Search Results (44)

HOX genes, a family of conserved transcription factors, are critical for reproductive tract development and endometrial functionality. This review highlights the molecular underpinnings of HOXA10/HOXA11 in reproductive health and their dysregulation in benign pathologies associated with infertility, such as endometriosis, adenomyosis, and endometrial polyps. These genes are dynamically regulated by estrogen and progesterone, with peak expression during the secretory phase of the menstrual cycle when implantation takes place. The molecular mechanisms underlying their action include the modulation of extracellular matrix (ECM) remodeling via metalloproteinases, cytokines like leukemia inhibitory factor, and cell adhesion molecules such as β3-integrin, all of which are essential for the differentiation of epithelial and stromal cells, as well as for trophoblast invasion. Aberrant HOX gene expression, driven by DNA hypermethylation or altered histone acetylation, compromises endometrial receptivity and implantation. For instance, reduced HOXA10 expression in endometriosis stems from hypermethylation and chronic inflammation, disrupting immune modulation and cytokine signaling. Similarly, adenomyosis alters HOXA11-regulated ECM remodeling and β3-integrin expression, impairing embryo attachment. Furthermore, regulatory pathways involving vitamin D and retinoic acid offer promising therapeutic avenues pathways, as they enhance HOXA10/HOXA11 expression and endometrial receptivity. This review underscores the critical molecular roles of HOXA10/HOXA11 genes as biomarkers and therapeutic targets to optimize fertility outcomes and address reproductive pathologies. Full article

Endometriosis is a complex gynecological disorder characterized by endometrial-like tissue growing outside the uterus, leading to chronic pain, infertility, and reduced quality of life. Its pathophysiology involves genetic, epigenetic, immune, and molecular factors. Theories such as retrograde menstruation, coelomic metaplasia, and stem cell involvement explain lesion formation. Endometrial mesenchymal stem cells (eMSCs) and epithelial progenitors (eEPs) contribute to lesion establishment by adhering to peritoneal surfaces, proliferating, and differentiating into ectopic tissue. Aberrant adhesion molecules, inflammatory cytokines, and molecular pathways like PI3K/Akt and Wnt/β-catenin drive proliferation, angiogenesis, and resistance to apoptosis. Elevated estrogen levels and progesterone resistance further promote lesion growth and immune evasion. Immune dysfunction, including altered macrophage activity and reduced natural killer (NK) cell function, contributes to inflammation and lesion persistence. Pain is linked to prostaglandin E2 (PGE2) and nerve infiltration, emphasizing the need for targeted pain management. Current therapies, such as GnRH agonists, suppress ovarian hormone production but face limitations in long-term efficacy and side effects. Integrating molecular insights into clinical practice may advance diagnostics and treatment, with emerging approaches focusing on molecular pathways, immune modulation, and hormonal regulation for more effective, personalized therapies. Future research should unravel the complex mechanisms driving endometriosis to improve patient outcomes. Full article

Endometriosis is a pathological condition characterized by the presence of the endometrial tissue, outside the uterine cavity. It affects nearly 10% of women of reproductive age and is responsible for infertility, chronic pain, and the weakening of the quality of life. Various pathogenetic mechanisms have been suggested; however, the essential pathogenesis of endometriosis remains insufficiently comprehended. A comprehensive literature search was conducted in databases such as PubMed, Scopus, and Web of Science up to December 2024. Inclusion criteria encompassed studies investigating the pathogenetic mechanisms of endometriosis, while exclusion criteria included reviews, case reports, and studies lacking primary data. The analyzed studies explored multiple pathogenetic mechanisms, including retrograde menstruation, coelomic metaplasia, embryological defects, stem cell involvement, and epigenetic modifications. Special emphasis was placed on the role of uterine adenogenesis factors in the development and progression of endometriosis. A deeper understanding of the various pathogenetic mechanisms underlying endometriosis is crucial for advancing targeted therapeutic strategies. Further research into uterine adenogenesis factors may provide new insights into the disease’s pathophysiology and pave the way for novel treatment approaches. Full article

