Pathogenesis Of Uterine Fibroids Research Articles

Disorders in cytokine synthesis in women with uterine fibroids

In the structure of gynecological diseases, uterine fibroids occupy an “honorable” second place after inflammatory processes of the genital organs, and its share reaches 40%. Uterine fibroids are a benign monoclonal tumor that develops from one abnormal smooth muscle cell of the myometrium, which, as a result of mutation, has the ability to grow unregulated. Common symptoms of the disease include pelvic discomfort or pain, excessive uterine bleeding, secondary anemia, infertility, and bowel and bladder dysfunction. Uterine fibroids can negatively affect the general condition of a woman, causing hormonal, vegetative-vascular and psycho-emotional disorders. Moreover, about 80% of patients with uterine fibroids undergo radical surgical treatment. The mechanisms of development and growth of this benign tumor have not been fully established and remain controversial. The role of immune disorders in the pathogenesis of fibroids is currently being discussed. It has been proven that the growth of fibroids is accompanied by a weakening of immune defense against the background of an increase in the level of proinflammatory cytokines, which are regulators of the processes of proliferation and apoptosis, mediators of the action of sex steroids. The aim of the study was to study the level of some pro-inflammatory cytokines (IL-1β, IL-2, TGF-β2 and MCP-1) in the blood serum of women of reproductive age with uterine fibroids, depending on the size and nature of tumor growth. A comparative analysis of the results of examination of 123 women with uterine fibroids, who made up 2 groups: 1st group of 65 women with simple uterine fibroids and 2nd group of 58 women with rapidly growing uterine fibroids, is presented. The examination included a comprehensive clinical and laboratory study. The level of cytokines (IL-1β, IL- 2, TGF-β2, MCP-1) in the blood serum was assessed by ELISA. It was found that in patients of reproductive age with uterine fibroids, there is an increase in the levels of IL-1β, TGF-β2 and MCP-1. In women with rapidly growing uterine fibroids, these changes are more pronounced. The concentration of IL-2 is reduced in all women with uterine fibroids, regardless of the size and nature of tumor growth. It has been established that an increase in the size of myomatous nodes is accompanied by an increase in immune imbalance: there is an increase in the levels of pro-inflammatory cytokines (IL-1β, TGF-β2, MCP-1) against the background of a reduced content of the lymphokine IL-2, which we regard as possible links in the pathogenesis of uterine fibroids. A pronounced deficiency of IL-2 in the blood serum against the background of a sharp increase in the concentration of TGF-β2 and MCP-1 in the blood of women with uterine fibroids can be considered as a negative criterion for predicting disease progression and used as an additional prognostic marker of tumor growth

Analysis of changes in the levels of soluble molecules CD50, CD54 and CD95 in the blood serum of patients with uterine fibroids depending on the characteristics of the disease (pilot study)

Background. Currently, the search for circulating immunological and inflammatory markers that play a significant role in the pathogenesis of uterine fibroids (UF) is relevant.Aim. Changes in the serum levels of soluble molecules CD50 (sCD50), CD54 (sCD54) and CD95 (sCD95) in patients with UF depending on the characteristics of the disease.Materials and methods. The study involved 78 patients with UF aged 31–59 years and 45 clinically healthy women of comparable age. The patients were divided into the following groups depending on the localization of the myomatous node: interstitial-subserous localization (n = 17), subserous localization (n = 16), submucosal localization (n = 15), interstitial-submucosal localization (n = 15), interstitial localization (n = 15). In 34.6 % patients, the number of myoma nodes was 4–6, in 46.2 % women there were 2–3 nodes, in 19.2 % – 1 node.Determination of the serum concentration of sCD50, sCD54 and sCD95 molecules was performed using a two-site enzyme immunoassay and expressed in conventional units (U / ml).Results. The average serum concentration of sCD95, sCD54 and sCD50 in all patients with UF was significantly higher than in the control group (p <0.05). The maximum level of the tested molecules was found in UF patients with submucosal localization and the presence of one myomatous node.Conclusions. The detected increase in sCD50, sCD54 and sCD95 levels in UF patients indicates the participation of these proteins in the immunopathogenesis of this pathology. The imbalance in studied proteins levels is most pronounced in submucosal localization of fibroids, which may indicate an unfavorable course of the disease and serve as an additional criterion for selecting patients in the preoperative period.

