Search Results (74)

Endometriosis is a chronic disease characterized by the ectopic presence of endometrial cells that evade apoptosis and survive and proliferate under harsh environmental conditions. It is closely associated with infertility and pregnancy-related complications. This review focuses on the molecular pathophysiology of endometriosis, particularly the disruption of the p53–AMPK–mTOR signaling axis, and highlights the dysregulation of decidualization and cellular senescence, incorporating recent findings in reproductive physiology. A comprehensive literature search was conducted using PubMed and Google Scholar without temporal restrictions. Endometriotic cells adapt to the hostile peritoneal environment through resistance to apoptosis and alterations in autophagy. In the early stages, autophagy activation may promote cell survival; however, as the disease progresses, autophagic activity tends to decline. Aberrant activation of mTOR signaling is implicated in this process, contributing to the suppression of autophagy, impaired decidualization, and promotion of cellular senescence, ultimately facilitating lesion progression and infertility. Indeed, in the eutopic endometrium of patients with endometriosis, progesterone resistance, elevated inflammatory cytokines, and epigenetic abnormalities are known to reduce endometrial receptivity. Moreover, suppression of autophagy leads to excessive cellular senescence and secretion of the senescence-associated secretory phenotype (SASP), thereby interfering with proper decidualization. Maintaining an appropriate balance between decidualization and cellular senescence is essential for reproductive function. Future development of therapeutic strategies targeting these processes is expected to help overcome infertility associated with endometriosis. Full article

Background/Objectives: Adenomyosis is a benign gynecological disorder associated with abnormal uterine bleeding, dysmenorrhea, and subfertility. Its pathogenesis has not yet been elucidated. The most widely accepted theory points to repeated mechanical or hormonal stress at the endometrial–myometrial interface, leading to activation of the tissue injury and repair (TIAR) mechanism. Studies suggest that the immune system may play a role in disease pathogenesis, but inconsistencies persist due to differences in studied samples and evaluated menstrual cycle phases. The goal of our study was to apply a novel technique (multiplex) to investigate different immune cell phenotypes in uteri from adenomyosis patients according to the cycle phase. Methods: This study analyzed immune cell populations in adenomyotic uteri using immunohistochemistry and multiplex immunofluorescence on 30 adenomyotic and 15 healthy hysterectomy samples. Results: Compared to eutopic endometrium, transitional and adenomyotic lesions displayed reduced immune infiltrates, particularly T cells, NK cells, B cells, macrophages, and dendritic cells. Conversely, mast cells were significantly elevated in transitional lesions. Conclusions: The present study suggests mast cell implication in adenomyosis development and pain, through their implication in tissue remodeling, angiogenesis, and neurogenic inflammation. Transitional lesions highlighted the progressive nature of adenomyosis, supporting the TIAR hypothesis. These findings emphasize the importance of mast cells in disease progression and underscore the need for further studies to explore immune-targeted therapies. Full article

Endometriosis is a complex gynecological disorder characterized by the presence of endometrial-like tissue outside the uterus, leading to chronic pain and infertility. Immunohistochemistry (IHC) serves as a vital technique for elucidating the molecular and cellular differences between ectopic endometriotic tissues and eutopic endometrium. IHC reveals significant variations in the expression of inflammatory markers, adhesion molecules, and cell cycle regulators. This literature review compiles findings from various studies that assess the role of key proteins, such as leukemia inhibitory factor (LIF), cyclooxygenase-2 (COX-2), and b-cell lymphoma 2 (BCL-2), across different menstrual phases and lesion types. Notably, elevated LIF levels and increased mast cell activity in ectopic tissues underscore the inflammatory landscape of endometriosis. Additionally, altered expression of adhesion molecules like integrins and cluster of differentiation 44 (CD44) suggests modified cellular interactions, while apoptotic markers reveal a survival advantage for ectopic cells. These insights enhance our understanding of endometriosis pathophysiology. Full article

