Endometrial Inflammation Research Articles

An axonemal alteration in apical endometria of human adenomyosis.

Is there any change in the distribution of microvilli and microtubules in the apical endometria of women with adenomyosis? We observed microvilli damage in the apical endometria and an axonemal alteration characterized by abnormal distribution of longitudinal bundles of microtubules within microvilli in women with adenomyosis. Human adenomyosis has a negative impact on female fertility. Abnormal utero-tubal sperm transport, tissue inflammation and toxic effect of chemical mediators have been proposed as contributing factors. Inflammation-induced damage of mucosal cilia in the Fallopian tube has been reported. However, information on inflammation-induced damage of microvilli on the apical endometrial cells and its core bundles of microtubules in adenomyosis remains unknown. This is a prospective cohort study with subjects undergoing laparoscopic surgery or hysterectomy for clinical indication and evaluations of endometrial biopsy samples in two academic university hospitals. During the period between March 2015 and December 2018, endometrial biopsy samples were prospectively collected from 15 control women and 45 women with adenomyosis for immunohistochemical analysis and a separate cohort of 10 control women with cervical intraepithelial neoplasia Grade 3 (CIN3) and 20 women with adenomyosis for analysis by immunohistochemistry and transmission electron microscopy (TEM). For immunohistochemical study, endometrial biopsy samples were prospectively collected from 15 control women with fibroids, 25 women with focal adenomyosis and 20 women with diffuse adenomyosis after surgery. The diagnosis of fibroid and adenomyosis was made clinically by transvaginal ultrasonography and magnetic resonance imaging and confirmed by histology. Immunohistochemical analysis was performed retrospectively using antibody against CD68 (marker of macrophages) in endometrial biopsy specimens of women with and without adenomyosis. TEM was performed with the apical endometria collected from a separate cohort of 10 control women with CIN3 and 20 women with focal and diffuse adenomyosis for the identification of any change in the distribution of microvilli and longitudinal bundles of microtubules within microvilli. Comparing to control endometria and contralateral side, tissue infiltration of macrophages (Mφ) in the endometria was significantly higher on the ipsilateral side of focal adenomyosis (P = 0.02 and P = 0.03, respectively) and anterior/posterior walls of diffuse adenomyosis (P = 0.01 for both). In a subgroup analysis of patients with focal adenomyosis with and without symptoms, the endometria of symptomatic women displayed a tendency of higher Mφ infiltration on the ipsilateral side than in asymptomatic women (P = 0.07). Comparing to contralateral side endometria of symptomatic women, Mφ infiltration was significantly higher in the endometria of symptomatic women collected from the ipsilateral side of focal adenomyosis (P = 0.03). We found a significantly less tissue infiltration of Mφ in the endometria of women with CIN3 than that in endometria of women with focal adenomyosis. TEM analysis showed that number of microvilli in the endometria was significantly decreased on the ipsilateral side (P = 0.003) comparing to that on the contralateral side of focal adenomyosis. The Chi-squared test indicated that cases with abnormal (disruption in the normal arrangement of 9 peripheral pairs + 1 central pair) microtubules (MT) were significantly higher in women with adenomyosis than in cases with normal patterns (P = 0.0016). While contralateral side displayed significantly less abnormal MT (P = 0.0002), ipsilateral side of focal adenomyosis showed significantly higher abnormal MT (P = 0.0164) comparing to normal patterns. Cases with symptomatic adenomyosis showed significantly higher abnormal MT than normal MT (P = 0.0004). An axonemal alteration characterized by abnormal structural distribution of microtubules within microvilli in the apical endometria in response to endometrial inflammation may be involved in adverse reproductive outcome in women with adenomyosis. The average age of women in this study was high that may be associated with overall decline in fertility regardless of the presence or absence of adenomyosis or endometriosis. We collected endometrial biopsy samples from two completely separate cohorts of women for analysis by immunohiostochemistry and TEM. We need future follow-up study with increased sample size and from the same patients to precisely clarify the mechanistic link between axonemal alteration and negative fertility outcome. Our current findings may have some biological implication to better understand the endometrial epithelial biology and pathology in women with adenomyosis and may open the avenue for future study in other reproductive diseases. The ultra-structural abnormalities of microvilli and microtubules in the apical endometria in response to tissue inflammatory reaction may clarify the possible association between negative fertility outcome and adenomyosis. Our findings may be clinically useful during counseling with symptomatic patients with adenomyosis desiring pregnancy. This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Sports, Culture, Science and Technology of Japan. There is no conflict of interest related to this study. N/A.