Prediction of uterine myoma growth rate: what's new? (Literature review)

Uterine fibroid remains a relevant issue in modern gynecology and reproductive medicine as the most common benign tumor of the female reproductive organs. Comprehensive diagnosis of the condition of the myomatous nodule and its potential growth rate plays a significant role in the rational selection of treatment tactics for women of reproductive age with uterine fibroids. Objective. To study and analyze existing methods of diagnosis and prediction the growth of uterine fibroids. Matherials and methods. Information search was conducted in the scientific literature in domestic and foreign publications, 46 sources were studied and analyzed. In the course of the study, a meta-analysis of the information obtained was carried out as to the set goal. Results and discussion. At present, at least three main mechanisms of activation of signal pathways stimulating leiomyocyte to pathological growth and division have been elucidated: cytokines, growth factors, and hormone-dependent channels. All links in the activation of signal pathways affecting the cell, which subsequently lead to pathological proliferation and tumor transformation, are interconnected. In recent years, the pathogenesis of uterine fibroids has been actively studied not only at the tissue level but also at the genetic and epigenetic levels. It has been definitively proven that disturbances in microRNAs, both tissue-specific and stable, play a leading role in regulating the expression of key genes associated with the pathogenesis of uterine leiomyomas, both in tumor foci and in biological fluids. Conclusions. Study of the expression of microRNAs is a promising method for understanding the further development of the pathological process and for predicting the growth of uterine fibroids.

Bromodomain-Containing Protein 9 Regulates Signaling Pathways and Reprograms the Epigenome in Immortalized Human Uterine Fibroid Cells.

Bromodomain-containing proteins (BRDs) are involved in many biological processes, most notably epigenetic regulation of transcription, and BRD dysfunction has been linked to many diseases, including tumorigenesis. However, the role of BRDs in the pathogenesis of uterine fibroids (UFs) is entirely unknown. The present study aimed to determine the expression pattern of BRD9 in UFs and matched myometrium and further assess the impact of a BRD9 inhibitor on UF phenotype and epigenetic/epitranscriptomic changes. Our studies demonstrated that the levels of BRD9 were significantly upregulated in UFs compared to matched myometrium, suggesting that the aberrant BRD expression may contribute to the pathogenesis of UFs. We then evaluated the potential roles of BRD9 using its specific inhibitor, I-BRD9. Targeted inhibition of BRD9 suppressed UF tumorigenesis with increased apoptosis and cell cycle arrest, decreased cell proliferation, and extracellular matrix deposition in UF cells. The latter is the key hallmark of UFs. Unbiased transcriptomic profiling coupled with downstream bioinformatics analysis further and extensively demonstrated that targeted inhibition of BRD9 impacted the cell cycle- and ECM-related biological pathways and reprogrammed the UF cell epigenome and epitranscriptome in UFs. Taken together, our studies support the critical role of BRD9 in UF cells and the strong interconnection between BRD9 and other pathways controlling the UF progression. Targeted inhibition of BRDs might provide a non-hormonal treatment option for this most common benign tumor in women of reproductive age.

Fibroid pseudocapsule: a modern view of the problem. A literature review

Uterine fibroids are a benign polyetiological, hormone-sensitive, monoclonal tumor originating from the smooth muscle cells of the myometrium. They differ in size, location, growth rate, parenchyma-stroma ratio, morphohistogenesis, and clinical manifestations. Despite the frequent occurrence of this disease, its pathogenesis is poorly understood. In particular, the role of the fibroid pseudocapsule is a topic of interest. The appropriateness of retaining the pseudocapsule during myomectomy and the association of its retention with the risk of disease recurrence also remain controversial. This article is a literature review of data ranging from 2013 to 2023, available in the PubMed and Scopus databases. The main aspects of domestic and international clinical guidelines are also presented. This review covers epidemiological features and clinical aspects of uterine fibroids, as well as intraoperative and morphological characteristics of the fibroid pseudocapsule. Current data on the role of the MED12 gene, PGP 9.5, SP, VIP, VEGFR, IGF-2, endoglin, and oxytocin in the pathogenesis of uterine fibroids are also presented. Literature on the effect of gonadotropin-releasing hormone agonists on the morphology and functions of the pseudocapsule is submitted in the text. Despite the possible regenerative properties of the fibroid pseudocapsule, there is still a lack of systematic studies in the literature regarding the molecular and biochemical characteristics of the pseudocapsule, which makes it necessary to further investigate this morphological structure.

