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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: 20 June 2025 | Viewed by 16050

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Dr. Alfonso Baldi

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Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "L. Vanvitelli", 81020 Caserta, Italy
Interests: electrochemotherapy; cancer; cell culture; gene expression; immunohistochemistry; cell signaling; apoptosis; cell proliferation; cancer biomarkers; regression analysis; phosphorylation; diagnosis; endometriosis; melanoma; osteoarthritis; articular cartilage; p53; chondrocytes; mesothelioma
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Dear Colleagues,

Endometriosis is a common disease in reproductive system that affects approximately 6–10% of women of reproductive age. It is the presence of endometrial-like endometrial cells, glands, and stroma outside the uterus, resulting in the symptoms such as pelvic pain, painful periods, pain with sexual intercourse, and subfertility. Despite the great advances in diagnostics, pharmacology, minimally invasive surgery and assisted reproduction technologies, endometriosis still represents an unsolved global health issue.

This Special Issue aims to publish advanced research and review articles in a basic science. Aiming to let readers have a better understanding of the molecular mechanisms governing endometriosis and its important prerequisite for the development of new therapeutic approaches.

Dr. Alfonso Baldi
Guest Editor

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Related Special Issues

Endometriosis Research: From Bench to Bedside in International Journal of Molecular Sciences (7 articles)
Molecular and Cellular Advances in Endometriosis Research in International Journal of Molecular Sciences (14 articles)
Molecular and Cellular Advances in Endometriosis Research 2.0 in International Journal of Molecular Sciences (12 articles)

Published Papers (9 papers)

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14 pages, 804 KiB

Open AccessArticle

Gut Microbiota Dysbiosis in Endometriosis: A Potential Link to Inflammation and Disease Progression

by Alexandra Irma Gabriela Baușic, Francesca Scurtu, Andrei Manu, Daniela Roxana Matasariu and Elvira Brătilă

Int. J. Mol. Sci. 2025, 26(11), 5144; https://doi.org/10.3390/ijms26115144 - 27 May 2025

Viewed by 398

Abstract

Endometriosis is a complex gynaecological disorder characterised by the presence of endometrial-like tissue outside the uterus, leading to chronic inflammation, pain, and infertility. Recent research suggests that gut microbiota may play a crucial role in the pathogenesis and progression of endometriosis by modulating immune responses and oestrogen metabolism. This study investigates the intestinal microbiota composition in women with endometriosis and its potential as a disease diagnosis and severity biomarker. Stool samples from nine patients diagnosed with endometriosis were analysed using the GI Effects^® Comprehensive Stool Profile test. The tests revealed significant dysbiosis, particularly an altered Firmicutes/Bacteroidetes ratio and increased levels of Bacteroidetes. Inflammatory markers, including β-glucuronidase and secretory IgA, were also elevated, suggesting a potential link between gut microbiota and systemic inflammation in endometriosis. While our findings align with previous studies, further research with larger cohorts is necessary to validate these observations. Understanding the role of the microbiome in endometriosis could open new avenues for noninvasive diagnostic tools in endometriosis and microbiota-targeted therapies. Full article

(This article belongs to the Special Issue Endometriosis: Focusing on Molecular and Cellular Research)

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16 pages, 1205 KiB

Open AccessArticle

Molecular Profile (Estrogen Receptor, Progesterone Receptor, Bcl-2 and Ki-67) of the Ectopic Endometrium in Patients with Endometriosis

by Ciprian-Andrei Coroleucă, Cătălin-Bogdan Coroleucă, Ruxandra Coroleucă, Petre Cornel Brătilă, Aniela-Roxana Nodiți, Ioana Roșca, Lăcrămioara Aurelia Brîndușe, Elvira Brătilă and Mihaela Boț

Int. J. Mol. Sci. 2025, 26(7), 2983; https://doi.org/10.3390/ijms26072983 - 25 Mar 2025

