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11 pages, 1073 KiB

Open AccessArticle

Eutopic and Ectopic Endometrial Interleukin-17 and Interleukin-17 Receptor Expression at the Endometrial—Myometrial Interface in Women with Adenomyosis: Possible Pathophysiology Implications

by Le-Tien Hsu, Pei-Chen Lu, Yi-Wen Wang, Hsien-Ming Wu, I-Ju Chen and Hong-Yuan Huang

Int. J. Mol. Sci. 2024, 25(20), 11155; https://doi.org/10.3390/ijms252011155 - 17 Oct 2024

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Abstract

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 [...] Read more.

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

(This article belongs to the Special Issue Endometriosis: From Molecular Basis to Therapy)

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24 pages, 8533 KiB

Open AccessArticle

The Regulation of MicroRNA-21 by Interleukin-6 and Its Role in the Development of Fibrosis in Endometriotic Lesions

by Maria Ariadna Ochoa Bernal, Yong Song, Niraj Joshi, Gregory W. Burns, Emmanuel N. Paul, Erin Vegter, Samantha Hrbek, Lorenzo F. Sempere and Asgerally T. Fazleabas

Int. J. Mol. Sci. 2024, 25(16), 8994; https://doi.org/10.3390/ijms25168994 - 19 Aug 2024

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Abstract

Endometriosis is one of the most common causes of chronic pelvic pain and infertility that affects 10% of women of reproductive age. It is currently defined as the presence of endometrial epithelial and stromal cells at ectopic sites; however, advances in endometriosis research [...] Read more.

Endometriosis is one of the most common causes of chronic pelvic pain and infertility that affects 10% of women of reproductive age. It is currently defined as the presence of endometrial epithelial and stromal cells at ectopic sites; however, advances in endometriosis research have some authors believing that endometriosis should be re-defined as “a fibrotic condition in which endometrial stroma and epithelium can be identified”. microRNAs (miRNAs) are regulatory molecules that potentially play a role in endometriotic lesion development. There is evidence that suggests that miRNAs, including microRNA-21 (miR-21), participate in fibrotic processes in different organs, including the heart, kidney, liver and lungs. The objective of this study was to understand the role of miR-21 and the mechanisms that can contribute to the development of fibrosis by determining how IL-6 regulates miR-21 expression and how this miRNA regulates the transforming growth factor beta (TGF-β) signaling pathway to promote fibrosis. We investigated the expression of miR-21 in the baboon and mouse model of endometriosis and its correlation with fibrosis. We demonstrated that inflammation and fibrosis are present at a very early stage of endometriosis and that the inflammatory environment in the peritoneal cavity, which includes interleukin 6 (IL-6), can regulate the expression of miR-21 in vitro and in vivo. Full article

(This article belongs to the Special Issue Endometriosis: From Molecular Basis to Therapy)

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26 pages, 9328 KiB

Open AccessArticle

N-Myc and STAT Interactor is an Endometriosis Suppressor

by Yuri Park, Xiaoming Guan and Sang Jun Han

Int. J. Mol. Sci. 2024, 25(15), 8145; https://doi.org/10.3390/ijms25158145 - 26 Jul 2024

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Abstract

In patients with endometriosis, refluxed endometrial fragments evade host immunosurveillance, developing into endometriotic lesions. However, the mechanisms underlying this evasion have not been fully elucidated. N-Myc and STAT Interactor (NMI) have been identified as key players in host immunosurveillance, including interferon (IFN)-induced cell [...] Read more.

In patients with endometriosis, refluxed endometrial fragments evade host immunosurveillance, developing into endometriotic lesions. However, the mechanisms underlying this evasion have not been fully elucidated. N-Myc and STAT Interactor (NMI) have been identified as key players in host immunosurveillance, including interferon (IFN)-induced cell death signaling pathways. NMI levels are markedly reduced in the stromal cells of human endometriotic lesions due to modulation by the Estrogen Receptor beta/Histone Deacetylase 8 axis. Knocking down NMI in immortalized human endometrial stromal cells (IHESCs) led to elevated RNA levels of genes involved in cell-to-cell adhesion and extracellular matrix signaling following IFNA treatment. Furthermore, NMI knockdown inhibited IFN-regulated canonical signaling pathways, such as apoptosis mediated by Interferon Stimulated Gene Factor 3 and necroptosis upon IFNA treatment. In contrast, NMI knockdown with IFNA treatment activated non-canonical IFN-regulated signaling pathways that promote proliferation, including β-Catenin and AKT signaling. Moreover, NMI knockdown in IHESCs stimulated ectopic lesions’ growth in mouse endometriosis models. Therefore, NMI is a novel endometriosis suppressor, enhancing apoptosis and inhibiting proliferation and cell adhesion of endometrial cells upon IFN exposure. Full article

(This article belongs to the Special Issue Endometriosis: From Molecular Basis to Therapy)

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12 pages, 499 KiB

Open AccessArticle

Validation of an In Vitro Diagnostic Test for Endometriosis: Impact of Confounding Medical Conditions and Lesion Location

by Elza Daoud, David F. Archer, Fabio Parazzini and Bárbara Herranz-Blanco

Int. J. Mol. Sci. 2024, 25(14), 7667; https://doi.org/10.3390/ijms25147667 - 12 Jul 2024

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Abstract

With the aim to shorten the time for diagnosis and accelerate access to correct management, a non-invasive diagnostic test for endometriosis was developed and validated. The IVD test combines an ELISA test kit to quantify CA125 and BDNF concentrations in serum and a [...] Read more.

