International Journal of Molecular Sciences

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Open AccessEditorial

Recent Advances in Endometriosis Pathophysiology and Pharmacological Treatment

by Alexandra Perricos and René Wenzl

Int. J. Mol. Sci. 2024, 25(12), 6575; https://doi.org/10.3390/ijms25126575 - 14 Jun 2024

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Abstract

Endometriosis, affecting an estimated 10% of women of reproductive age [...] Full article

(This article belongs to the Special Issue Recent Advances in Endometriosis Pathophysiology and Pharmacological Treatment)

Research

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15 pages, 1573 KiB

Open AccessArticle

Exploring the Impact of Endometrioma Aspiration and Dienogest Combination Therapy on Cyst Size, Inflammatory Cytokines in Follicular Fluid and Fertility Outcomes

by Mamoru Shigeta, Isao Tsuji, Shu Hashimoto, Udayanga Sanath Kankanam Gamage, Masaya Yamanaka, Aisaku Fukuda, Yoshiharu Morimoto and Daisuke Tachibana

Int. J. Mol. Sci. 2023, 24(16), 12891; https://doi.org/10.3390/ijms241612891 - 17 Aug 2023

Viewed by 1349

Abstract

Endometriomas (chocolate cysts) are cystic lesions that can develop on ovaries, and are characterized by the presence of ectopic endometrial tissue or similar tissue. Such lesions can cause a decline in the number and quality of oocytes, and lead to implantation failure. In [...] Read more.

Endometriomas (chocolate cysts) are cystic lesions that can develop on ovaries, and are characterized by the presence of ectopic endometrial tissue or similar tissue. Such lesions can cause a decline in the number and quality of oocytes, and lead to implantation failure. In this study, we retrospectively assessed the efficacy of repeated endometrioma aspiration and dienogest combination therapy in patients suffering endometriosis-associated infertility with endometriomas. A comparison was made between a treated group that underwent combination therapy followed by controlled ovarian hyperstimulation (COH) (n = 30) and a control group that did not undergo treatment (n = 40), at the IVF Osaka Clinic from September 2019 to September 2021. There were no differences in patient background between the two groups. A reduction in endometrioma size continued for 12 months after treatment. The numbers of follicles that developed to 15 mm or greater in size following COH and mature oocytes were significantly lower in the treated group compared to those in the control group. The levels of inflammatory cytokines in the follicular fluid significantly decreased in the treated group (p < 0.05). In patients in the treated group who underwent a second ova retrieval, the results were compared between those in the first ova retrieval (immediately after the end of treatment) and those in the second ova retrieval (four months after the first retrieval). The numbers of follicles following COH, retrieved, mature and fertilized ova were significantly increased in the second ova retrieval. Full article

(This article belongs to the Special Issue Recent Advances in Endometriosis Pathophysiology and Pharmacological Treatment)

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13 pages, 1360 KiB

Open AccessArticle

Does the Use of the “Proseek^® Multiplex Inflammation I Panel” Demonstrate a Difference in Local and Systemic Immune Responses in Endometriosis Patients with or without Deep-Infiltrating Lesions?

by Alexandra Perricos, Heinrich Husslein, Lorenz Kuessel, Manuela Gstoettner, Andreas Weinhaeusel, Thomas Eiwegger, Gabriel Beikircher and René Wenzl

Int. J. Mol. Sci. 2023, 24(5), 5022; https://doi.org/10.3390/ijms24055022 - 6 Mar 2023

Cited by 3 | Viewed by 1690

Abstract

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 [...] Read more.

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

(This article belongs to the Special Issue Recent Advances in Endometriosis Pathophysiology and Pharmacological Treatment)

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18 pages, 3523 KiB

Open AccessArticle

Higher Oxidative Stress in Endometriotic Lesions Upregulates Senescence-Associated p16^ink4a and β-Galactosidase in Stromal Cells

by Helena Malvezzi, Bruna Azevedo Cestari, Juliana Meola and Sérgio Podgaec

Int. J. Mol. Sci. 2023, 24(2), 914; https://doi.org/10.3390/ijms24020914 - 4 Jan 2023

Cited by 5 | Viewed by 1812

Abstract

Endometriosis affects a significant proportion of women worldwide; however, no definitive cure for this disease has been discovered to date. Oxidative stress promotes endometriotic lesion maintenance in the peritoneal cavity in women. Furthermore, there is evidence of the mitogen-activated protein kinase (MAPK) signaling [...] Read more.