Blood and cell infiltrate neutrophilic leucocytes As inflammation markers in chronic endometritis: A prospective non-randomised controlled trial

Background. Inflammation declares itself with the presence of cellular tissue infiltrate, which composition reflects the inflammation type. Chronic inflammation is predominated by mononuclear cell infiltration with a certain amount of neutrophils, which role and significance are not fully understood to date.Objectives. Assessment of the infiltrated neutrophil count at various chronic endometritis severity and its dependency on the functional and metabolic activity in neutrophilic leucocytes in peripheral blood.Methods. This prospective non-randomised controlled trial estimated the CD45+ leucocyte and activated CD16b+ neutrophil counts in inflammation infiltrate using immunohistochemistry protocols. Cell counts per section 1 mm2 were measured with computer morphometry. The content of and NADPH oxidase activity in activated neutrophilic leucocytes in venous blood were estimated with a nitroblue tetrazolium reduction test.Results. The study included 40 women with a history of chronic endometritis (CE) divided in two cohorts by endometrial biopsy data, with inactive (n = 25) and active CE (n = 15). A control cohort comprised 20 women with no signs of CE. The inactive CE cohort had higher counts of CD45+ leucocytes and activated CD16b+ neutrophils in infiltrate compared to control. Higher content of activated neutrophilic leucocytes with higher NADPH oxidase activity were found in peripheral blood. Morphological exacerbation markers of EC were associated with sharper peaks of CD45+ and CD16b+ cell counts in infiltrate and an elevated functional metabolic activity in circulating neutrophilic leucocytes. A strong direct correlation was revealed between blood activated neutrophil and endometrial CD16b+ neutrophil counts, as well as NADPH oxidase activity in blood neutrophils and infiltrate CD16b+ cell counts.Conclusion. Even minor morphological markers of exacerbated endometrial inflammation are accompanied by the elevated infiltrate counts of both total CD45+ leucocytes and activated CD16b+ neutrophils. The functional metabolic activity of peripheral blood neutrophilic leucocytes is interlinked with the inflammatory infiltrate cell composition and reflects severity of chronic endometrial inflammation.

Canine pyometra – an update and revision of diagnostic terminology

Pyometra is frequently diagnosed in the female dogs, and it is characterized by endometrial inflammation, accumulation of purulent exudate within the lumen, and bacterial infection. In the dog, pyometra affects more often aged nulliparous bitches during the luteal phase. Pathogenesis of pyometra is multifactorial and progesterone seems to be a key factor. Cystic endometrial hyperplasia has been described as a predisposing condition for canine pyometra. However, a recent study demonstrated that cystic endometrial hyperplasia is not significantly associated with naturally occurring pyometra, whereas there is a significant association of this condition with pseudoplacentational endometrial hyperplasia. The aim of this review is to provide an update on canine pyometra, with focus on its association with uterine hyperplasic lesions, which supports a proposal for adoption of more adequate diagnostic terminology.

Efficacy of a Y‐Design Silastic Elastomer Intrauterine Device as a Horse Contraceptive

ABSTRACTTo successfully manage population growth rates of free‐roaming horses (Equus ferus caballus), an effective, long‐acting contraceptive could be beneficial. We evaluated the efficacy and safety of an intrauterine device (IUD) in a breeding trial using seasonal pasture assemblages of 2 males individually pastured in large enclosures (~81 ha) each with 10 females per male. The study took place at a large animal research facility at Oklahoma State University in Stillwater, Oklahoma, USA. Specific objectives of the study were to evaluate the effectiveness of IUDs in preventing pregnancy over 20.5 months with return to fertility assessed over the subsequent 6 months and to evaluate potential effects of this IUD on ovarian function and uterine health (e.g., endometrial inflammation, infection, fibrosis). We developed a Y‐design IUD, made of silastic elastomer, and set the desired retention rate at 75%. After procurement of endometrial biopsies, we inserted IUDs into the uteri of 20 females and examined them via transrectal ultrasound every 2 weeks for detection of the device and assessment of uterine health. After 20.5 months we removed the remaining 15 IUDs, obtained a second endometrial biopsy for comparision, and returned the females to their respective males for continued breeding in efforts to assess uterine return to health as indicated by pregnancy rates. The Y‐design IUD met the 75% retention rate goal, with 100% contraception in females that retained the device; 12 of 20 treated females became pregnant (i.e. returned to fertility) after removal of the IUD. Based on these results, we conclude that the Y‐design IUD is a safe and effective device to control fertility in free‐roaming horses. © 2021 The Wildlife Society.