With the aim to shorten the time for diagnosis and accelerate access to correct management, a non-invasive diagnostic test for endometriosis was developed and validated. The IVD test combines an ELISA test kit to quantify CA125 and BDNF concentrations in serum and a data treatment algorithm hosted in medical software processing results from the ELISA test and responses to six clinical variables. Serum samples and clinical variables extracted from psychometric questionnaires from 77 patients were collected from the Oxford Endometriosis CaRe Centre biobank (UK). Case/control classification was performed based on laparoscopy and histological verification of the excised lesions. Biomarkers serum concentrations and clinical variables were introduced to the software, which generates the qualitative diagnostic result (“positive” or “negative”). This test allowed the detection of 32% of cases with superficial endometriosis, which is an added value given the limited efficacy of existing imaging techniques. Even in the presence of various confounding medical conditions, the test maintained a specificity of 100%, supporting its suitability for use in patients with underlying medical conditions. Full article

(This article belongs to the Special Issue Endometriosis: From Molecular Basis to Therapy)

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14 pages, 1413 KiB

Open AccessArticle

Inflammatory Changes after Medical Suppression of Suspected Endometriosis for Implantation Failure: Preliminary Results

by Bruce A. Lessey, Allan Dong, Jeffrey L. Deaton, Daniel Angress, Ricardo F. Savaris and Stephen J. Walker

Int. J. Mol. Sci. 2024, 25(13), 6852; https://doi.org/10.3390/ijms25136852 - 22 Jun 2024

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Abstract

Unexplained euploid embryo transfer failure (UEETF) is a frustrating and unanswered conundrum accounting for 30 to 50% of failures in in vitro fertilization using preimplantation genetic testing for aneuploidy (PGT-A). Endometriosis is thought by many to account for most of such losses and [...] Read more.

Unexplained euploid embryo transfer failure (UEETF) is a frustrating and unanswered conundrum accounting for 30 to 50% of failures in in vitro fertilization using preimplantation genetic testing for aneuploidy (PGT-A). Endometriosis is thought by many to account for most of such losses and menstrual suppression or surgery prior to the next transfer has been reported to be beneficial. In this study, we performed endometrial biopsy in a subset of women with UEETF, testing for the oncogene BCL6 and the histone deacetylase SIRT1. We compared 205 PGT-A cycles outcomes and provide those results following treatment with GnRH agonist versus controls (no treatment). Based on these and previous promising results, we next performed a pilot randomized controlled trial comparing the orally active GnRH antagonist, elagolix, to oral contraceptive pill (OCP) suppression for 2 months before the next euploid embryo transfer, and monitored inflammation and miRNA expression in blood, before and after treatment. These studies support a role for endometriosis in UEETF and suggest that medical suppression of suspected disease with GnRH antagonist prior to the next transfer could improve success rates and address underlying inflammatory and epigenetic changes associated with UEETF. Full article

(This article belongs to the Special Issue Endometriosis: From Molecular Basis to Therapy)

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Review

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16 pages, 1104 KiB

Open AccessReview

Immune Checkpoints in Endometriosis—A New Insight in the Pathogenesis

by Dorota Suszczyk, Wiktoria Skiba, Anna Pawłowska-Łachut, Izabela Dymanowska-Dyjak, Karolina Włodarczyk, Roman Paduch and Iwona Wertel

Int. J. Mol. Sci. 2024, 25(11), 6266; https://doi.org/10.3390/ijms25116266 - 6 Jun 2024

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Abstract

Endometriosis (EMS) is an oestrogen-dependent, chronic disease affecting women of a reproductive age. One of the important factors involved in the development of this disease is the complex disorders associated with the functioning of the immune system. Recent evidence has shown that EMS [...] Read more.