(1) Background and Objectives: Endometriosis is defined as the presence of endometrial glands and stroma outside the uterine cavity. It affects 5–15% of women of reproductive age. Ovarian cancer develops in approximately 1% of patients with endometriosis. Prediction of those with endometriosis who will develop ovarian cancer is among the current research topics. (2) Materials and Methods: With this study, we aimed to reveal the role of miRNA 200b and miRNA 21 in endometriosis-associated ovarian carcinoma (EAOC). Thirteen patients diagnosed as having EAOC between 2015 and 2023 were included, with their endometriosis and eutopic endometrium tissues (Group 3: 13 patients, 39 tissue samples). Two separate groups were then detected to compare with these cases: Group 2 composed of tuba-ovarian endometriosis with its eutopic endometrium (10 patients, 20 tissue samples) and Group 1 composed of eutopic endometrium only (10 patients, 10 tissue samples). The foci marked on H&E sections were determined from the area on the relevant paraffin blocks and small tissue samples were taken in tubes to be studied with real-time PCR. (3) Results: No significant difference was detected for miRNA 21 and miRNA 200b expression levels among eutopic endometrium, endometriosis, and cancer foci in Group 3. However, miRNA 21 and miRNA 200b expression levels in the eutopic endometrial tissue of cases with ovarian cancer were significantly higher than in the eutopic endometrial tissues of cases with (Group 2) and without endometriosis (Group 1). (4) Conclusions: This study suggests that increased miRNA 200b and miRNA 21 expression levels detected in eutopic endometrial tissue of patients with endometriosis may contribute to identifying cases that may develop EAOC. Full article

Endometriosis is a chronic gynecological disorder characterized by the presence of endometrial tissue outside the uterine cavity. A common feature of this pathology is the impaired decidualization of endometrial stromal cells, a critical process that prepares the uterus for embryo implantation. This decidualization defect has been mechanistically linked to progesterone resistance in endometriotic lesions. However, the presence and underlying mechanisms of decidualization defects in the eutopic endometrium of women with endometriosis remain controversial. The aim of the present study is to integrate and discuss molecular evidence from both in vivo and in vitro studies examining decidualization alterations in the eutopic endometrium of patients with endometriosis. Multiple studies have demonstrated impaired decidualization in the eutopic endometrium of women with endometriosis. These alterations have been reported on multiple genes, signaling pathways, and epigenetic processes. However, additional functional studies are warranted to elucidate whether these decidualization defects directly contribute to endometriosis-associated infertility. A better understanding of the decidualization process and its dysregulation in endometriosis will not only advance the development of targeted fertility treatments but also facilitate the design of more effective therapeutic strategies for managing this chronic condition. Full article

Background/Objectives: Epithelial–Mesenchymal Transition (EMT) is the process by which epithelial cells acquire mesenchymal properties, which helps endometriotic cells migrate and invade. This study looks at the expression of E-CADHERIN, a critical epithelial marker, and miR-200b, an EMT regulator, in several types of endometriosis, including endometriomas and deep infiltrating endometriotic (DIE) nodules. Methods: We examined 19 individuals with endometriosis (9 with just endometriotic cysts and 10 with both DIE and endometriotic cysts) and 8 controls with benign gynecological abnormalities. Tissue samples were taken during laparoscopic surgery, and E-CADHERIN and miR-200b expression were measured using Real-Time PCR, with G6PD and U6 as controls. Results:E-CADHERIN expression was maintained in the eutopic endometrium of both ovarian and DIE types, but it was considerably reduced in endometriotic cysts, indicating heightened mesenchymal features. miR-200b was downregulated in the eutopic endometrium of ovarian endometriosis but upregulated in DIE. Endometriotic cysts in both groups had greater miR-200b expression than their corresponding eutopic endometrium. E-CADHERIN and miR-200b expression in DIE lesions was similar to that found in matched eutopic endometrium. Conclusions: The regulation of E-CADHERIN and miR-200b varies across ovarian and DIE lesions. The miR-200b-ZEB1 feedback loop is increased in DIE eutopic endometrium but downregulated in ovarian endometriosis. E-CADHERIN downregulation in endometriotic cysts indicates heightened mesenchymal dynamics, whereas DIE nodules have gene expression patterns similar to eutopic endometrium. These findings emphasize the distinct regulatory processes that govern endometriotic lesions. Full article