Integrative study of phytochemicals for anti-fibroid agent: A perspective on protein networks, molecular docking, ADMET, simulation, DFT and bioactivity

PurposeBeyond the pains of pregnancy, miscarriages and other child-bearing risks associated with the pride of motherhood, Uterine fibroids (UFs) are another significant reproductive age detriment in women's health. These tumours are often challenging to detect in the early stage until they become large outgrowth which always requires surgical removal to mitigate risks. However, with the understanding of alteration in the complex signalling pathways, specific protein targets in UFs pathogenesis have been identified, and this study is directed to evaluate selected dietary phytochemicals for the remedy. MethodsConsequently, this computer-aided quantum study explores thirty-one phytochemicals for anti-fibroid agents through investigation of density functional theory, molecular docking, mechanics’ free energy, absorption, distribution, metabolism, elimination, toxicity, dynamic simulation and bioactivity properties towards some selected targets. ResultsFrom the study, the gene-disease association revealed an evidence index between 0 and 1 for six reproductive conditions including UFs. The molecular docking shows capsaicin, epigallocatechin gallate, genistein, naringin and quercetin to interact with yes-associated protein 1 (-10.019 kcal/mol), insulin-like growth factor 1 (-14.224 kcal/mol), oestrogen receptor protein (-10.152 kcal/mol), epidermal growth factor receptor protein (-11.016 kcal/mol) and progesterone receptor (-12.462 kcal/mol), with highest affinity respectively. These interaction findings correlate with the molecular mechanics’ free energy combined with generalized born and surface area affinity obtained in the regression line of the dietary phytochemicals to the mapped proteins’ active site. In addition, 50 % of the phytochemicals, plus best-docked candidates exhibit good physicochemical, satisfy drug-likeness rules and medicinal chemistry as compared to the standard drugs and co-ligands. Hence, their bioactivity supports anti-cancer potential with a good Pa>Pi ratio, and with less electronic reactivity and stable interaction from the quantum mechanical calculation and simulation at 100 ns. ConclusionUltimately, these phytochemicals are proposed for further experimental evaluation for efficacy in managing and treating UFs.

#207 : Mendelian Randomization Study Reveals a Casual Effect of Blood Lipids and Apolipoprotein on Uterine Fibroids

Background and Aims: Despite an early insight into the risk factors of uterine fibroids (UFs), there is still controversy about the roles of blood lipids and apolipoprotein on UFs. Therefore, to provide more reliable evidence, we investigated the causal effect of blood lipids and apolipoprotein on the risk of UFs through Mendelian randomization (MR). Method: We utilized the large genome-wide association studies of blood lipids and apolipoprotein as instruments and integrated them in the inverse-variance-weighted (IVW) model in two-sample MR to investigate their causal relationship in large sample sizes. To eliminate potential pleiotropy, we listed a conclusive table of genes related to confounding factors, such as body mass index, waist circumference, blood pressure, glucose, hypertension, the metabolic syndrome and smoking and removed the repeated SNPs in the exposure data.To adjust for multiple comparisons, the statistical significance of the MR effect estimates was evaluated in a false discovery rate correlation of less than 5%. Neither pleiotropy nor heterogeneity was reported in all MR sensitivity analysis, including IVW, MR-Egger, simple median, weighted median, weighted mode and Mendelian Randomization Pleiotropy Residual Sum and Outlier methods. Results: Total triglycerides, very low-density lipoprotein (VLDL) cholesterol, including large, medium and small VLDL particles and free cholesterol in large VLDL cholesterol showed positive association with UFs. Meanwhile, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A1, free cholesterol in small and medium VLDL and total cholesterol are not statistically related to the development of UFs. Conclusion: Exposure to various aberrant blood lipids increases the risk of UFs, providing genetic evidence for the vital role of aberrant lipid levels in the pathogenesis of UFs. Meanwhile, our results provided genetic insights suggesting intervention in blood lipids might be a prospective strategy in the early prevention and treatment of UFs.