Hydroxysafflor Yellow A Inhibits Staphylococcus aureus-Induced Mouse Endometrial Inflammation via TLR2-Mediated NF-kB and MAPK Pathway.

The present study is designed to investigate the effect of hydroxysafflor yellow A (HYA) on Staphylococcus aureus (S. aureus)-induced mouse endometrial inflammation and to explore its molecular mechanism. We established a mouse endometritis model by intrauterine injection of S. aureus and intrauterine injection of HYA for treatment. Immunohistochemistry, immunofluorescence, and Western blot were used to detect protein expression in uterine tissue, and qPCR was used to measure mRNA expression. HYA could significantly weak uterine pathological changes caused by S. aureus and reduce MPO activity, CD45, CD3, and ED-1 protein expression in uterine tissues of S. aureus-infected mice. Similarly, HYA also significantly decreased S. aureus induced the increase in TNF-α, IL-1β, and IL-6 in uterine tissue. In vivo, we found that knockdown of TLR2 was very important could significantly reduce S. aureus induced the elevated expression of TNF-α, IL-1β, and IL-6 in mEECs. Importantly, in terine tissues of S. aureus-infected mice, HYA significantly decreased the ratio of p-p65/p65, p-IKBα/IKBα, p-p38/p38, p-Erk/Erk, and p-JNK/JNK expression. HYA displays anti-inflammatory effects on S. aureus mouse endometrial inflammation, and this effect might be related to HYA which could block TLR2-mediated NF-kB and MAPK pathway.

Obesity is associated with heavy menstruation that may be due to delayed endometrial repair.

Heavy menstrual bleeding is common and debilitating but the causes remain ill defined. Rates of obesity in women are increasing and its impact on menstrual blood loss (MBL) is unknown. Therefore, we quantified BMI and MBL in women not taking hormones and with regular menstrual cycles and revealed a positive correlation. In a mouse model of simulated menstruation, diet-induced obesity also resulted in delayed endometrial repair, a surrogate marker for MBL. BrdU staining of mouse uterine tissue revealed decreased proliferation during menstruation in the luminal epithelium of mice on a high-fat diet. Menstruation is known to initiate local endometrial inflammation and endometrial hypoxia; hence, the impact of body weight on these processes was investigated. A panel of hypoxia-regulated genes (VEGF, ADM, LDHA, SLC2A1) showed consistently higher mean values in the endometrium of women with obesity and in uteri of mice with increased weight vs normal controls, although statistical significance was not reached. The inflammatory mediators, Tnf and Il6 were significantly increased in the uterus of mice on a high-fat diet, consistent with a pro-inflammatory local endometrial environment in these mice. In conclusion, obesity was associated with increased MBL in women. Mice given a high-fat diet had delayed endometrial repair at menstruation and provided a model in which to study the influence of obesity on menstrual physiology. Our results indicate that obesity results in a more pro-inflammatory local endometrial environment at menstruation, which may delay endometrial repair and increase menstrual blood loss.