Abdominal wall endometriosis (AWE) is a clinical disorder with unknown pathogenesis with an incidence between 0.03% and 1% in women affected by cutaneous/scar endometriosis. We investigated the pathological, molecular cytogenetic and cell proliferation features of a primary AWE developed in rectus abdominis muscle in a patient without co-existing pelvic endometriosis. An investigational model of cultured stromal cells was additionally established. Histologically, the lesion revealed areas of endometrial-like glands surrounded by a thick stromal layer in addition to numerous disseminated foci composed exclusively of stromal cells. Beyond the strong expression of Estrogen (ER) and Progesterone receptors (PRs), consistent immunolabeling for several mesenchymal stromal/stem cell antigens and oncoproteins was revealed in both the endometrioma as well as in the cultured stromal cells. The Fluorescence in situ hybridization (FISH) analysis of the endometrioma demonstrated a structural alteration of the c-MYC protooncogene, with a mean of three gene copies in 3% to 5% of both glandular and stromal cells. The FISH assay applied on the cultured cells showed c-MYC gene amplification, with an average number of more than six gene copies in 18% to 25% of the cellular nuclei. Altogether, these results markedly highlight the pathological and molecular features of idiopathic AWE essential for histo-pathogenetic categorization. Full article

Endometriosis is a benign disease but with malignant behavior, sharing numerous features with cancers. Endometriosis is the development of endometrial tissue outside the uterus, with the presence of both glands and stroma. Approximately 10% of women of reproductive age suffer from endometriosis; it involves high social costs and affects the patient’s quality of life. In this review, we attempt to capture the pathogenesis mechanisms that are common to endometriosis and cancer based on molecular biology, focusing more on the principle of immunological changes and stemness. Clinical applicability will consist of targeted treatments that represent future directions in these diseases, which impose a burden on the healthcare system. Unlike endometriosis, cancer is a disease with fatal evolution, with conventional treatment based on chemo/radiotherapy. Here, we focus on the niche of personalized treatments that target molecular pathways. Our findings show that, in both pathologies, the resistance to treatments is due to the stemness of the stem cells, which might play a role in the appearance and evolution of both diseases. More research is needed before we can draw firm conclusions. Full article

Endometriosis is an oestrogen-dependent inflammatory disease affecting menstruating women, with varying levels of severity. Oestrogen dysregulation is responsible for chronic inflammation, angiogenesis, endometrial lesion development, progression, and infertility during menarche in afflicted women. The inflammatory mediators associated with this chronic painful disease have been established, with research also indicating the relationship between dysbiosis and disease manifestation. Endometriosis is also present with several painful comorbidities, including endometrial cancer, cardiovascular disease, and autoimmunity. The lack of specific and sensitive non-invasive diagnostic procedures, coupled with poor response to current therapeutic approaches, means that treatment needs remain unmet. Surgical procedures are performed to remove endometriosis ectopic lesions, for which the recurrence rate of disease is up to 50%, with certain patients exhibiting no alleviation of symptoms. This review aims to outline the aetiology of endometriosis, detailing novel diagnostic approaches and potential therapeutic approaches, namely advanced therapeutic medical products (ATMPs), including stem cell therapy and clustered regularly interspaced short palindromic repeats (CRISPR) gene editing. This timely review also provides novel insights into the important recent modalities which may be applied for the diagnosis and therapeutic response of endometriosis, including biomarkers, microfluidic platforms, and organoid systems. Undoubtedly, reliable, reproducible, sensitive, and specific models of endometriosis in humans are urgently needed to investigate and detail the aetiology of this debilitating disease. Full article