The Role of Nutrition in Pathogenesis of Uterine Fibroids

Uterine fibroids are benign tumors that arise from the smooth muscle tissue of the uterus and are the most common tumors in women. Due to their high prevalence, costs for the health care system and the substantial impact on women’s quality of life, they are a significant public health concern. Previous literature on the impact of diet on the occurrence, growth and symptoms of fibroids is limited. Recently, many papers have been written on this topic. A scoping review of PubMed and Cochrane databases was performed using the following keywords: uterine fibroids, antioxidants, diet, diet, vegetarian, vegetables, fruits, meat and soy foods, dairy products, tea, vitamin D, vitamin C, ascorbic acid. Preliminary research has shown a beneficial effect of vegetable and fruit consumption on the occurrence of fibroids. A relationship between hypovitaminosis D and an increased risk of fibroids has also been demonstrated. Studies on epigallocatechin gallate showed its apoptosis-promoting and antifibrinolytic effect in fibroid cells. Initial results are promising, but further randomized trials are needed to draw firm conclusions about the effects of diet and nutrients on uterine fibroids.

DNA methylation of ICAM4 and NOXO1 participate in the formation of uterine fibroids via regulating immune cell infiltration.

This atudy aimed to reveal the effect of DNA methylation on immune infiltration of uterine fibroids (UFs) and to further classify UFs based on transcriptomic characteristics. The transcriptome and DNA methylation data of UFs were collected from the GEO database. After taking the intersection of the differentially expressed genes in these two types of data, the intersection gene was used to draw ROC curves and to filtrate the candidate genes with AUC≥0.8. Immune infiltration analysis was performed in the online tool EPIC. The correlation between gene with AUC≥0.8 and the abundance of each immune cell type was calculated with |R|>0.3 and P<0.05. ConsensusClusterPlus package in R software was used to further cluster the samples of UFs. In this study, a total of 41 RNA-seq data (10 normal uterine samples and 31 UFs samples) and 34 DNA methylation data (10 from normal subjects and 24 from patients with UFs) were involved. The significantly down-regulated ICAM4, SPECC1L, and NOXO1 were the top three methylated drive genes of UFs. Therefore, NOXO1 and ICAM4 present an intimate correlation to immune cell infiltration. Besides, UFs could be clustered into two subtypes, including a TSAB1 up-regulated subtype and a FOSB up-regulated subtype. DNA methylation of ICAM4 and NOXO1 are involved in the pathogenesis of UFs via regulating immune cell infiltration. Further classification based on transcriptomic characteristics could divide UFs into sexual steroids-related and biomechanics-related subtypes, which would promote its non-invasive treatment.

RISING STARS: Role of MED12 mutation in the pathogenesis of uterine fibroids.

Uterine fibroids (UFs) are benign tumors arising from the uterus, characterized by accumulation of abundant extracellular matrix (ECM) and sex steroid-dependent growth. Women with symptomatic UFs have reduced quality of life and decreased labor productivity. Among the driver gene mutations identified in UFs, mutations in MED12, a component of the cyclin-dependent kinase (CDK) Mediator module, are the most common and observed in 50-80% of UFs. They are gain-of-function mutations and are more frequently observed in Black women and commonly observed even in small UFs. MED12 mutation-positive UFs (MED12-UFs) often develop multiple rather than solitary and have distinct gene expression profiles, DNA methylomes, transcriptomes, and proteomes. Gene expressions related to ECM organization and collagen-rich ECM components are upregulated, and impaired Mediator kinase activity and dysregulation of Wnt/β-catenin signaling are identified in MED12-UFs. Clinically, the UF shrinking effect of gonadotropin-releasing hormone agonists and ulipristal acetate is dependent on the MED12 mutation status. Understanding of characteristics of MED12-UFs and functions of MED12 mutations for UF tumorigenesis may elucidate the pathophysiology of UFs, leading to the development of new therapeutic options in women with symptomatic UFs.