A eutopic endometrium in endometriosis shows altered immune responses, including abnormalities of NK cells and expression of plasma cells, related to reproductive issues. This study investigated the counts of CD56-positive NK cells and CD138-positive plasma cells in the basal decidua of term placentas in singleton pregnancies after endometriosis-related infertility conceived by assisted reproductive technology (ART). This single-center, case-control study involved immunohistochemical analysis of CD56-positive NK cells and CD138-positive plasma cells in basal decidua using primary monoclonal mouse antibodies, followed by secondary antibodies using a standardized protocol. CD56 and CD138 immunohistochemically positive cells were reported as the total cell count for each studied antibody expressed per 1 mm² of basal decidua (Olympus BX46 and Olympus Image Analyzer). Placental samples containing basal decidua from 36 participants with endometriosis-related infertility who conceived by ART, 31 participants with male factor infertility who conceived by ART and 40 healthy controls were included. Endometriosis decidua showed the lowest median count of CD56-positive NK cells (11.5 / mm², p = 0.039) in BD compared to male factor group (25 / mm²) and healthy controls (24.5 / mm²). No differences were found for CD138-positive plasma cells counts between study groups. Basal decidua in pregnancies after endometriosis-related infertility showed reduced total count of CD56-positive NK cells, without differences in the CD138-positive plasma cell counts compared to control groups. Future studies should investigate how changes in NK cells throughout pregnancy affect the development of perinatal complications and placental pathologies in women with endometriosis, which could uncover potential diagnostic and therapeutic targets. Full article

Endometriosis is a chronic inflammatory, estrogenic disorder caused by endometrial tissue growth places other than uterine lumen, resulting in infertility and severe pelvic pain. Thymol, an extract of Thymus vulgaris, processes diverse biological properties, including anti-inflammatory, local anesthetic, decongestant, and antiseptic effects. However, the efficacy of thymol in treating endometriosis has still not been explored. Herein, this research aimed to investigate the role of thymol in the treatment of endometriosis using a murine model and Ishikawa cells. Thirty C57BL/6 mice were administered 17β-E2 (100 ng/mouse) subcutaneously for three consecutive days to induce synchronous estrus. On the last day of injection, the mice underwent surgical induction of endometriosis. After that, the mice were divided into three groups, i.e., Control (CTRL), Thymol 30 mg/kg and Thymol 60 mg/kg, receiving oral administration of either saline or thymol (30 mg/kg/d or 60 mg/kg/d, as 0.1 mL/kg/d, respectively) for a three-week duration. Each group consisted of ten mice and was evenly divided into estrus and diestrus according to the vaginal cytology on the last day of treatment. Thymol significantly (p < 0.05) reduced the weight and volume of ectopic tissue, hindered cell proliferation, and stimulated apoptosis compared to the CTRL group. Additionally, in the thymol-treated group, the levels of pro-inflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6, as well as the numbers of neutrophils and macrophages, were significantly (p < 0.05) decreased. Moreover, a novel role of thymol in rebalancing estrogen and progesterone (E₂-P₄) signaling was explored, and it was distributed in the ectopic endometrium. Next, the role of thymol on Ishikawa cells was determined. The results demonstrated that thymol significantly (p < 0.05) suppressed the E₂-induced proliferation of Ishikawa cells. Furthermore, molecular docking analyses suggested that thymol potentially binds to ESR1-like estrogens, indicating its antagonistic activity against estrogens. The estrogen receptor 1 (ESR1) and its target gene expression exhibited significant (p < 0.05) downregulation, while progesterone receptor (PGR) and target genes were markedly (p < 0.05) upregulated following thymol treatment in the ectopic endometrium. Most importantly, our data revealed the minimal impact of thymol treatment on the eutopic endometrium and its crucial role in supporting pregnancy, thus indicating the safety of thymol in treating endometriosis. Overall, our study suggests that thymol holds promising therapeutic implications for endometriosis by virtue of its anti-inflammatory properties and ability to antagonize estrogen activity. Full article