22732 Impact of Type-I Interferon Manipulation During Embryo Implantation and Placentation

ABSTRACT IMPACT: This research will promote understanding the role of the Type-I Interferon signaling pathway during embryo implantation, potentially leading to a new diagnostic or treatment target in early pregnancy failure. OBJECTIVES/GOALS: Studies suggest interferon signaling regulation is tightly balanced between physiologic and pathophysiologic growth in early pregnancy. We propose to determine the impact of interferon-mediated inflammation on embryo implantation and early pregnancy failure in normal conditions and chronic inflammatory diseases in a novel mixed-mouse model. METHODS/STUDY POPULATION: To probe the role of type-I interferons (IFNs) in implantation, we will utilize a mouse model and non-surgically transfer both Ifnar1-/- and Ifnar1-/+ embryos into an immune-competent pseudopregnant wild-type female recipient. This will allow analysis of a litter with distinct genotypes within the same, immune-competent, uterine environment. Type-I IFN stimulation will be systemically induced with Poly-(I:C) at various time points around implantation. A similar approach will be used in mouse models of chronic inflammatory disease states associated with early pregnancy loss (e.g. systemic lupous erythematous). With this model, we will be able to control for deficiencies in maternal immune response to specifically determine the embryonic response to inflammation during implantation and development. RESULTS/ANTICIPATED RESULTS: We anticipate the Ifnar1-/+ embryos - those able to respond to Type-I IFN - and their surrounding implantation sites will exhibit more maternal-fetal barrier dysfunction in the form of impaired trophoblast fusion, improper formation of the microvascular architecture, and increased permeability of the maternal-fetal barrier, compared to embryos unable to respond to IFN. We will also conduct similar analyses in mouse models of chronic inflammatory diseases. We hypothesize these mice to have baseline endometrial inflammation that stimulated the IFN-pathway in IFN-capable embryos, producing breakdown of the maternal-fetal barrier. In these mice, we predict Ifnar1-/- embryos will show improved molecular outcomes when compared to Ifnar1-/+ embryos, and thus improved associated pregnancy outcomes. DISCUSSION/SIGNIFICANCE OF FINDINGS: This work can insight into the immunological mechanisms that govern embryo implantation and early placentation. This could provide more pointed means for management and intervention of early pregnancy failure and/or disease states that are commonly associated with poor reproductive outcomes.

Uterine metabolic disorder induced by silica nanoparticles: biodistribution and bioactivity revealed by labeling with FITC

Extensive application of nanomaterials has dramatically increased the risk of silica nanoparticle (SiNP, SiO2) exposure, yet their biological effect on reproduction has not been fully elucidated. By tracking the uterine biodistribution of SiNP in pregnant mice, this study was conducted to evaluate the biological effect of SiNP on reproduction. First, SiNP was conjugated with FITC, and then the FITC-SiNP was administrated to trophoblast (100 µg/mL, 24 h) in vitro and pregnant mice (0.25 mg/mouse, 2–24 h) in vivo. It was found that the FITC-SiNP was internalized by trophoblast and deposited in the uterus. The internalization of SiNP caused trophoblast dysfunction and apoptosis, while SiNP accumulation in the uterus induced diffuse inflammatory infiltration. The genome-wide alteration of gene expression was studied by high throughput sequencing analysis, where 75 genes were found to be dysregulated after SiNP exposure, among which ACOT2, SCD1, and CPT1A were demonstrated to regulate the biosynthesis of unsaturated fatty acids. Moreover, the suppression of unsaturated fatty acids caused mitochondrial overload of long-chain fatty acyl-CoA (LACoA), which further induced both trophoblast apoptosis and endometrial inflammation. In conclusion, the successful conjugation of FITC onto SiNP facilitated the tracking of SiNP in vitro and in vivo, while exposure to FITC-SiNP induced uterine metabolic disorder, which was regulated by the ACOT/CPT1A/SCD1 axis through the biosynthesis of unsaturated fatty acids signaling pathway.

The evolutionary biology of endometriosis.

We provide the first analysis and synthesis of the evolutionary and mechanistic bases for risk of endometriosis in humans, structured around Niko Tinbergen's four questions about phenotypes: phylogenetic history, development, mechanism and adaptive significance. Endometriosis, which is characterized by the proliferation of endometrial tissue outside of the uterus, has its phylogenetic roots in the evolution of three causally linked traits: (1) highly invasive placentation, (2) spontaneous rather than implantation-driven endometrial decidualization and (3) frequent extensive estrogen-driven endometrial proliferation and inflammation, followed by heavy menstrual bleeding. Endometriosis is potentiated by these traits and appears to be driven, proximately, by relatively low levels of prenatal and postnatal testosterone. Testosterone affects the developing hypothalamic–pituitary–ovarian (HPO) axis, and at low levels, it can result in an altered trajectory of reproductive and physiological phenotypes that in extreme cases can mediate the symptoms of endometriosis. Polycystic ovary syndrome, by contrast, is known from previous work to be caused primarily by high prenatal and postnatal testosterone, and it demonstrates a set of phenotypes opposite to those found in endometriosis. The hypothesis that endometriosis risk is driven by low prenatal testosterone, and involves extreme expression of some reproductive phenotypes, is supported by a suite of evidence from genetics, development, endocrinology, morphology and life history. The hypothesis also provides insights into why these two diametric, fitness-reducing disorders are maintained at such high frequencies in human populations. Finally, the hypotheses described and evaluated here lead to numerous testable predictions and have direct implications for the treatment and study of endometriosis. Lay summary: Endometriosis is caused by endometrial tissue outside of the uterus. We explain why and how humans are vulnerable to this disease, and new perspectives on understanding and treating it. Endometriosis shows evidence of being caused in part by relatively low testosterone during fetal development, that ‘programs’ female reproductive development. By contrast, polycystic ovary syndrome is associated with relatively high testosterone in prenatal development. These two disorders can thus be seen as ‘opposite’ to one another in their major causes and correlates. Important new insights regarding diagnosis, study and treatment of endometriosis follow from these considerations.