Viewed by 2455

Abstract

Endometriosis is characterized by alterations of the action and control mechanisms that lead to the development of ectopic endometrial tissue. This study aimed to analyze the molecular profile of ectopic endometrium by evaluating the expression of several biomarkers [estrogen receptor (ER), progesterone receptor (PR), anti-apoptotic protein Bcl-2, and Ki-67 antigen] in relation to the stage of the disease and symptoms. A prospective study over a period of one year, consisting of 14 patients with endometriosis, was performed. All patients received laparoscopic surgical treatment for excision of the lesions and staging of the disease. The expression of the aforementioned biomarkers was assessed in the ectopic endometrial tissue from the excised lesions using immunohistochemistry to determine their expression in the glandular epithelium and stroma. The mean expression of biomarkers in the epithelial and stromal levels did not differ significantly based on disease stage. Epithelial ER expression was significantly positively correlated with stromal ER, epithelial PR, and stromal PR. Stromal ER was significantly positively correlated with epithelial PR and stromal Ki-67. Epithelial Bcl-2 was significantly positively correlated with stromal Bcl-2. Epithelial Ki-67 was significantly positively correlated with stromal Ki-67. Finally, epithelial Bcl-2 expression was significantly positively correlated with the intensity of dyspareunia. The correlation between epithelial Bcl-2 expression and the intensity of dyspareunia highlights a potential molecular link to the severity of symptoms in endometriosis. These results suggest that further exploration of these biomarkers could lead to improved understanding of their clinical implications and more personalized therapies for patients with endometriosis. Full article

(This article belongs to the Special Issue Endometriosis: Focusing on Molecular and Cellular Research)

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13 pages, 746 KiB

Open AccessCommunication

The Cellular Respiration of Endometrial Biopsies from Patients with Various Forms of Endometriosis

by Konstantin A. Toniyan, Artyom A. Malkov, Nikolay S. Biryukov, Elena Yu. Gorbacheva, Valery V. Boyarintsev and Irina V. Ogneva

Int. J. Mol. Sci. 2024, 25(7), 3680; https://doi.org/10.3390/ijms25073680 - 26 Mar 2024

Cited by 3 | Viewed by 1756

Abstract

Endometriosis is one of the leading pathologies of the reproductive system of women of fertile age, which shows changes in cell metabolism in the lesions. We conducted a study of the cellular respiration according to the polarography and the mRNA content of the main metabolic proteins using qRT-PCR of intraoperative endometrial biopsies from patients in the control group and with different localizations of endometriosis (adenomyosis, endometrioma, pelvic peritoneum). In biopsy samples of patients with endometriomas and pelvic peritoneum endometriotic lesions, the rate of oxygen absorption was significantly reduced, and, moreover, in the extragenital case, there was a shift to succinate utilization. The mRNA content of the cytochrome c, cytochrome c oxidase, and ATP synthase was also reduced, but hexokinase HK2 as well as pyruvate kinase were significantly higher than in the control. These oxidative phosphorylation and gene expression profiles suggest the Warburg effect and a shift in metabolism toward glycolysis. For adenomyosis, on the contrary, cellular respiration was significantly higher than in the control group due to the terminal region of the respiratory chain, ATP synthase, and its mRNA was increased as well. These data allow us to suggest that the therapeutic strategies of endometriosis based on modulation energy metabolism should take lesion localization into account. Full article

(This article belongs to the Special Issue Endometriosis: Focusing on Molecular and Cellular Research)

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35 pages, 8672 KiB

Open AccessArticle

Clinical Characteristics and Local Histopathological Modulators of Endometriosis and Its Progression

by Anca-Maria Istrate-Ofiţeru, Carmen Aurelia Mogoantă, George-Lucian Zorilă, Gabriela-Camelia Roşu, Roxana Cristina Drăguşin, Elena-Iuliana-Anamaria Berbecaru, Marian Valentin Zorilă, Cristina Maria Comănescu, Stelian-Ștefăniță Mogoantă, Constantin-Cristian Vaduva, Elvira Brătilă and Dominic Gabriel Iliescu

Int. J. Mol. Sci. 2024, 25(3), 1789; https://doi.org/10.3390/ijms25031789 - 1 Feb 2024