Progesterone Signaling and Uterine Fibroid Pathogenesis; Molecular Mechanisms and Potential Therapeutics.

Uterine fibroids (UFs) are the most important benign neoplastic threat to women's health worldwide, with a prevalence of up to 80% in premenopausal women, and can cause heavy menstrual bleeding, pain, and infertility. Progesterone signaling plays a crucial role in the development and growth of UFs. Progesterone promotes the proliferation of UF cells by activating several signaling pathways genetically and epigenetically. In this review article, we reviewed the literature covering progesterone signaling in UF pathogenesis and further discussed the therapeutic potential of compounds that modulate progesterone signaling against UFs, including selective progesterone receptor modulator (SPRM) drugs and natural compounds. Further studies are needed to confirm the safety of SPRMs as well as their exact molecular mechanisms. The consumption of natural compounds as a potential anti-UFs treatment seems promising, since these compounds can be used on a long-term basis-especially for women pursuing concurrent pregnancy, unlike SPRMs. However, further clinical trials are needed to confirm their effectiveness.

Update on the Role and Regulatory Mechanism of Extracellular Matrix in the Pathogenesis of Uterine Fibroids

Uterine fibroids (UFs), also known as leiomyomas, are benign tumors of the myometrium affecting over 70% of women worldwide, particularly women of color. Although benign, UFs are associated with significant morbidity; they are the primary indication for hysterectomy and a major source of gynecologic and reproductive dysfunction, ranging from menorrhagia and pelvic pain to infertility, recurrent miscarriage, and preterm labor. So far, the molecular mechanisms underlying the pathogenesis of UFs are still quite limited. A knowledge gap needs to be filled to help develop novel strategies that will ultimately facilitate the development of therapies and improve UF patient outcomes. Excessive ECM accumulation and aberrant remodeling are crucial for fibrotic diseases and excessive ECM deposition is the central characteristics of UFs. This review summarizes the recent progress of ascertaining the biological functions and regulatory mechanisms in UFs, from the perspective of factors regulating ECM production, ECM-mediated signaling, and pharmacological drugs targeting ECM accumulation. In addition, we provide the current state of knowledge by discussing the molecular mechanisms underlying the regulation and emerging role of the extracellular matrix in the pathogenesis of UFs and in applications. Comprehensive and deeper insights into ECM-mediated alterations and interactions in cellular events will help develop novel strategies to treat patients with this common tumor.

Gut and genital tract microbiomes: Dysbiosis and link to gynecological disorders.

Every year, millions of women are affected by genital tract disorders, such as bacterial vaginosis (BV), endometrial cancer, polycystic ovary syndrome (PCOS), endometriosis, and uterine fibroids (UFs). These disorders pose a significant economic burden on healthcare systems and have serious implications for health and fertility outcomes. This review explores the relationships between gut, vaginal, and uterine dysbiosis and the pathogenesis of various diseases of the female genital tract. In recent years, reproductive health clinicians and scientists have focused on the microbiome to investigate its role in the pathogenesis and prevention of such diseases. Recent studies of the gut, vaginal, and uterine microbiomes have identified patterns in bacterial composition and changes across individuals' lives associated with specific healthy and diseased states, particularly regarding the effects of the estrogen-gut microbiome axis on estrogen-driven disorders (such as endometrial cancer, endometriosis, and UFs) and disorders associated with estrogen deficiency (such as PCOS). Furthermore, this review discusses the contribution of vitamin D deficiency to gut dysbiosis and altered estrogen metabolism as well as how these changes play key roles in the pathogenesis of UFs. More research on the microbiome influences on reproductive health and fertility is vital.

