Peritoneal endometriosis and infertility

Peritoneal endometriosis and infertility in most of patients (in 80%) are pathogenetically conjugated. Both peritoneal endometriosis and infertility are based in ovarian failure. These women have a low endometrial receptivity for blastocysts implantation (retardation development of glands, vessels, and stroma; changes in the microrelief of the epithelium). Even at the beginning of the menstruation patients with peritoneal endometriosis and infertility have cells with a great adhesive and proliferative potential in the endometrium. This kind of cells have an ability for long autonomous existence. Ovarian failure in these women is a promotion factor for development of the retrograde menstruation. In these conditions the endometrial cells with adhesive potential are frequently bringing in the abdominal cavity. Active endometrium heterotopias support the ovarian failure and create conditions for uterine infertility (implantation disorders).

circPTPN12/miR-21–5 p/∆Np63α pathway contributes to human endometrial fibrosis

Emerging evidence demonstrates the important role of circular RNAs (circRNAs) in regulating pathological processes in various diseases including organ fibrosis. Endometrium fibrosis is the leading cause of uterine infertility, but the role of circRNAs in its pathogenesis is largely unknown. Here, we provide the evidence that upregulation of circPTPN12 in endometrial epithelial cells (EECs) of fibrotic endometrium functions as endogenous sponge of miR-21–5 p to inhibit miR-21–5 p expression and activity, which in turn results in upregulation of ΔNp63α to induce the epithelial mesenchymal transition (EMT) of EECs (EEC–EMT). In a mouse model of endometrium fibrosis, circPTPN12 appears to be a cofactor of driving EEC–EMT and administration of miR-21–5 p could reverse this process and improve endometrial fibrosis. Our findings revealed that the dysfunction of circPTPN12/miR-21–5 p/∆Np63α pathway contributed to the pathogenesis of endometrial fibrosis.

Targeting circPTPN12/1 miR-21-5p/ΔNp63α pathway as a therapeutic strategy for human endometrial fibrosis

Emerging evidence demonstrates the important role of circular RNAs (circRNAs) in regulating pathological processes in various diseases including organ fibrosis. Endometrium fibrosis is the leading cause of uterine infertility, but the role of circRNAs in its pathogenesis is largely unknown. Here, we provide the evidence that upregulation of circPTPN12 in endometrial epithelial cells (EECs) of fibrotic endometrium functions as endogenous sponge of miR-21-5p to inhibit miR-21-5p expression and activity, which in turn results in upregulation of ΔNp63α to induce the epithelial mesenchymal transition (EMT) of EECs (EEC-EMT). In a mouse model of endometrium fibrosis, circPTPN12 appears to be a cofactor of driving EEC-EMT. Our findings reveal the novel mechanism in the pathogenesis of endometrium fibrosis and the potential therapeutic strategy for endometrium fibrosis via targeting circPTPN12/miR-21-5p/∆Np63α pathway.

The efficacy of alternative treatment tactics for uterine infertility

Chronic endometritis is associated with adverse reproductive outcomes such as implantation failure and miscarriage. A high percentage of ineffective use of assisted reproductive technologies in chronic endometritis determines the need to study morphogenesis, timely diagnosis and pathogenetic therapy of this disease. The article presents a modern view of etiopathogenesis, diagnosis, treatment tactics, as well as a clinical case of managing a patient with uterine infertility associated with repeated implantation failures, according to domestic and foreign literature.

Intrauterine synechia and Asherman’s syndrome: a comprehensive approach to diagnosis and treatment

Objective. To study the efficacy of different treatment options for patients with intrauterine synechia. Patients and methods. The results of the observation and treatment of 1218 patients of reproductive age with intrauterine synechia and Asherman’s syndrome were analyzed. Patients were retrospectively divided into 4 groups depending on the treatment option (mechanical dissection of synechiae, laser destruction without or under ultrasound or laparoscopic control). Results. The role and diagnostic value of office hysteroscopy for determining treatment tactics were defined; high efficacy of complex treatment (laser surgery, anti-adhesion gels, postoperative care and rehabilitation) for patients with uterine factor infertility was established: there was no relapse in 98% of patients, and pregnancy occurred in 57% of patients. Intraoperative ultrasound monitoring of patients with Asherman’s syndrome allowed to avoid intraoperative complications in all patients; menstrual cycle was restored in 97.5%, pregnancy occurred in 24%, repeated intervention was necessary in 18%. Conclusion. A comprehensive method including hysteroscopy, laser destruction of synechiae, administration of anti-adhesion gels, postoperative laser therapy, and rehabilitation with the use of chlorophyll-containing medications allows to achieve high efficacy in the treatment of patients with uterine infertility caused by intrauterine synechiae. The results of the analysis indicate the advisability of intraoperative ultrasound monitoring in the surgical treatment of Asherman’s syndrome. Key words: intrauterine synechiae, Asherman’s syndrome, laser destruction, uterine factor infertility

