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Endometriosis: Biological Targets and New Therapeutical Approaches

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

Deadline for manuscript submissions: closed (31 August 2021) | Viewed by 83416

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Special Issue Editors

Prof. Dr. Jacques Donnez

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Guest Editor

Department of Gynaecology, Université Catholique de Louvain, 1200 Brussels, Belgium
Interests: fertility preservation; ovarian tissue cryopreservation; ovarian tissue transplantation; endometriosis; uterine adenomyosis; uterine fibroids
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Dr. Luciana Cacciottola

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Co-Guest Editor

Gynecology Research Unit, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Av. Mounier 52, 1200 Brussels, Belgium
Interests: fertility preservation; ovarian tissue cryopreservation; gynecological endocrinology

Special Issue Information

Dear Colleagues,

As you undoubtedly know, endometriosis is a chronic inflammatory disease affecting 5–10% of women, causing significant impairment to their fertility potential and quality of life. After its very first description, many attempts have been made to elucidate its pathogenesis in order to determine the most appropriate treatment. However, the pathogenesis of endometriosis, which appears to be multifactorial, has still not been clearly defined.

The aim of this Special Issue is to provide a valuable update on ongoing investigations into new biological targets in the wake of recent findings on various pathophysiological aspects of this condition, such as genetics, inflammation, oxidative stress, and hormone sensitivity. New insights into these different aspects allow development of novel therapeutic approaches, not only to treat endometriosis-related symptoms like chronic pain and infertility, but also act on the progression of the disease itself.

Potential contributors are invited to submit their work on new biological targets and their potential application in clinical practice. Papers on the development of novel pharmacotherapies based on new or well-known biological targets of endometriosis are particularly welcome, looking to broaden treatment options in the near future.

Prof. Dr. Jacques Donnez
Guest Editor
Dr. Luciana Cacciottola
Co-Guest Editor

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Keywords

Endometriosis
Inflammation
Adenomyosis
Hormonal treatment
GnRH antagonists
Genetics
Microbiota
Oxidative stress

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Published Papers (10 papers)

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Editorial

Jump to: Research, Review

5 pages, 193 KiB

Open AccessEditorial

Endometriosis: An Inflammatory Disease That Requires New Therapeutic Options

by Jacques Donnez and Luciana Cacciottola

Int. J. Mol. Sci. 2022, 23(3), 1518; https://doi.org/10.3390/ijms23031518 - 28 Jan 2022

Cited by 21 | Viewed by 3391

Abstract

Endometriosis, defined as the presence of endometrium-like tissue outside the uterus, is estimated to affect 10% of women of reproductive age [...] Full article

(This article belongs to the Special Issue Endometriosis: Biological Targets and New Therapeutical Approaches)

Research

Jump to: Editorial, Review

14 pages, 1818 KiB

Open AccessArticle

N-Acyl Dopamines Induce Apoptosis in Endometrial Stromal Cells from Patients with Endometriosis

by Alina M. Gamisonia, Marina N. Yushina, Irina A. Fedorova-Gogolina, Mikhail G. Akimov, Chupalav M. Eldarov, Stanislav V. Pavlovich, Vladimir V. Bezuglov, Natalia M. Gretskaya, Gennady T. Sukhikh and Mikhail Yu. Bobrov

Int. J. Mol. Sci. 2021, 22(19), 10648; https://doi.org/10.3390/ijms221910648 - 30 Sep 2021

Cited by 6 | Viewed by 2159

Abstract

Endometriosis is characterized by the formation and development of endometrial tissues outside the uterus, based on an imbalance between proliferation and cell death, leading to the uncontrolled growth of ectopic foci. The potential target for the regulation of these processes is the endocannabinoid system, which was found to be involved in the migration, proliferation, and survival of tumor cells. In this paper, we investigated the effect of endocannabinoid-like compounds from the N-acyl dopamine (NADA) family on the viability of stromal cells from ectopic and eutopic endometrium of patients with ovarian endometriosis. N-arachidonoyldopamine, N-docosahexaenoyldopamine, and N-oleoyldopamine have been shown to have a five-times-more-selective cytotoxic effect on endometrioid stromal cells. To study the mechanisms of the toxic effect, inhibitory analysis, measurements of caspase-3/9 activity, reactive oxygen species, and the mitochondrial membrane potential were performed. It was found that NADA induced apoptosis via an intrinsic pathway through the CB1 receptor and downstream serine palmitoyltransferase, NO synthase activation, increased ROS production, and mitochondrial dysfunction. The higher selectivity of NADA for endometriotic stromal cells and the current lack of effective drug treatment can be considered positive factors for further research of these compounds as possible therapeutic agents against endometriosis. Full article

(This article belongs to the Special Issue Endometriosis: Biological Targets and New Therapeutical Approaches)

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12 pages, 1420 KiB

Open AccessArticle

Autophagy and Mitophagy Promotion in a Rat Model of Endometriosis

by Rosalba Siracusa, Ramona D’Amico, Daniela Impellizzeri, Marika Cordaro, Alessio Filippo Peritore, Enrico Gugliandolo, Rosalia Crupi, Angela Trovato Salinaro, Emanuela Raffone, Tiziana Genovese, Salvatore Cuzzocrea, Roberta Fusco and Rosanna Di Paola