Endometriosis affects a significant proportion of women worldwide; however, no definitive cure for this disease has been discovered to date. Oxidative stress promotes endometriotic lesion maintenance in the peritoneal cavity in women. Furthermore, there is evidence of the mitogen-activated protein kinase (MAPK) signaling pathway and senescence involvement in the physiopathogenesis of endometriosis. Reactive oxygen species (ROS) cause oxidative damage and are expected to trigger senescence in the endometrium while also causing alterations in MAPK signaling. However, the role of ROS in the senescence-associated phenotype in endometriosis remains unknown. In this context, this study attempted to delineate the pathways linking ROS to senescence in endometrial and endometriotic lesions of healthy individuals and those with endometriosis. Our results indicate a higher presence of ROS in endometriotic lesions, and the upregulation of MAPK. Furthermore, we show that endometriotic lesions in stromal cells stimulated with hydrogen peroxide develop more senescence traits than eutopic and non-endometriosis endometrium. Overall, endometriotic cells respond differently to extracellular distress. Our contribution to further research in this field contributed to the roadmap of endometriosis’ search for alternative treatments. Full article

(This article belongs to the Special Issue Recent Advances in Endometriosis Pathophysiology and Pharmacological Treatment)

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Review

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16 pages, 912 KiB

Open AccessReview

MicroRNAs in Endometriosis: Insights into Inflammation and Progesterone Resistance

by Jing-Xian Hon, Norhazlina Abdul Wahab, Abdul Kadir Abdul Karim, Norfilza Mohd Mokhtar and Mohd Helmy Mokhtar

Int. J. Mol. Sci. 2023, 24(19), 15001; https://doi.org/10.3390/ijms241915001 - 9 Oct 2023

Cited by 3 | Viewed by 1824

Abstract

Endometriosis, a non-malignant gynecological disorder influenced by estrogen, involves the growth of endometrial tissue outside the uterus. Its development includes processes such as inflammation, progesterone resistance, angiogenesis, and cell proliferation. Epigenetic factors, particularly the dysregulation of microRNAs (miRNAs), have emerged as key factors [...] Read more.

Endometriosis, a non-malignant gynecological disorder influenced by estrogen, involves the growth of endometrial tissue outside the uterus. Its development includes processes such as inflammation, progesterone resistance, angiogenesis, and cell proliferation. Epigenetic factors, particularly the dysregulation of microRNAs (miRNAs), have emerged as key factors in these mechanisms in endometriosis. This review aims to unveil the intricate molecular processes that control inflammation, progesterone resistance, and miRNA functions in endometriosis. In addition, it provides a comprehensive overview of the current understanding regarding the involvement of miRNAs in the inflammatory aspects of this condition. This synthesis encompasses research investigating the molecular underpinnings of inflammation, along with the biogenesis and roles of miRNAs in endometriosis. Furthermore, it examines human studies and functional analyses to establish the intricate connection between miRNAs, inflammation, and progesterone resistance in the context of endometriosis. The results highlight the significant impact of dysregulated miRNAs on the inflammatory pathways and hormonal imbalances characteristic of endometriosis. Consequently, miRNAs hold promise as potential non-invasive biomarkers and targeted therapeutic agents aimed at addressing inflammation and enhancing the response to progesterone treatment in individuals with endometriosis. Full article

(This article belongs to the Special Issue Recent Advances in Endometriosis Pathophysiology and Pharmacological Treatment)

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25 pages, 6928 KiB

Open AccessReview

A Lifelong Impact on Endometriosis: Pathophysiology and Pharmacological Treatment

by Liang-Hsuan Chen, Wei-Che Lo, Hong-Yuan Huang and Hsien-Ming Wu

Int. J. Mol. Sci. 2023, 24(8), 7503; https://doi.org/10.3390/ijms24087503 - 19 Apr 2023

Cited by 8 | Viewed by 10054

Abstract

Endometriosis is a chronic inflammatory disease associated with bothersome symptoms in premenopausal women and is complicated with long-term systemic impacts in the post-menopausal stage. It is generally defined by the presence of endometrial-like tissue outside the uterine cavity, which causes menstrual disorders, chronic [...] Read more.

Endometriosis is a chronic inflammatory disease associated with bothersome symptoms in premenopausal women and is complicated with long-term systemic impacts in the post-menopausal stage. It is generally defined by the presence of endometrial-like tissue outside the uterine cavity, which causes menstrual disorders, chronic pelvic pain, and infertility. Endometriotic lesions can also spread and grow in extra-pelvic sites; the chronic inflammatory status can cause systemic effects, including metabolic disorder, immune dysregulation, and cardiovascular diseases. The uncertain etiologies of endometriosis and their diverse presentations limit the treatment efficacy. High recurrence risk and intolerable side effects result in poor compliance. Current studies for endometriosis have paid attention to the advances in hormonal, neurological, and immunological approaches to the pathophysiology and their potential pharmacological intervention. Here we provide an overview of the lifelong impacts of endometriosis and summarize the updated consensus on therapeutic strategies. Full article

(This article belongs to the Special Issue Recent Advances in Endometriosis Pathophysiology and Pharmacological Treatment)

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13 pages, 862 KiB

Open AccessReview

The Main Theories on the Pathogenesis of Endometriosis

by Jelizaveta Lamceva, Romans Uljanovs and Ilze Strumfa

Int. J. Mol. Sci. 2023, 24(5), 4254; https://doi.org/10.3390/ijms24054254 - 21 Feb 2023

Cited by 43 | Viewed by 15499

Abstract

Endometriosis is a complex disease, which is defined by abnormal growth of endometrial tissue outside the uterus. It affects about 10% of women of reproductive age all over the world. Endometriosis causes symptoms that notably worsen patient’s well-being—such as severe pelvic pain, dysfunction [...] Read more.