The Lipiodol Uterine Bathing Effect to Improve Fertility May Include Uterine Natural Killer Cell Up-regulation in the Endometrium

BACKGROUND: Lipiodol has a dramatic short term fertility enhancing effect for women with endometriosis. Microarray studies have shown transcriptomic regulation of molecular markers of endometrial inflammation, most notably a consistent down-regulation of endometrial osteopontin. We further explored the endometrial bathing effect of lipiodol on leukocyte expression in endometrium. METHODS: A cohort of four women, nested within a randomised trial of twelve women assessing the lipiodol uterine bathing effect, was studied as an ‘own control’ group, with their mid-luteal endometrium assessed before and after endometrial lipiodol exposure. Pipelle endometrial sampling allowed endometrial assessment by immunochemistry. Endometrial tissue samples were assessed by immunochemistry for total CD45+ leukocytes, CD68+ macrophages, CD3+ T-cells and CD56+ uterine natural killer cells. RESULTS: There was a statistically significant increase in the mean density of uterine natural killer cells in the endometrium of women post-lipiodol. No other significant differences were found in the mean densities of all leukocytes, macrophages or T cells in the endometrium of women post-lipiodol. CONCLUSIONS: These preliminary data further support the concept of a uterine bathing effect of lipiodol. Whether the increase in the mean density of uterine natural killer cells in the endometrium might contribute to an improvement in endometrial receptivity to embryo implantation merits further investigation.

Magnesium-containing composition influencing morphological parameters and gelatinase B activity in endometrial tissues in experimental chronic endometrial inflammation

Aim: to assess an effect of medicinal magnesium-containing composition on gelatinase B expression intensity and morphological parameters of chronic experimental endometrial inflammation.Materials and Methods. There were conducted experiments with 60 sexually mature female Wistar rats to determine an effect of medicinal magnesium-containing composition (contains magnesium chloride – a natural polymineral Bischofite) on gelatinase B activity in endometrial tissues (counting number of gelatinase-B-positive cells and intensity of gelatinase B expression), morphological parameters of cell infiltration, as well as amount of magnesium in red blood cell mass collected from the inferior vena cava and subclavian vein. All such parameters were assessed in experimental animals from 4 groups: group 1 – animals in baseline state, group 2 – control, group 3 – experimental chronic endometritis (CE), group 4 – experimental CE after treatment with medicinal magnesium-containing composition. Results. It was found that use of medicinal magnesium-containing composition increased amount of erythrocyte magnesium up to the baseline level and increased both number and expression intensity of stromal gelatinase B-positive cells. In addition, magnesium level in erythrocyte mass from the inferior vena cava was increased and accompanied with restored eosinophil-plasmacyte as well as significantly elevated macrophage-lymphocyte infiltration in endometrial tissues compared to CE animals lacking therapy. Conclusion. The results of this study allow us to conclude about importance of gelatinase B in pathogenesis of experimental chronic endometrial inflammation as well as an opportunity of regulating gelatinase B activity by applying medicinal magnesium containing drug in pathogenetic therapy of experimental CE.