Endometriosis (EMS) is an oestrogen-dependent, chronic disease affecting women of a reproductive age. One of the important factors involved in the development of this disease is the complex disorders associated with the functioning of the immune system. Recent evidence has shown that EMS development is associated with changes in systemic and local immunity, including functional disturbances of effector and antigen-presenting cells. One of the reasons for immune imbalance can be the improper expression of immune checkpoints (ICPs). ICPs and their ligands are responsible for maintaining self-tolerance and the modulation of the initiation, duration, and magnitude of the immune response of effector cells in normal tissues to avoid tissue damage. Considering the complex nature of co-stimulatory or co-inhibitory ICPs and the signalling between effector cells and APCs, we hypothesise that changes in cells’ activity caused by ICPs may lead to serious immune system disturbances in patients with endometriosis. Moreover, both upregulation and downregulation in the expression of ICPs may be implicated in this process, including the reduced activity of effector cells against endometrial implants and disturbances in the antigen-presenting process. In this narrative review, we discuss, for the first time, key findings from the emerging literature, describing the associations between ICPs and their possible implication in the pathogenesis of endometriosis. Full article

(This article belongs to the Special Issue Endometriosis: From Molecular Basis to Therapy)

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14 pages, 1366 KiB

Open AccessReview

Immune Dysregulation in Endometriomas: Implications for Inflammation

by Izabela Dymanowska-Dyjak, Barbara Terpiłowska, Izabela Morawska-Michalska, Adam Michalski, Grzegorz Polak, Michał Terpiłowski, Mansur Rahnama-Hezavah and Ewelina Grywalska

Int. J. Mol. Sci. 2024, 25(9), 4802; https://doi.org/10.3390/ijms25094802 - 28 Apr 2024

Cited by 2 | Viewed by 1406

Abstract

The most common manifestation of endometriosis, a condition characterized by the presence of endometrial-like tissue outside of the uterus, is the endometrioma, a cystic ovarian lesion. It is a commonly occurring condition associated with chronic pelvic pain exacerbated prior to and during menstruation, [...] Read more.

The most common manifestation of endometriosis, a condition characterized by the presence of endometrial-like tissue outside of the uterus, is the endometrioma, a cystic ovarian lesion. It is a commonly occurring condition associated with chronic pelvic pain exacerbated prior to and during menstruation, as well as infertility. The exact pathomechanisms of the endometrioma are still not fully understood. Emerging evidence suggests a pivotal role of immune dysregulation in the pathogenesis of endometriomas, primarily influencing both local and systemic inflammatory processes. Among the factors implicated in the creation of the inflammatory milieu associated with endometriomas, alterations in both serum and local levels of several cytokines stand out, including IL-6, IL-8, and IL-1β, along with abnormalities in the innate immune system. While numerous signaling pathways have been suggested to play a role in the inflammatory process linked to endometriomas, only NF-κB has been conclusively demonstrated to be involved. Additionally, increased oxidative stress, both resulting from and contributing to endometriomas, has been identified as a primary driver of both systemic and local inflammation associated with the condition. This article reviews the current understanding of immune dysfunctions in the endometrioma and their implications for inflammation. Full article

(This article belongs to the Special Issue Endometriosis: From Molecular Basis to Therapy)

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15 pages, 688 KiB

Open AccessReview

The Efficacy and Safety of Transvaginal Ethanol Sclerotherapy in the Treatment of Endometrial Cysts—A Systematic Review

by Karolina Frankowska, Izabela Dymanowska-Dyjak, Monika Abramiuk and Grzegorz Polak

Int. J. Mol. Sci. 2024, 25(2), 1337; https://doi.org/10.3390/ijms25021337 - 22 Jan 2024

Cited by 2 | Viewed by 2537

Abstract

Endometriosis, as a chronic disorder that is a source of severe pain ailments and infertility, requires a comprehensive therapeutic approach. Sclerotherapy, consisting of the administration of sclerosing agents into the cyst, is a constantly evolving minimally invasive treatment method for this disease. Hence, [...] Read more.

Endometriosis, as a chronic disorder that is a source of severe pain ailments and infertility, requires a comprehensive therapeutic approach. Sclerotherapy, consisting of the administration of sclerosing agents into the cyst, is a constantly evolving minimally invasive treatment method for this disease. Hence, the main objective of this systematic review was to evaluate the impact of its most often used variant, transvaginal ethanol sclerotherapy, on endometriosis-related symptoms, endometrial cyst recurrence rate, ovarian reserve, assisted reproductive technology (ART) outcomes, and pregnancy outcomes, as well as to assess potential complications resulting from this treatment. This systematic review was undertaken using PubMed, Scopus, Web of Science, and Cochrane Library databases on 24 November 2023. The risk of bias in included studies was assessed with the use of the Newcastle–Ottawa scale (NOS) and the revised Cochrane risk of bias 2.0 tool for randomized controlled trials. From the 1141 records obtained from all databases, 16 studies have been included in this review. The use of ethanol sclerotherapy was characterized by a low rate of post-procedural complications. The recurrence rate of endometrial cysts after the procedure depended on the ethanol instillation time within the cyst. Although ethanol sclerotherapy had negligible influence on ovarian reserves when compared to laparoscopic cystectomy, the effects of both these methods on pregnancy outcomes were comparable. This review identifies that sclerotherapy is safe, provides significant relief of symptoms, and does not impair the reproductive potential of the patients. Full article

(This article belongs to the Special Issue Endometriosis: From Molecular Basis to Therapy)

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