 0.05). Conclusion Physicians should pay close attention to abnormal uterine bleeding in patients taking tamoxifen after surgery for breast cancer. Hysteroscopy should be used to confirm the nature of lesions, and patients without symptoms should be followed up.

Clinical value of transvaginal three-dimensional ultrasonography in the differential diagnosis of benign and malignant endometrial diseases after menopause / 中国基层医药

Objective@#To investigate the clinical value of transvaginal three-dimensional ultrasonography in the differential diagnosis of benign and malignant endometrial diseases after menopause.@*Methods@#From April 2015 to April 2017, the imaging data of transvaginal three-dimensional ultrasonography of 184 patients with benign and malignant breast tumors in the Second People's Hospital of Yuhang District were retrospectively analyzed.The peak systolic flow velocity, resistance index, peak systolic velocity, intimal arterial resistance index and blood flow display rate of uterine artery of benign and malignant endometrial diseases were compared.@*Results@#The accuracy, sensitivity and specificity of transvaginal three-dimensional ultrasonography in the diagnosis of endometrial diseases were 91.30%(168/184), 92.00%(46/50), 91.04%(122/134), respectively.There were no statistically significant differences in the peak systolic flow velocity, resistance index, peak systolic velocity of patients with benign and malignant endometrial diseases by transvaginal three-dimensional ultrasonography(t=1.17, 0.88, 0.51, all P>0.05). The intimal arterial resistance index of patients with malignant endometrial diseases by transvaginal three-dimensional ultrasonography was significantly lower than patients with benign endometrial diseases(t=2.59, P<0.05). The blood flow display rates of uterine artery of patients with malignant endometrial diseases by transvaginal three-dimensional ultrasonography were 19.40%(26/134), 92.00%(46/50). The blood flow display rate of uterine artery of patients with malignant endometrial diseases by transvaginal three-dimensional ultrasonography was significantly higher than patients with benign endometrial diseases(χ2=7.26, P<0.05).@*Conclusion@#Transvaginal three-dimensional ultrasonography in the differential diagnosis of benign and malignant endometrial diseases after menopause has higher accuracy, sensitivity and specificity.

Application of 3D Ultrasonography in Detection of Uterine Abnormalities.

Structural pathologies in the uterine cavity such as müllerian duct anomalies (MDAs) and intrauterine lesions (fibroids, polyps, synechiae) may have important roles in subinfertility, implantation failure and pregnancy outcome. Various imaging modalities such as hysterosalpingography (HSG), sonography, laparoscopy and hysteroscopy are used in the evaluation of MDAs and intrauterine lesions. Recently, three-dimensional ultrasound (3DUS) has been introduced as a non-invasive, outpatient diagnostic modality. With increased spatial awareness, it is superior to other techniques used for the same purpose.

Transvaginal color Doppler ultrasound in identifying endometrium abnormality / 中国介入影像与治疗学

Objective To observe the value of transvaginal color Doppler ultrasound (TVCDU) in the diagnosis of endo-metrial lesions.Methods All 246 patients suspected of endometrial diseases underwent TVCDU and transabdominal ultra-sonography.Ultrasonographic characteristics,especially the uterine endometrial thickness and blood flow distribution were observed,and the results were compared with surgery and pathological results.Results A total of 242 patients were pathologically diagnosed as endometrial diseases.TVCDU diagnosed 232 cases,with the diagnostic accordance rate of 95.87%.Transabdominal ultrasonography diagnosed 182 cases,with the diagnostic accordance rate of 75.21%.TVCDU was superior to transabdominal color Doppler examination (P<0.05).Conclusion TVCDU has high diagnosis accordance rate and can be used as routine examination of endometrial diseases.