(1) Background: Endometriosis is a highly prevalent gynecological disease affecting 10% of women of reproductive age worldwide. miRNAs may play a role in endometriosis, though their exact function remains unclear. This study aimed to identify differentially expressed miRNAs in endometriosis and study their functions in the disease. (2) Methods: Endometrial tissue was collected from women with endometriosis (n = 15) and non-endometriosis controls (n = 17). Dysregulated miRNAs were identified through small RNA-sequencing, and their biological significance was explored by target gene prediction and pathway analysis. Selected miRNAs were examined in paired ectopic endometriomas and eutopic endometrium (n = 10) using qRT-PCR. Their roles in cell migration and proliferation were further examined in vitro using functional assays. To identify potential target genes, we performed mRNA sequencing on transfected cells and the endometrioma cohort. (3) Results: We identified 14 dysregulated miRNAs in the eutopic endometrium of women with endometriosis compared to endometrial tissue from women without endometriosis. Pathway analysis indicated enrichment in cell migration and proliferation-associated pathways. Further ex vivo studies of miR-193b-5p and miR-374b-5p showed that both miRNAs were upregulated in endometrioma. Overexpression of these two miRNAs in vitro inhibited cell migration, and mRNA sequencing revealed several migration-related genes that are targeted by these miRNAs. (4) Conclusions: Our study identified two key endometrial miRNAs that may be involved in the pathogenesis of endometriosis by regulating cell migration. Full article

Adenomyosis involves the infiltration of endometrial glands and stroma deep into the uterine tissue, causing disruption to the endometrial–myometrial interface (EMI). The role of interleukin-17 (IL-17) has been extensively studied in endometriosis, but its involvement in adenomyosis remains unclear. This study aimed to investigate the expression of IL-17 in eutopic and ectopic endometrium (adenomyosis) of individuals with adenomyosis at the level of EMI. Paired tissues of eutopic endometrium and adenomyoma were collected from 16 premenopausal women undergoing hysterectomy due to adenomyosis. The IL-17 system was demonstrated in paired tissue samples at the level of EMI by the immunochemistry study. Gene expression levels of IL-17A and IL-17 receptor (IL-17R) were assessed through quantitative real-time reverse transcription polymerase chain reaction (RT-PCR). Comparative gene transcript amounts were calculated using the delta-delta Ct method. By immunohistochemical staining, CD4, IL-17A, and IL-17R proteins were detected in both eutopic endometrium and adenomyosis at the level of EMI. IL-17A and IL-17R were expressed mainly in the glandular cells, and the expression of both IL-17A and IL-17R was found to be stronger in adenomyosis than in endometrium. 3-Diaminobenzidine (DAB) staining revealed greater IL-17A expression in adenomyosis compared to eutopic endometrium. Quantitative RT-PCR showed 7.28-fold change of IL-17A and 1.99-fold change of IL-17R, and the fold change level of both IL-17A and IL-17R is significantly higher in adenomyosis (IL-17A: p = 0.047, IL-17R: p = 0.027) versus eutopic endometrium. We found significantly higher IL-17 levels in adenomyosis compared to eutopic endometrium at the level of EMI. The results showed that the IL-17 system may play a role in adenomyosis. Full article

In this focused genetic case–control study, we analyzed two functional single-nucleotide variants (SNVs) associated with breast cancer risk (rs2046210, rs9383590) and one risk SNV for an implantation defect and infertility (rs9340799) for their association with endometriosis susceptibility, progression and ESR1 gene regulation in endometriosis patients. The rs2046210, rs9383590 and rs9340799 SNVs were genotyped in 153 endometriosis patients and 87 control subjects with Caucasian ancestry. We analyzed the association of all SNVs with endometriosis susceptibility in all patients and in subgroups and assessed the concordance between the SNVs. Quantitative reverse transcription PCR was used to determine ESR1 gene expression in the eutopic endometrial tissue of the controls and endometriosis patients. The heterozygous rs2046210 GA genotype was associated with significantly increased endometriosis risk, particularly in younger, leaner and infertile women and with an increased ESR1 gene expression in the eutopic endometrium of these patients, compared to controls. The minor AA genotype of rs2046210 was identified as a potential risk factor for endometriosis progression in women with mild endometriosis. The results from this analysis indicate that rs2046210 may be a functional genetic variant associated with endometriosis development and progression. Full article