Uterine fibroids: a look at the problem

Despite scientific progress, there is currently no sigle opinion about the cause of the occurrence and recurrence of uterine fibroids, but due to the high level of molecular medicine, progress is being made in the hormonal and molecular genetic mechanisms of initiation, formation and growth of the fibroisds. The issue of pathogenetic treatment and prevention of recurrence of uterine fibroids in reproductive age remains relevant. The aims of the review. The aim of this review is to summarize current data about microRNA in biology of uterine leiomyoma (LM). This information can improve our understanding of the broad molecular interaction of signaling pathways in the formation of LM, and further maintaining epigenetic regulation as an important mechanism in the pathogenesis of uterine leiomyoma. In leiomyomas, the expression of a number of non-proteincoding genes is altered, such as microRNAs (miRNAs), which target genes that code protein. Material and research methods. Original and review articles, book chapters in the PubMed database related to the study of the pathogenesis of uterine fibroids in the period from 2004 to 2022 were found and analyzed. Results and discussions. Based on an analytical review of the literature, it becomes obvious that as evidence should be considered: 1. Abnormal myometrial and fibroid stem cells show an increased response to estrogen and progesterone exposure, stimulating processes such as cell proliferation, inhibition of apoptosis, and extracellular matrix (ECM) formation. 2. A number of tumor suppressor genes are abnormally hypermethylated in the LM when compared to normal myometrium, genes that form and regulate collagen, and a subset of estrogen receptor genes. 3. Multiple studies using microarray analysis or sequencing have demonstrated the existence of dysregulation of a number of protein-coding genes involved in cell proliferation and apoptosis, which are critical for the growth and progression of uterine fibroids. There are no reliable evidence base and do not provide an opportunity for practical application of clinically significant risk factors, the possibility of mathematical prediction of the growth of uterine fibroids in women of reproductive age. Data on the effect of the expression of a number of microRNAs on the growth of uterine fibroids in vivo are rather contradictory. The epigenetic processes of regulation and pathogenesis of the growth of leiofibromyomas in reproductive age have not been fully studied and substantiated. There are practically no data on predicting the growth of uterine fibroids in reproductive age, which will allow us to assess the risk of growth and determine further treatment tactics. Conclusion. Further work on the identification of specific genes, miRNAs, that are involved in the pathogenesis of LM may inspire the creation of new pathogenetic treatments. Such treatment is especially relevant for those groups of patients of reproductive age for whom surgical treatment may be ineffective. Targeted treatment can also prevent the recurrence of uterine fibroids, hence the need for repeat surgery.

Different DNA methylome, transcriptome and histological features in uterine fibroids with and without MED12 mutations

Somatic mutations in Mediator complex subunit 12 (MED12m) have been reported as a biomarker of uterine fibroids (UFs). However, the role of MED12m is still unclear in the pathogenesis of UFs. Therefore, we investigated the differences in DNA methylome, transcriptome, and histological features between MED12m-positive and -negative UFs. DNA methylomes and transcriptomes were obtained from MED12m-positive and -negative UFs and myometrium, and hierarchically clustered. Differentially expressed genes in comparison with the myometrium and co-expressed genes detected by weighted gene co-expression network analysis were subjected to gene ontology enrichment analyses. The amounts of collagen fibers and the number of blood vessels and smooth muscle cells were histologically evaluated. Hierarchical clustering based on DNA methylation clearly separated the myometrium, MED12m-positive, and MED12m-negative UFs. MED12m-positive UFs had the increased activities of extracellular matrix formation, whereas MED12m-negative UFs had the increased angiogenic activities and smooth muscle cell proliferation. The MED12m-positive and -negative UFs had different DNA methylation, gene expression, and histological features. The MED12m-positive UFs form the tumor with a rich extracellular matrix and poor blood vessels and smooth muscle cells compared to the MED12m-negative UFs, suggesting MED12 mutations affect the tissue composition of UFs.

Uterine Fibroid Patients Reveal Alterations in the Gut Microbiome.

The gut microbiota is associated with reproductive disorders in multiple ways. This research investigated possible differences in gut microbiome compositions between patients with uterine fibroids (UFs) and healthy control subjects in order to further provide new insight into its etiology. Stool samples were collected from 85 participants, including 42 UF patients (case group) and 43 control subjects (control group). The gut microbiota was examined with 16S rRNA quantitative arrays and bioinformatics analysis. The α-diversity in patients with UFs was significantly lower than that of healthy controls and negatively correlated with the number of tumorigeneses. The microbial composition of the UF patients deviated from the cluster of healthy controls. Stool samples from patients with UFs exhibited significant alterations in terms of multiple bacterial phyla, such as Firmicutes, Proteobacteria, Actinobacteria, and Verrucomicrobia. In differential abundance analysis, some bacteria species were shown to be downregulated (e.g., Bifidobacteria scardovii, Ligilactobacillus saerimneri, and Lactococcus raffinolactis) and upregulated (e.g., Pseudomonas stutzeri and Prevotella amnii). Furthermore, the microbial interactions and networks in UFs exhibited lower connectivity and complexity as well as higher clustering property compared to the controls. Taken together, it is possible that gut microbiota dysbiosis has the potential as a risk factor. This study found that UFs are associated with alterations of the gut microbiome diversity and community network connectivity. It provides a new direction to further explore the host–gut microbiota interplay and to develop management and prevention in UF pathogenesis.