Cited by 24 | Viewed by 3671

Abstract

Endometriosis (E) and adenomyosis (A) are associated with a wide spectrum of symptoms and may present various histopathological transformations, such as the presence of hyperplasia, atypia, and malignant transformation occurring under the influence of local inflammatory, vascular and hormonal factors and by the alteration of tumor suppressor proteins and the inhibition of cell apoptosis, with an increased degree of lesion proliferation. Material and methods: This retrospective study included 243 patients from whom tissue with E/A or normal control uterine tissue was harvested and stained by histochemical and classical immunohistochemical staining. We assessed the symptomatology of the patients, the structure of the ectopic epithelium and the presence of neovascularization, hormone receptors, inflammatory cells and oncoproteins involved in lesion development. Atypical areas were analyzed using multiple immunolabeling techniques. Results: The cytokeratin (CK) CK7+/CK20− expression profile was present in E foci and differentiated them from digestive metastases. The neovascularization marker cluster of differentiation (CD) 34+ was increased, especially in areas with malignant transformation of E or A foci. T:CD3+ lymphocytes, B:CD20+ lymphocytes, CD68+ macrophages and tryptase+ mast cells were abundant, especially in cases associated with malignant transformation, being markers of the proinflammatory microenvironment. In addition, we found a significantly increased cell division index (Ki67+), with transformation and inactivation of tumor suppressor genes p53, B-cell lymphoma 2 (BCL-2) and Phosphatase and tensin homolog (PTEN) in areas with E/A-transformed malignancy. Conclusions: Proinflammatory/vascular/hormonal changes trigger E/A progression and the onset of cellular atypia and malignant transformation, exacerbating symptoms, especially local pain and vaginal bleeding. These triggers may represent future therapeutic targets. Full article

(This article belongs to the Special Issue Endometriosis: Focusing on Molecular and Cellular Research)

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16 pages, 4154 KiB

Open AccessArticle

The Presence of Pre-Existing Endometriotic Lesions Promotes the Growth of New Lesions in the Peritoneal Cavity

by Ilinca T. Mihai, Jeannette Rudzitis-Auth, Michael D. Menger and Matthias W. Laschke

Int. J. Mol. Sci. 2023, 24(18), 13858; https://doi.org/10.3390/ijms241813858 - 8 Sep 2023

Cited by 1 | Viewed by 1588

Abstract

Endometriosis is a common gynecological disease which is characterized by endometriotic lesions outside the uterine cavity. In this study, we investigated whether the presence of pre-existing endometriotic lesions promotes the development of new lesions due to the exchange of cells and an altered peritoneal environment. For this purpose, uterine tissue samples from FVB/N wild-type donor mice were transplanted simultaneously or time-delayed with samples from transgenic FVB-Tg(CAG-luc-GFP)L2G85Chco/J donor mice into the abdominal cavity of FVB/N wild-type recipient mice. The formation of endometriotic lesions was analyzed by means of high-resolution ultrasound, bioluminescence imaging, histology and immunohistochemistry. Moreover, immune cells and inflammatory factors in the peritoneal fluid were assessed by flow cytometry and a cytokine array. These analyses revealed that the growth of newly developing endometriotic lesions is promoted by the presence of pre-existing ones. This is not due to an exchange of cells between both lesion types but rather caused by peritoneal inflammation induced by already established lesions. These findings indicate that, among other pathogenic mechanisms, the chronic nature of endometriosis may be driven by a lesion-induced inflammatory milieu in the peritoneal cavity, which creates favorable conditions for the development of new lesions. Full article

(This article belongs to the Special Issue Endometriosis: Focusing on Molecular and Cellular Research)

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9 pages, 727 KiB

Open AccessArticle

Impact of Continuous Estroprogestin Treatment on Circulating Microparticle Levels in Deep Endometriosis Patients

by Pilar Carrillo Torres, María Ángeles Martínez-Zamora, Dolors Tàssies, Helena Castillo, Meritxell Gracia, Georgina Feixas, Joan Carles Reverter and Francisco Carmona

Int. J. Mol. Sci. 2023, 24(14), 11802; https://doi.org/10.3390/ijms241411802 - 22 Jul 2023

Cited by 3 | Viewed by 1528

Abstract

There has been increasing interest in the study of new pathogenic mechanisms in endometriosis (END), including the coagulation/fibrinolysis system and its link with inflammation and tissue remodeling. It has been suggested that END patients, especially with deep-infiltrating (DE) forms, could present a hypercoagulable state revealing higher levels of proinflammatory and procoagulant markers, such as total circulating microparticles (cMPs) and cMP-TF (tissue factor), released by cells in response to damage, activation, or apoptosis. However, no previous study has assessed the effect of END hormonal treatments on cMP and cMP-TF levels. Therefore, the aim of this study was to evaluate the impact of these treatments on cMP and cMP-TF levels in DE patients. Three groups were compared: DE patients receiving a continuous combined oral contraceptive regimen (CCOCR) (n = 41), DE patients without CCOCR (n = 45), and a control group (n = 43). cMP and cMP-TF levels were evaluated in platelet-free plasma. A significant decrease in the total cMP levels was found in the DE group with CCOCR versus the group without CCOCR, reflecting a higher chronic inflammatory status in DE patients that decreased with the treatment. cMP-TF levels were higher in DE patients receiving CCOCR versus those not receiving CCOCR, suggesting that treatments containing estrogens play a predominant role in suppressing the inhibitory pathway of TF. Full article