Autophagy is a cellular process crucial for maintaining homeostasis by degrading damaged proteins and organelles. It is stimulated in response to stress, recycling nutrients and generating energy for cell survival. In normal endometrium, it suppresses tumorigenesis by preventing toxic accumulation and maintaining cellular homeostasis. It is involved in the cyclic remodelling of the endometrium during the menstrual cycle and contributes to decidualisation for successful pregnancy. Such a process is regulated by various signalling pathways, including PI3K/AKT/mTOR, AMPK/mTOR, and p53. Dysregulation of autophagy has been associated with benign conditions like endometriosis and endometrial hyperplasia but also with malignant neoplasms such as endometrial carcinoma. In fact, it has emerged as a crucial player in endometrial carcinoma biology, exhibiting a dual role in both tumour suppression and tumour promotion, providing nutrients during metabolic stress and allowing cancer cell survival. It also regulates cancer stem cells, metastasis and therapy resistance. Targeting autophagy is therefore a promising therapeutic strategy in endometrial carcinoma and potential for overcoming resistance to standard treatments. The aim of this review is to delve into the intricate details of autophagy’s role in endometrial pathology, exploring its mechanisms, signalling pathways and potential therapeutic implications. Full article

Stress-inducible heat shock protein 70 (Hsp70), which functions as a molecular chaperone and is frequently overexpressed in different cancer cell types, is present on the cell surface of tumor cells and is actively released into the circulation in free and extracellular lipid vesicle-associated forms. Since the exact pathomechanism of endometriosis has not yet been elucidated (although it has been associated with the development of endometrial and ovarian cancer), we asked whether extracellular Hsp70 and circulating endometriotic cells (CECs) reflect the presence and development of endometriosis. Therefore, circulating levels of free and lipid microvesicle-associated Hsp70 were measured using the Hsp70-exo ELISA, and the presence of circulating CECs in the peripheral blood of patients with endometriosis was determined using membrane Hsp70 (mHsp70) and EpCAM monoclonal antibody (mAb)-based bead isolation approaches. Isolated CECs were further characterized by immunofluorescence using reagents directed against cytokeratin (epithelial marker), CD45 (leukocyte marker), CD105/CD44 (mesenchymal stemness markers) and by comparative RNA analysis. Similar to the situation in patients with cancer, the levels of circulating Hsp70 were elevated in the blood of patients with histologically proven endometriosis compared to a healthy control cohort, with significantly elevated Hsp70 levels in endometriosis patients with lesions outside the uterine cavity. Moreover, CECs could be isolated using the cmHsp70.1 mAb-based, and to a lesser extent EpCAM mAb-based, bead approach in all patients with endometriosis, with the highest counts obtained using the mHsp70-targeting procedure in patients with extra-uterine involvement. The longevity in cell culture and the expression of the cytokeratins CD105 and CD44, together with differentially expressed genes related to epithelial-to-mesenchymal transition (EMT), revealed similarities between mHsp70-expressing CECs and circulating tumor cells (CTCs) and suggest a mesenchymal stem cell origin. These findings support the involvement of mHsp70-positive stem cell-like cells in the development of endometriotic lesions. In summary, elevated levels of Hsp70 and CECs in the circulation could serve as liquid biopsy markers for endometriosis with extra-uterine involvement and help to elucidate the underlying pathomechanism of the disease. Full article

Infertility is a global phenomenon that impacts people of both the male and the female sex; it is related to multiple factors affecting an individual’s overall systemic health. Recently, investigators have been using mesenchymal stem cell (MSC) therapy for female-fertility-related disorders such as polycystic ovarian syndrome (PCOS), premature ovarian failure (POF), endometriosis, preeclampsia, and Asherman syndrome (AS). Studies have shown promising results, indicating that MSCs can enhance ovarian function and restore fertility for affected individuals. Due to their regenerative effects and their participation in several paracrine pathways, MSCs can improve the fertility outcome. However, their beneficial effects are dependent on the methodologies and materials used from isolation to reimplantation. In this review, we provide an overview of the protocols and methods used in applications of MSCs. Moreover, we summarize the findings of published preclinical studies on infertility treatments and discuss the multiple properties of these studies, depending on the isolation source of the MSCs used. Full article