A Drug Release Mechanism Controlled by Hydrophobic/Hydrophilic Balance of the Matrix. Theoretical and Experimental Perspectives

Controlled drug release is a promising pathway of biomedicine, meant to suppress side effects with the aim of increasing patient s comfort. A route to achieve this goal represents the encapsulation of drugs into matrixes, capable to develop physical forces, which further can control the drugs release. To this purpose, mathematical modeling is an important tool, which offers the possibility to understand the drug release mechanisms and to further design new performant systems. In this paper, a theoretical model for drug release from an amphiphilic matrix is presented. This is achieved using a conservation multifractal law of probability density followed by validation of the model. Moreover, because non-steroidal anti-inflammatory drugs (NSAIDs), such as diclofenac, are widely used in endometriosis as painkillers for dysmenorrhea management or Asherman syndrome for reducing the endometrial inflammation, some implications of our model for drug delivery systems applied in the field of gynecology have been discussed.

Хронический эндометрит. Пути улучшения методов диагностики

This paper reviews an important issue that significantly affects female fertility, chronic endometritis. This condition is characterized by clinical presentations of various severity and abnormalities of endometrial morphology. The rate of chronic endometritis varies greatly, mainly due to predominantly asymptomatic course and imperfect diagnostics. Pathogenic mechanisms of endometrial inflammation and different views on its effects on female reproductive potential are addressed. Further search for endometrial receptivity markers is needed as these markers will allow for assessing the severity of endometrial damage to develop the algorithm of preconception care. The authors focus on diagnostic techniques for chronic endometritis and their value. Immunohistochemistry of endometrium is a promising tool to be applied to diagnose endometrial inflammation and monitor treatment efficacy. A complex diagnostic approach to chronic endometritis that includes pelvic ultrasound, Doppler ultrasound, assessment of endometrial microbiota, diagnostic hysteroscopy and endometrial histopathology, and evaluation of endometrial receptivity is useful. KEYWORDS: chronic endometritis, termination of pregnancy, infertility, autoimmune processes, chronic inflammation, endometrial structure, immunohistochemistry. FOR CITATION: Shamilova A.M., Il’ina I.Yu., Borovkova E.I., Dobrokhotova Yu.E. Chronic endometritis. Towards the improvement of diagnostic methods. Russian Journal of Woman and Child Health. 2021;4(3):243–249 (in Russ.). DOI: 10.32364/2618-8430-2021-4-3-243-249.

Predisposing factors, diagnostic and therapeutic aspects of persistent endometritis in postpartum cows.

A certain level of endometrial bacterial infection and inflammation is involved in bovine uterine involution during the puerperal period. Factors that hamper normal uterine involution expose the uterine environment to pathological conditions, causing different endometritis levels. The lack of proper diagnostic tools extends the time to conception. Efforts have been made to elucidate the postpartum uterine environment, including bacterial flora, changes in transient endometrial inflammation, and the pathophysiology of endometritis, to improve bovine reproductive performance. E. coli and Trueperella pyogenes in the uterus are likely to cause persistent infection, and Mycoplasma bovigenitalium infection is associated with dystocia and cytological endometritis in postpartum dairy cows. Due to the widespread use of cytobrush as a diagnostic tool for bovine subclinical endometritis (SE) that enables quantification of the degree of inflammation, we found that endometritis at week 5 postpartum was associated with delayed first ovulation. Approximately 30% of open cows have SE during the postpartum period, and cows with low blood glucose during prepartum have a high risk of developing SE. Additionally, cows with purulent vaginal discharge do not always have endometritis but only vaginitis and/or cervicitis. Intrauterine infusion of polyvinylpyrrolidone-iodine (PVP-I) improves fertility and promotes endometrial epithelial cell regeneration after inducing transient uterine inflammation, suggesting that PVP-I could be a good alternative to antibiotics. In conclusion, prepartum management to prevent glucose deficiency, prompt diagnosis to identify causative agents and intrauterine inflammation levels, and appropriate treatment to minimize antimicrobial resistance is beneficial for tackling endometritis and improving reproductive performance in bovine herds.

FOXO1 Is a Critical Switch Molecule for Autophagy and Apoptosis of Sow Endometrial Epithelial Cells Caused by Oxidative Stress.