Endometrial Infertility in Patients of Late Reproductive age (a review)

Background. Endometrial infertility is a frequent cause of failure in assisted reproduction. Causes of endometrial infertility are manifold and require comprehensive assessment for a successful choice of treatment strategy.Objectives. A review of infertility concepts accounting for endometrial infertility in women of late reproductive age.Methods. Bibliographic analysis: sources for review were mined in the PubMed, MedLine, eLibrary and Cyberleninka databases at a depth of 10 years. Keyword queries were: endometrial factors of infertility, uterine infertility [маточные факторы бесплодия], causes of infertility. Selected articles related to female infertility and, particularly, endometrial factors of infertility. Low-informative articles were not considered.Results. A total of 51 sources were analysed, with 36 selected in the review. The reviewed evidence suggests that endometrial female infertility in late reproductive age is associated with cumulative gynaecological pathology and age-related change adversely impacting endometrial receptivity and synchrony with embryo maturation in assisted reproductive protocols.Conclusion. Determining the functional status of endometrium is prerequisite for the outcome prognosis in assisted reproduction due to feasible failures to conceive with a vital embryo but reduced endometrial receptivity. This observation warrants a timely diagnosis and treatment of endometrial disorders prior to having assisted reproductive interventions. Woman’s age is the main predictor of successful pregnancy in IVF/ICSI protocols. Among the main markers of successful implantation is endometrial thickness. Uterine infertility may relate to impaired local immunity and autoimmune responses in uterine cavity. The most common mechanisms of uterine infertility are associated uterine myoma, endometriosis and endometritis. Women with uterine infertility attempting IVF/ICSI procedures often exhibit asynchronous endometrial development relative to the embryo maturity for implantation.

Vascular endothelial growth factor 165 inhibits pro-fibrotic differentiation of stromal cells via the DLL4/Notch4/smad7 pathway

Endometrial fibrosis is the main pathological feature of Asherman’s syndrome (AS), which is the leading cause of uterine infertility. Much is known about the expression of VEGF165 in luminal/glandular epithelial cells and stromal cells of the endometrium in normal menstrual cycles; however, less is known about the role and mechanism of VEGF165 in endometrial fibrosis. Herein, we report that VEGF165 is a key regulator in endometrial stromal cells to inhibit α-SMA and collagen 1 expression. Compared to human control subjects, patients with AS exhibited decreased VEGF165 expression in the endometrium along with increased fibrotic marker expression and collagen production. A fibrotic phenotype was shown in both mice with conditional VEGF reduction and VEGF165-deleted endometrial stromal cells. Exogenous VEGF165 could suppress TGFβ1-induced α-SMA and collagen 1 expression in human primary endometrial stromal cells. However, this beneficial effect was hindered when the expression of smad7 or Notch4 was inhibited or when Notch signaling was blocked, suggesting that smad7 and Notch4 are essential downstream molecules for VEGFA functioning. Overall, our results uncover a clinical targeting strategy for VEGF165 to inhibit pro-fibrotic differentiation of stromal cells by inducing DLL4/Notch4/smad7, which paves the way for AS treatment.

Metabolic alterations of uterine grafts after extended cold ischemic storage: experimental study in ewes

Uterine transplantation from a deceased donor could become an available option for widely treating uterine infertility. However, this procedure requires more precise knowledge about the graft’s tolerance to extended cold ischemia. Here, we sought to assess the uterine metabolic alterations after extended cold ischemic storage in a model of auto-transplantation in ewe. A total of 14 uterine auto-transplantations were performed, divided into 2 groups: 7 after 3 h of cold ischemia time (CIT) and 7 after 24 h. Venous uterine blood was collected before uterus retrieval and during reperfusion (30, 60 and 90 min); thereafter, blood gases, lactate, glucose and amino acids (AAs) were analyzed. Apoptosis analyses were performed before uterus retrieval and following reperfusion in uterus biopsies. A total of 12 uterine auto-transplantations were successfully performed and 7 ewes were alive ≥8 days after transplantation. After reperfusion, a decrease in pH, a rise of lactate and lactate/glucose ratio and a delayed decrease of pO2 were found in the 3 h CIT group. No significant variation of these parameters was observed in the 24 h CIT group. Significant decreases of AAs were observed during reperfusion and these decreases were more pronounced and concerned a larger number of compounds in the 24 h CIT group than in the 3 h CIT group. There was no significant uterine apoptotic signal in either group. Overall, these results suggest that extended CIT storage delayed restoration of aerobic glycolysis and induced an increase in AA requirements of the uterus after reperfusion. However, this biochemical alteration did not reduce success rate for uterine transplantation.