Adenomyosis and endometriosis are distinct gynecological disorders characterized by ectopic growth of endometrial tissue. Their etiology remains unclear, but stem cells have been implicated in both. The aim of this study was to investigate and compare the quantity of NOTCH1+ and CD117+ stem cells in endometriosis and adenomyosis lesions. Immunohistochemical staining of ectopic endometrium biopsies using antibodies against NOTCH1 and CD117 was performed. The quantity and spatial distribution of endometrial stromal cells positive for these markers were determined and compared between endometriosis and adenomyosis lesions. Additionally, their quantities were compared between endometriosis lesion types. Mann–Whitney U test showed that the median percentages of both NOTCH1+ and CD117+ cells in the endometriosis lesions were significantly higher than those in the adenomyosis lesions (2.26% vs. 0.13%, p = 0.002 and 0.44% vs. 0.26%, p = 0.016, respectively). Spearman’s test showed a positive correlation between NOTCH1+ and CD117+ cells in endometriosis lesions (R = 0.45, p = 0.027) but no significant correlation in adenomyosis lesions (R = −0.11, p = 0.69). The quantity of both stem cell types was highest in extragenital endometriotic lesions. Unlike adenomyosis, endometriosis lesions are associated with higher quantities of NOTCH1+ and CD117+ stem cells and a coordinated increase in their number. These findings support the distinct origin of the two conditions. Full article

Background: There has been considerable progress in our understanding of endometriosis, but its pathophysiology remains uncertain. Uncovering the underlying mechanism of the rare instances of endometriosis reported in early postmenarcheal years and in girls before menarche can have wide implications. Methods: We conducted a literature review of all relevant articles on Medline. Results: In the review, we explore the pathogenetic theories of premenarcheal endometriosis, the role of retrograde menstruation in the adult and its potential role in early-onset disease, as well as the factors that argue against the existence of a link between early-onset endometriosis (EOE) and neonatal uterine bleeding (NUB). Conclusions: As with endometriosis in adult women, the pathogenesis of early-onset disease remains unclear. A link between NUB and EOE is plausible, but there are considerable challenges to collating supporting evidence. The state of our understanding of early uterine development and of the pathophysiology of NUB leaves many unknowns that need exploration. These include proof of the existence of viable endometrial cells or endometrial mesenchymal stem cells in NUB, their passage to the pelvic cavity, their possible response to steroids, and whether they can reside within the pelvic cavity and remain dormant till menarche. Full article

There are several critical events that occur in the uterus during early pregnancy which are necessary for the establishment and maintenance of pregnancy. These events include blastocyst implantation, uterine decidualization, uterine neoangiogenesis, differentiation of trophoblast stem cells into different trophoblast cell lineages, and formation of a placenta. These processes involve several different cell types within the pregnant uterus. Communication between these cell types must be intricately coordinated for successful embryo implantation and the formation of a functional maternal–fetal interface in the placenta. Understanding how this intricate coordination transpires has been a focus of researchers in the field for many years. It has long been understood that maternal endometrial tissue plays a key role in intercellular signaling during early pregnancy, sending signals to nearby tissues in a paracrine manner. Recently, insights have been obtained into the mechanisms by which these signaling events occur. Notably, the endometrium has been shown to secrete extracellular vesicles (EVs) that contain crucial cargo (proteins, lipids, RNA, miRNA) that are taken up by recipient cells to initiate a response leading to the occurrence of critical events during implantation and placentation. In this review, we aim to summarize the role that endometrium-derived EVs play in mediating cell-to-cell communications within the pregnant uterus to orchestrate the events that must occur to establish and maintain pregnancy. We will also discuss how aberrant endometrial EV signaling may lead to pathophysiological conditions, such as endometriosis and infertility. Full article