Oxidative stress (OS) is involved in various reproductive diseases and can induce autophagy and apoptosis, which determine the different fates of cells. However, the sequence and the switch mechanism between autophagy and apoptosis are unclear. Here, we reported that chronic restraint stress (CRS) induced OS (decreased T-AOC, T-SOD, CAT and GSH-Px and increased MDA) and then disturbed the endocrine environment of sows during early pregnancy, including the hypothalamic-pituitary-ovarian (HPO) and the hypothalamic-pituitary-adrenal (HPA) axes. Meanwhile, after CRS, the KEAP1/NRF2 pathway was inhibited and attenuated the antioxidative ability to cause OS of the endometrium. The norepinephrine (NE) triggered β2-AR to activate the FOXO1/NF-κB pathway, which induced endometrial inflammation. CRS induced the caspase-dependent apoptosis pathway and caused MAP1LC3-II accumulation, SQSTM1/p62 degradation, and autophagosome formation to initiate autophagy. Furthermore, in vitro, a cellular OS model was established by adding hydrogen peroxide into cells. Low OS maintained the viability of endometrial epithelial cells by triggering autophagy, while high OS induced cell death by initiating caspase-dependent apoptosis. Autophagy preceded the occurrence of apoptosis, which depended on the subcellular localization of FOXO1. In the low OS group, FOXO1 was exported from the nucleus to be modified into Ac-FOXO1 and bound to ATG7 in the cytoplasm, which promoted autophagy to protect cells. In the high OS group, FOXO1 located in the nucleus to promote transcription of proapoptotic proteins and then induce apoptosis. Here, FOXO1, as a redox sensor switch, regulated the transformation of cell autophagy and apoptosis. In summary, the posttranslational modification of FOXO1 may become the target of OS treatment.

Патогенетические механизмы аномального воспаления в эутопическом эндометрии женщин с эндометриоз-ассоциированным бесплодием и методы его коррекции

This review aims to explore existing literature surrounding the pathogenic mechanisms causing inflammation in the eutopic endometrium of women with endometriosis-associated infertility. We discuss morphological and functional changes in the eutopic endometrium in patients with endometriosis and infertility. We also cover endometrial receptivity defects and the vicious circle of endometrial inflammation in patients with external genital endometriosis associated with infertility. There is a description of treatment methods for estrogen-induced inflammation in the eutopic endometrium in women with endometriosis-associated infertility. Key words: endometriosis, infertility, endometrium, dienogest

Impact of fibroids on fertility rate. Surgical management and obstetric outcome

Background. Uterine fibroids are the most common benign tumor in reproductive-age women; when symptomatic, they typically cause pain or pelvic pressure, abnormal uterine bleeding and potential reproductive effects, such as infertility or adverse pregnancy outcome. The intramural and submucosal types produce most prejudice on actual or future pregnancies by distorting the uterine cavity, by affecting the implantation process, as well as by increasing the uterine contractility and producing endometrial inflammation. Myomectomy is cited as the most suitable surgical approach, with benefits and risks. Objectives. To determine the impact of fibroids on fertility rate and the obstetric outcomes of leiomyomas, together with establishing the proper surgical approach for each type, with its benefits. Materials and method. We performed a literature review by searching Cochrane and UpToDate databases, using the keywords: fibroids, fertility, pregnancy, obstetric outcome, myomectomy. Results. Intramural and submucosal fibroids are involved in decreasing implantation and pregnancy rates, with most frequent obstetric outcomes under the form of miscarriage, growth restriction and fetal abnormalities. Myomectomy is suggested to be the best surgical approach for women desiring to preserve fertility, with the possibility to be performed hysteroscopic, laparoscopic or by open surgery, depending on the type, size and clinical picture. Conclusions. Overall, there is an important impact of fibroids on fertility rate and obstetric outcome and hysteroscopic myomectomy performed prior to a pregnancy can improve the fertility rate. The mode of delivery should be individualized in case of myoma and pregnancy.

Association of intrauterine presence of Lactobacillus spp. with inflammation and pathogenic bacteria in the uterus in postpartum dairy cows.

The aim of this study was to clarify the influence of Lactobacillus spp. on the degree of endometrial inflammation in the postpartum period and the relationship between Lactobacillus spp. and pathogenic bacteria in the endometrium of postpartum dairy cows. Endometrial samples were collected from 41 Holstein-Friesian cows at 4 and 8 weeks postpartum using cytobrushes for polymorphonuclear neutrophil (PMN) count and bacterial culture to isolate Lactobacillus spp., Escherichiacoli, and Trueperella pyogenes. The 4-week samples were divided into four groups (E+L+), (E+L−), (E−L+), (E−L−) according to whether endometritis was diagnosed (E+) and Lactobacillus spp. was isolated (L+). The diagnostic criterion for cytological endometritis was > 18% PMN. The average PMN% in the E+L+ group was lower than that in the E+L-group (P < 0.05) at 8 weeks postpartum. There were no significant correlations between the number of colonies of Lactobacillus spp. and E. coli or between that of Lactobacillus spp. and T. pyogenes. Lactobacillus spp. could reduce PMN% in dairy cows with endometritis during the puerperal period. In conclusion, the intrauterine presence of Lactobacillus spp. may have a positive effect on uterine involution in postpartum dairy cows.