Telocytes: Newly Discovered Interstitial Cells in the Human Female Internal Reproductive Organs – Identification of a Suitable Immunohistochemical Marker and Possible Significance in the Pathogenesis of Uterine Fibroids

IntroductionTelocytes are a cell population discovered in 2005. Within the organs of the female reproductive system (FRS), telocytes were described as having an immunomodulatory role and also functioning as hormone sensors. From the pathological perspective, telocytes were described in the pathogenesis of a wide spectrum of different conditions, including a role in tumorigenesis. The gold standard of telocyte research is electron microscopy, but immunohistochemistry is also widely applied. The main objective was to identify the most suitable immunohistochemical marker and subsequently use it in the study of uterine specimens from patients with uterine fibroids (leiomyomas).Material andMethodsUterine specimens were obtained from 26 patients who underwent hysterectomy for various indications, including ectopic pregnancy and uterine fibroids. From all the uteruses, representative specimens were obtained from the myometrium and endometrium of the uterine body, and also from the endo‐ and exocervical mucosa. 5 μm thick sections were further processed for immunohistochemistry. To identify the most suitable marker of telocytes, 8 primary antibodies were used: CD117/c‐kit, CD34, vimentin, α‐smooth muscle actin, progesterone and estrogen receptor, desmin and S100 protein (DAKO, Denmark).ResultsThe most specific marker was c‐kit. C‐kit‐positive cells were spindle‐shaped, triangular and star‐shaped. C‐kit positive cells were located in the endometrium, myometrium, exocervical, and endocervical mucosa. Comparing the distribution within the individual parts of the uterus, the most numerous population was observed within the myometrium. A considerable number of telocytes was also observed within the endocervical mucosa, while the fewest telocytes were described in the endometrium and exocervical mucosa. In the specimens of uterine fibroids, the non‐affected parts of the myometrium contained c‐kit positive cells within all the myometrial sublayers. The average c‐kit positivity expressed in percentage was 2.19 ± 0.51%. Those parts of the myometrium affected by uterine fibroids displayed complete c‐kit negativity.ConclusionC‐kit is the most suitable marker in the research of telocytes in the FRS. The loss of telocytes in the myometrium may have a role in the pathogenesis of uterine fibroids via three mechanisms: 1) hormonal imbalance, 2) stem cell dysregulation and 3) diminished angiogenesis. Therefore, therapeutic targeting of telocytes can be a potential future approach in the treatment of this condition.

Identification and Validation of miRNA-TF-mRNA Regulatory Networks in Uterine Fibroids.

Uterine fibroids (UF) are the most common benign gynecologic tumors and lead to heavy menstrual bleeding, severe anemia, abdominal pain, and infertility, which seriously harm a women’s health. Unfortunately, the regulatory mechanisms of UF have not been elucidated. Recent studies have demonstrated that miRNAs play a vital role in the development of uterine fibroids. As a high-throughput technology, microarray is utilized to identify differentially expressed genes (DEGs) and miRNAs (DEMs) between UF and myometrium. We identified 373 candidate DEGs and the top 100 DEMs. Function enrichment analysis showed that candidate DEGs were mainly enriched in biological adhesion, locomotion and cell migration, and collagen-containing extracellular matrix. Subsequently, protein-protein interaction (PPI) networks are constructed to analyze the functional interaction between DEGs and screen hub DEGs. Subsequently, the expression levels of hub DEGs were validated by real-time PCR of clinical UF samples. The DGIdb database was used to select candidate drugs for hub DEGs. Molecular docking was applied to test the affinity between proteins and drugs. Furthermore, target genes for 100 candidate DEMs were predicted by miRwalk3.0. After overlapping with 373 candidate DEGs, 28 differentially expressed target genes (DEGTs) were obtained. A miRNA-mRNA network was constructed to investigate the interactions between miRNA and mRNA. Additionally, two miRNAs (hsa-miR-381-3p and hsa-miR-181b-5p) were identified as hub DEMs and validated through RT-PCR. In order to better elucidate the pathogenesis of UF and the synergistic effect between miRNA and transcription factor (TF), we constructed a miRNA-TF-mRNA regulatory network. Meanwhile, in vitro results suggested that dysregulated hub DEMs were associated with the proliferation, migration, and apoptosis of UF cells. Our findings provided a novel horizon to reveal the internal mechanism and novel targets for the diagnosis and treatment of UF.