The changes in endometrial cells, both in the eutopic endometrium of patients with and without endometriosis and in lesions at ectopic sites, are frequently described and often compared to tumorigenesis. In tumorigenesis, the concept of “seed and soil” is well established. The seed refers to tumor cells with metastatic potential, and the soil is any organ or tissue that provides a suitable environment for the seed to grow. In this systematic review (PRISMA-S), we specifically compared the development of endometriosis with the “seed and soil” hypothesis. To determine changes in the endometrial seed, we re-analyzed the mRNA expression data of the eutopic and ectopic endometrium, paying special attention to the epithelial–mesenchymal transition (EMT). We found that the similarity between eutopic endometrium without and with endometriosis is extremely high (~99.1%). In contrast, the eutopic endometrium of patients with endometriosis has a similarity of only 95.3% with the ectopic endometrium. An analysis of EMT-associated genes revealed only minor differences in the mRNA expression levels of claudin family members without the loss of other cell–cell junctions that are critical for the epithelial phenotype. The array data suggest that the changes in the eutopic endometrium (=seed) are quite subtle at the beginning of the disease and that most of the differences occur after implantation into ectopic locations (=soil). Full article

Endometriosis in half of affected women is closely related to problems with fertility. Endometriosis-associated infertility is caused by a wide range of abnormalities affecting the female reproductive tract, from oocyte quality impairment to disturbances in the eutopic endometrium or mechanical abnormalities resulting from disease progression. Since supportive antioxidant therapies, in addition to surgical treatment or assisted reproductive techniques (ARTs), have overall been proven to be effective tools in endometriosis management, the objective of our review was to analyze the role of antioxidant substances, including vitamins, micronutrients, N-acetylcysteine (NAC), curcumin, melatonin, and resveratrol, in endometriosis-related infertility. Most of these substances have been proven to alleviate the systemic oxidant predominance, which has been expressed through decreased oxidative stress (OS) markers and enhanced antioxidative defense. In addition, we demonstrated that the predominant effect of the aforementioned substances is the inhibition of the development of endometriotic lesions as well as the suppression of pro-inflammatory molecules. Although we can undoubtedly conclude that antioxidants are beneficial in fertility support, further studies explaining the detailed pathways of their action are needed. Full article

The coordinated action of VEGF, IGF1/2 and H19 factors influences the development of endometriosis. The aim of this study was to analyze the expression level of these genes in patients with endometriosis. The study group consisted of 100 patients who were diagnosed with endometriosis on laparoscopic and pathological examination. The control group consisted of 100 patients who were found to be free of endometriosis during the surgical procedure and whose eutopic endometrium wasnormal on histopathological examination. These patients were operated on for uterine fibroids. Gene expression was determined by RT-PCR. The expression of the VEGF gene was significantly higher in the samples classified as clinical stage 1–2 compared to the control material (p < 0.05). There was also a statistically significant difference between the samples studied at clinical stages 1–2 and 3–4 (p < 0.01). The expression of the VEGF gene in the group classified as 1–2 was significantly higher. IGF1 gene expression was significantly lower both in the group of samples classified as clinical stages 1–2 and 3–4 compared to the control group (p < 0.05 in both cases). The expression of the H19 gene was significantly lower in the group of samples classified as clinical stage 3–4 compared to the control group (p < 0.01). The reported studies suggest significant roles of VEGF, IGF and H19 expression in the pathogenesis of endometriosis. Full article

Endometriosis is a common disease among women of reproductive age in which endometrial tissue grows in ectopic localizations, primarily within the pelvic cavity. These ectopic “lesions” grow as well as migrate and invade underlying tissues. Despite the prevalence of the disease, an understanding of factors that contribute to these cellular attributes remains poorly understood. Prefoldin-5 (PFDN5) has been associated with both aberrant cell proliferation and migration, but a potential role in endometriosis is unknown. As such, the purpose of this study was to examine PFDN5 expression in endometriotic tissue. PFDN5 mRNA and protein were examined in ectopic (lesion) and eutopic endometrial tissue from women with endometriosis and in eutopic endometrium from those without endometriosis using qRT-PCR and immunohistochemistry, respectively, while function of PFDN5 in vitro was evaluated using cell count and migration assays. PFDN5 mRNA and protein were expressed in eutopic and ectopic endometrial tissue, predominantly in the glandular epithelium, but not in endometrium from control subjects. Expression of both mRNA and protein was variable among endometriotic eutopic and ectopic endometrial tissue but showed an overall net increase. Knockdown of PFDN5 by siRNA transfection of endometriotic epithelial 12Z cells was associated with reduced cell proliferation/survival and migration. PFDN5 is expressed in eutopic and ectopic glandular epithelium and may play a role in proliferation and migration of these cells contributing to disease pathophysiology. Full article