TLR4-Associated IRF-7 and NFκB Signaling Act as a Molecular Link Between Androgen and Metformin Activities and Cytokine Synthesis in the PCOS Endometrium.

Low-grade chronic inflammation is commonly seen in polycystic ovary syndrome (PCOS) patients with elevated levels of inflammatory cytokines in the endometrium. This work aimed to increase the limited understanding of the mechanisms underlying cytokine synthesis and increased endometrial inflammation in PCOS patients. Endometrial biopsy samples were collected from non-PCOS (n = 17) and PCOS (n = 22) patients either during the proliferative phase of the menstrual cycle or with hyperplasia. Endometrial explants were prepared from PCOS patients and underwent pharmacological manipulation in vitro. The expression and localization of toll-like receptor 2 (TLR2)/4, key elements of innate immune signal transduction and nuclear factor κB (NFκB) signaling pathways, and multiple cytokines were comprehensively evaluated by Western blotting, immunohistochemistry, and immunofluorescence in endometrial tissues. We demonstrated the distribution of protein expression and localization associated with the significantly increased androgen receptor, TLR2, and TLR4-mediated activation of interferon regulatory factor-7 (IRF-7) and NFκB signaling, cytokine production, and endometrial inflammation in PCOS patients compared to non-PCOS patients with and without endometrial hyperplasia. In vitro experiments showed that 5-dihydrotestosterone (DHT) enhanced androgen receptor, TLR4, IRF-7, and p-NFκB p65 protein expression along with increased interferon α (IFNα) and IFNɣ abundance. The effects of DHT on IRF-7, p-NFκB p65, and IFN abundance were abolished by flutamide, an antiandrogen. Although 17β-estradiol (E2) decreased p-IRF-7 expression with little effect on TLR-mediated IRF7 and NFκB signaling or on cytokine protein levels, exposure to metformin alone or in combination with E2 suppressed interleukin-1 receptor-associated kinase 4 (IRAK4), p-IRF-7, IRF-7, IκB kinase α (IKKα), p-NFκB p65, IFNɣ, and tumor necrosis factor α protein expression. Cytokine synthesis and increased endometrial inflammation in PCOS patients are coupled to androgen-induced TLR4/IRF-7/NFκB signaling, which is inhibited by metformin treatment.

Estrogen and progesterone endometrial cell receptors in cows with subclinical endometritis

Pathological processes that strongly affect the uterine endometrium lead to infertility and abortion. The most common of these pathologies are clinical and subclinical endometritis. Subclinical endometritis is characterized by endometrial inflammation in the absence of clinical signs of endometritis. In this study, we used uterine samples obtained from Ukrainian black-and-white dairy cows aged 4 to 7 years to compare the histology of the uterine endometrium and changes in estrogen-α (ER-α), estrogen-β (ER-β) and progesterone (PgR) nuclear receptor sensitivity in cows with subclinical endometritis. Cows were separated based on cytological examination of the endometrium into a healthy group, or those presenting with subclinical endometritis. From these groups endometrial and epithelial tissue samples were obtained using biopsy forceps and an endoscope then analyzed using immunohistochemistry. Our results demonstrate that the sensitivity of ER-α and ER-β is lower while PgR sensitivity is elevated in cows with subclinical endometritis compared to the healthy control group. Additionally, we observed markedly altered histological changes characterized by enlargement of uterine glands, epithelial desquamation, and infiltration of leukocytes. These results suggest that there are significant changes in the endometrium linked to the sensitivity of nuclear steroid hormone receptors that may also play an immunoregulatory role in cows with subclinical endometriosis. While the interaction of steroid hormones and immunoregulation in the uterus remains to be elucidated, it may provide key insights into the uterine immune response.