Microorganisms inhabiting the human body play an extremely key role in its proper functioning, as well as in the development of the immune system, which, by maintaining the immune balance, allows you to enjoy health. Dysbiosis of the intestinal microbiota, or in the oral cavity or reproductive tract, understood as a change in the number and diversity of all microorganisms inhabiting them, may correlate with the development of many diseases, including endometriosis, as researchers have emphasized. Endometriosis is an inflammatory, estrogen-dependent gynecological condition defined by the growth of endometrial cells outside the uterine cavity. Deregulation of immune homeostasis resulting from microbiological disorders may generate chronic inflammation, thus creating an environment conducive to the increased adhesion and angiogenesis involved in the development of endometriosis. In addition, research in recent years has implicated bacterial contamination and immune activation, reduced gastrointestinal function by cytokines, altered estrogen metabolism and signaling, and abnormal progenitor and stem cell homeostasis, in the pathogenesis of endometriosis. The aim of this review was to present the influence of intestinal, oral and genital microbiota dysbiosis in the metabolic regulation and immunopathogenesis of endometriosis. Full article

Menstrual blood mesenchymal stem cells (MenSCs) have gained prominence in the endometriosis scientific community, given their multifunctional roles in regenerative medicine as a noninvasive source for future clinical applications. In addition, changes in post-transcriptional regulation via miRNAs have been explored in endometriotic MenSCs with a role in modulating proliferation, angiogenesis, differentiation, stemness, self-renewal, and the mesenchymal–epithelial transition process. In this sense, homeostasis of the miRNA biosynthesis pathway is essential for several cellular processes and is related to the self-renewal and differentiation of progenitor cells. However, no studies have investigated the miRNA biogenesis pathway in endometriotic MenSCs. In this study, we profiled the expression of eight central genes for the miRNA biosynthesis pathway under experimental conditions involving a two-dimensional culture of MenSCs obtained from healthy women (n = 10) and women with endometriosis (n = 10) using RT-qPCR and reported a two-fold decrease in DROSHA expression in the disease. In addition, miR-128-3p, miR-27a-3p, miR-27b-3p, miR-181a-5p, miR-181b-5p, miR-452-3p, miR-216a-5p, miR-216b-5p, and miR-93-5p, which have been associated with endometriosis, were identified through in silico analyses as negative regulators of DROSHA. Because DROSHA is essential for miRNA maturation, our findings may justify the identification of different profiles of miRNAs with DROSHA-dependent biogenesis in endometriosis. Full article

Endometriotic lesions are able to infiltrate surrounding tissue. This is made possible partly by an altered local and systemic immune response that helps achieve neoangiogenesis, cell proliferation and immune escape. Deep-infiltrating endometriosis (DIE) differs from other subtypes through the invasion of its lesions over 5 mm into affected tissue. Despite the invasive nature of these lesions and the wider range of symptoms they can trigger, DIE is described as a stable disease. This elicits the need for a better understanding of the underlying pathogenesis. We used the “Proseek^® Multiplex Inflammation I Panel” in order to simultaneously detect 92 inflammatory proteins in plasma and peritoneal fluid (PF) of controls and patients with endometriosis, as well as in particular patients with DIE, in order to gain a better insight into the systemically and locally involved immune response. Extracellular newly identified receptor for advanced gycation end-products binding protein (EN-RAGE), C-C motif Chemokine ligand 23 (CCL23), Eukaryotic translation initiation factor 4—binding protein 1 (4E-BP1) and human glial cell-line derived neurotrophic factor (hGDNF) were significantly increased in plasma of endometriosis patients compared to controls, whereas Hepatocyte Growth factor (HGF) and TNF-related apoptosis inducing ligand (TRAIL) were decreased. In PF of endometriosis patients, we found Interleukin 18 (IL-18) to be decreased, yet Interleukin 8 (IL-8) and Interleukin 6 (IL-6) to be increased. TNF-related activation-induced cytokine (TRANCE) and C-C motif Chemokine ligand 11 (CCL11) were significantly decreased in plasma, whereas C-C motif Chemokine ligand 23 (CCL23), Stem Cell Factor (SCF) and C-X-C motif chemokine 5 (CXCL5) were significantly increased in PF of patients with DIE compared to endometriosis patients without DIE. Although DIE lesions are characterized by increased angiogenetic and pro-inflammatory properties, our current study seems to support the theory that the systemic immune system does not play a major role in the pathogenesis of these lesions. Full article