Endometriosis is a complex disease, which is defined by abnormal growth of endometrial tissue outside the uterus. It affects about 10% of women of reproductive age all over the world. Endometriosis causes symptoms that notably worsen patient’s well-being—such as severe pelvic pain, dysfunction of the organs of pelvic cavity, infertility and secondary mental issues. The diagnosis of endometriosis is quite often delayed because of nonspecific manifestations. Since the disease was defined, several different pathogenetic pathways have been considered, including retrograde menstruation, benign metastasis, immune dysregulation, coelomic metaplasia, hormonal disbalance, involvement of stem cells and alterations in epigenetic regulation, but the true pathogenesis of endometriosis remains poorly understood. The knowledge of the exact mechanism of the origin and progression of this disease is significant for the appropriate treatment. Therefore, this review reports the main pathogenetic theories of endometriosis based on current studies. Full article

(This article belongs to the Special Issue Recent Advances in Endometriosis Pathophysiology and Pharmacological Treatment)

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16 pages, 995 KiB

Open AccessReview

Rodent Animal Models of Endometriosis-Associated Pain: Unmet Needs and Resources Available for Improving Translational Research in Endometriosis

by Miguel A. Tejada, Carles Antunez, Paulina Nunez-Badinez, Bianca De Leo, Philippa T. Saunders, Katy Vincent, Antonio Cano, Jens Nagel and Raul Gomez

Int. J. Mol. Sci. 2023, 24(3), 2422; https://doi.org/10.3390/ijms24032422 - 26 Jan 2023

Cited by 6 | Viewed by 3068

Abstract

Chronic pain induced by endometriosis is a maladaptive pain experienced by half of women with this disease. The lack of pharmacological treatments suitable for the long-term relief of endometriosis-associated pain, without an impact on fertility, remains an urgent unmet need. Progress has been [...] Read more.

Chronic pain induced by endometriosis is a maladaptive pain experienced by half of women with this disease. The lack of pharmacological treatments suitable for the long-term relief of endometriosis-associated pain, without an impact on fertility, remains an urgent unmet need. Progress has been slowed by the absence of a reproducible rodent endometriosis model that fully replicates human physiopathological characteristics, including pain symptoms. Although pain assessment in rodents is a complicated task requiring qualified researchers, the choice of the behavioral test is no less important, since selecting inappropriate tests can cause erroneous data. Pain is usually measured with reflex tests in which hypersensitivity is evaluated by applying a noxious stimulus, yet this ignores the associated emotional component that could be evaluated via non-reflex tests. We conducted a systematic review of endometriosis models used in rodents and the number of them that studied pain. The type of behavioral test used was also analyzed and classified according to reflex and non-reflex tests. Finally, we determined the most used reflex tests for the study of endometriosis-induced pain and the main non-reflex behavioral tests utilized in visceral pain that can be extrapolated to the study of endometriosis and complement traditional reflex tests. Full article

(This article belongs to the Special Issue Recent Advances in Endometriosis Pathophysiology and Pharmacological Treatment)

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17 pages, 2731 KiB

Open AccessReview

Endometriosis and Opioid Receptors: Are Opioids a Possible/Promising Treatment for Endometriosis?

by Qihui Guan, Renata Voltolini Velho, Jalid Sehouli and Sylvia Mechsner

Int. J. Mol. Sci. 2023, 24(2), 1633; https://doi.org/10.3390/ijms24021633 - 13 Jan 2023

Cited by 3 | Viewed by 3895

Abstract

Endometriosis (EM), defined as the presence of endometrial-like tissue with surrounding smooth muscle cells outside the uterus, is a disregarded gynecological disease reported to affect 6–10% of women of reproductive age, with 30–50% of them suffering from chronic pelvic pain and infertility. Since [...] Read more.

Endometriosis (EM), defined as the presence of endometrial-like tissue with surrounding smooth muscle cells outside the uterus, is a disregarded gynecological disease reported to affect 6–10% of women of reproductive age, with 30–50% of them suffering from chronic pelvic pain and infertility. Since the exact pathogenic mechanisms of EM are still unclear, no curative therapy is available. As pain is an important factor in EM, optimal analgesia should be sought, which to date has been treated primarily with non-steroidal anti-inflammatory drugs (NSAIDs), metamizole or, in extreme cases, opioids. Here, we review the pain therapy options, the mechanisms of pain development in EM, the endogenous opioid system and pain, as well as the opioid receptors and EM-associated pain. We also explore the drug abuse and addiction to opioids and the possible use of NOP receptors in terms of analgesia and improved tolerability as a target for EM-associated pain treatment. Emerging evidence has shown a promising functional profile of bifunctional NOP/MOP partial agonists as safe and nonaddictive analgesics. However, until now, the role of NOP receptors in EM has not been investigated. This review offers a thought which still needs further investigation but may provide potential options for relieving EM-associated pain. Full article

(This article belongs to the Special Issue Recent Advances in Endometriosis Pathophysiology and Pharmacological Treatment)

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