Epigenetic Regulation in Uterine Fibroids-The Role of Ten-Eleven Translocation Enzymes and Their Potential Therapeutic Application.

Uterine fibroids (UFs) are monoclonal, benign tumors that contain abnormal smooth muscle cells and the accumulation of extracellular matrix (ECM). Although benign, UFs are a major source of gynecologic and reproductive dysfunction, ranging from menorrhagia and pelvic pain to infertility, recurrent miscarriage, and preterm labor. Many risk factors are involved in the pathogenesis of UFs via genetic and epigenetic mechanisms. The latter involving DNA methylation and demethylation reactions provide specific DNA methylation patterns that regulate gene expression. Active DNA demethylation reactions mediated by ten-eleven translocation proteins (TETs) and elevated levels of 5-hydroxymethylcytosine have been suggested to be involved in UF formation. This review paper summarizes the main findings regarding the function of TET enzymes and their activity dysregulation that may trigger the development of UFs. Understanding the role that epigenetics plays in the pathogenesis of UFs may possibly lead to a new type of pharmacological fertility-sparing treatment method.

Потенційний вплив мелатоніну на розвиток міоми матки у жінок репродуктивного віку (огляд літератури)

For a long time, Ukraine has been showing negative dynamics between birth and death rates. The demographic situation in any country is an important indicator. Therefore, the issue of women's health and ability to reproduce is significant and urgent. The purpose of the study was to analyze current data from domestic and foreign literature on provoking factors, etiology and pathogenesis of uterine fibroids, new approaches to treatment and the impact of this pathology on a woman's reproductive potential. Hyperplastic processes of the uterus in women of reproductive age are among the most common gynecological diseases. Uterine leiomyoma is the most common benign proliferative pathology. The presence of uterine leiomyoma leads to disorders of women's reproductive health, is one of the causes of infertility, in addition, significantly affects the quality of life of the patient due to constant pain, excessive uterine bleeding, dysfunction of adjacent organs. Many studies confirm the unfavorable course of pregnancy and the postpartum period in women with fibroids, namely: complicated pregnancy, reproductive losses, birth defects and postpartum complications. Despite the intensive work of scientists, the implementation of a large number of studies, the pathogenesis to this day remains multifaceted and poorly understood. Results and discussion. After analyzing current data from domestic and foreign literature on provoking factors, etiology and pathogenesis of uterine fibroids, the review article presents data on current opportunities, new approaches to treatment and the impact of this pathology on a woman's reproductive potential. For a long time, the pineal gland with the hormone melatonin has not been studied. During the scientific research, the review of the current domestic and foreign literature on the potential inhibitory effect of melatonin on uterine fibroid cells, and the direct and indirect effect on fertility was reviewed and analyzed. As a result of analysis of experimental and clinical data presented in the literature, it can be argued that melatonin has the ability not only to regulate biological rhythms, but also that it is promising to study metabolic and immunomodulatory effects, as well as antitumor effects, which gives us a chance to reduce surgery of this group of patients. Conclusion. The information presented in the review suggests that melatonin has the potential as a therapeutic agent for clinical trials against uterine leiomyoma in women of reproductive age. Therefore, there is a need to study deeply the etiopathogenesis of uterine leiomyoma and in particular the effect of melatonin on growth, reduction of surgical interventions, the impact on the pre- and postoperative period, and to determine melatonin as a therapeutic drug