(This article belongs to the Special Issue Endometriosis: Focusing on Molecular and Cellular Research)

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13 pages, 686 KiB

Open AccessArticle

Downregulation of DROSHA: Could It Affect miRNA Biogenesis in Endometriotic Menstrual Blood Mesenchymal Stem Cells?

by Ana Clara Lagazzi Cressoni, Letícia B. C. Penariol, Cristiana Carolina Padovan, Maristela D. Orellana, Júlio Cesar Rosa-e-Silva, Omero Benedicto Poli-Neto, Rui Alberto Ferriani, Cláudia Cristina Paro de Paz and Juliana Meola

Int. J. Mol. Sci. 2023, 24(6), 5963; https://doi.org/10.3390/ijms24065963 - 22 Mar 2023

Cited by 6 | Viewed by 2248

Abstract

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

(This article belongs to the Special Issue Endometriosis: Focusing on Molecular and Cellular Research)

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14 pages, 520 KiB

Open AccessReview

The Role of Adenogenesis Factors in the Pathogenesis of Endometriosis

by Pietro G. Signorile, Alfonso Baldi, Rosa Viceconte and Mariarosaria Boccellino

Int. J. Mol. Sci. 2025, 26(5), 2076; https://doi.org/10.3390/ijms26052076 - 27 Feb 2025

Viewed by 794

Abstract

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

(This article belongs to the Special Issue Endometriosis: Focusing on Molecular and Cellular Research)

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9 pages, 247 KiB

Open AccessBrief Report

Evaluation of Proinflammatory Cytokines Concentrations in Plasma, Peritoneal, and Endometrioma Fluids in Women Operated on for Ovarian Endometriosis—A Pilot Study

by Mariusz Wójtowicz, Dariusz Zdun, Aleksander Jerzy Owczarek, Violetta Skrzypulec-Plinta and Magdalena Olszanecka-Glinianowicz

Int. J. Mol. Sci. 2025, 26(11), 5117; https://doi.org/10.3390/ijms26115117 - 26 May 2025

Viewed by 344

Abstract

Some studies indicate the role of TNF-α, IL-6, and IL-8 in the development of endometriosis. However, a comprehensive assessment of plasma, peritoneal, and endometrioma fluids of proinflammatory cytokine concentrations in women with ovarian endometriosis has not yet been performed. Therefore, this study aimed to analyze plasma, peritoneal, and endometrioma fluids for selected proinflammatory cytokine concentrations in women operated on for ovarian endometriosis. A retrospective study was conducted with 56 women who underwent surgery for ovarian endometriosis. Body mass, height, and waist circumference were measured, as well as BMI being calculated. Plasma, peritoneal, and endometrioma fluids’ interleukin-6 (IL-6), IL-8, and tumor necrosis factor-alpha (TNF-α) were determined by ELISA. Levels of IL-6 and TNF-α were significantly higher in endometrioma fluid compared to plasma and peritoneal fluid. In addition, levels of IL-6 and TNF-α were significantly higher in peritoneal fluid than found in plasma. Levels of IL-8 did not significantly differ between plasma and both peritoneal and endometrioma fluids, or between peritoneal and endometrioma fluids. There were also positive correlations among IL-6, IL-8, and TNF-α levels in endometrioma and peritoneal fluids (ρ = 0.29; p < 0.05; ρ = 0.51; p < 0.001; ρ = 0.52; p < 0.001, respectively). There were no associations between cytokine levels in plasma, peritoneal, and endometrioma fluids and endometriosis stage. Plasma IL-8 levels can be considered an emerging biomarker of severity of local inflammation related to endometrioma. Further studies are needed for understanding the role of IL-6 and TNF-α as the markers of local inflammation in endometrioma. Full article

(This article belongs to the Special Issue Endometriosis: Focusing on Molecular and Cellular Research)

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