Int. J. Mol. Sci. 2021, 22(10), 5074; https://doi.org/10.3390/ijms22105074 - 11 May 2021

Cited by 35 | Viewed by 3610

Abstract

Endometriosis is a gynecological condition affecting patients in reproductive age. The aim of this paper was to assess the effects of the autophagy and mitophagy induction in a rat model of endometriosis. Endometriosis was induced by the injection of uterine fragments, and rapamycin (0. 5 mg/kg) was administered once per week. One week from the induction, rats were sacrificed, and laparotomy was performed to collect the endometriotic implants and to further process them for molecular analysis. Western blot analysis was conducted on explanted lesions to evaluate the autophagy pathway during the pathology. Elevated phospho-serine/threonine kinase (p-AKT) and mammalian target of rapamycin (mTOR) expressions were detected in vehicle-treated rats, while Beclin and microtubule-associated protein 1A/1B-light chain 3 II (LC3II) expressions were low. Additionally, samples collected from vehicle groups indicated low Bnip3, Ambra1, and Parkin expressions, demonstrating impaired autophagy and mitophagy. Rapamycin administration reduced p-AKT and mTOR expressions and increased Beclin and LC3II, Bnip3, Ambra1, and Parkin expressions, activating both mechanisms. We also evaluated the impact of the impaired autophagy and mitophagy pathways on apoptosis and angiogenesis. Rapamycin was administered by activating autophagy and mitophagy, which increased apoptosis (assessed by Western blot analysis of Bcl-2, Bax, and Cleaved-caspase 3) and reduced angiogenesis (assessed by immunohistochemical analysis of vascular endothelial grow factor (VEGF) and CD34) in the lesions. All of these mechanisms activated by the induction of the autophagy and mitophagy pathways led to the reduction in the lesions’ volume, area and diameter. Full article

(This article belongs to the Special Issue Endometriosis: Biological Targets and New Therapeutical Approaches)

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Review

Jump to: Editorial, Research

14 pages, 565 KiB

Open AccessReview

Pathogenesis of Endometriosis: New Insights into Prospective Therapies

by Radhika Kapoor, Christina Anna Stratopoulou and Marie-Madeleine Dolmans

Int. J. Mol. Sci. 2021, 22(21), 11700; https://doi.org/10.3390/ijms222111700 - 28 Oct 2021

Cited by 63 | Viewed by 6387

Abstract

Endometriosis is a female reproductive disorder characterized by growth of uterine cells and tissue in distant sites. Around 2–10% of women experience this condition during reproductive age, 35–50% of whom encounter fertility issues or pain. To date, there are no established methods for its early diagnosis and treatment, other than surgical procedures and scans. It is difficult to identify the disease at its onset, unless symptoms such as infertility and/or pain are present. Determining the mechanisms involved in its pathogenesis is vital, not only to pave the way for early identification, but also for disease management and development of less invasive but successful treatment strategies. Endometriosis is characterized by cell proliferation, propagation, evasion of immunosurveillance, and invasive metastasis. This review reports the underlying mechanisms that are individually or collectively responsible for disease establishment and evolution. Treatment of endometriosis mainly involves hormone therapies, which may be undesirable or have their own repercussions. It is therefore important to devise alternative strategies that are both effective and cause fewer side effects. Use of phytochemicals may be one of them. This review focuses on pharmacological inhibitors that can be therapeutically investigated in terms of their effects on signaling pathways and/or mechanisms involved in the pathogenesis of endometriosis. Full article

(This article belongs to the Special Issue Endometriosis: Biological Targets and New Therapeutical Approaches)

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15 pages, 2532 KiB

Open AccessReview

GnRH Antagonists with or without Add-Back Therapy: A New Alternative in the Management of Endometriosis?

by Jacques Donnez and Marie-Madeleine Dolmans

Int. J. Mol. Sci. 2021, 22(21), 11342; https://doi.org/10.3390/ijms222111342 - 20 Oct 2021

Cited by 28 | Viewed by 7944

Abstract

To evaluate the effectiveness of a new class of medical drugs, namely oral gonadotropin-releasing hormone (GnRH) antagonists, in the management of premenopausal women with endometriosis-associated pelvic pain. We reviewed the most relevant papers (n = 27) on the efficacy of new medical alternatives (oral GnRH antagonists) as therapy for endometriosis. We first briefly summarized the concept of progesterone resistance and established that oral contraceptives and progestogens work well in two-thirds of women suffering from endometriosis. Since clinical evidence shows that estrogens play a critical role in the pathogenesis of the disease, lowering their levels with oral GnRH antagonists may well prove effective, especially in women who fail to respond to progestogens. There is a need for reliable long-term oral treatment capable of managing endometriosis symptoms, taking into consideration both the main symptoms and phenotype of the disease. Published studies reviewed and discussed here confirm the efficacy of GnRH antagonists. There is a place for GnRH antagonists in the management of symptomatic endometriosis. Novel algorithms that take into account the different phenotypes are proposed. Full article

(This article belongs to the Special Issue Endometriosis: Biological Targets and New Therapeutical Approaches)

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16 pages, 2757 KiB

Open AccessReview

Ectopic Endometrium: The Pathologist’s Perspective

by Alessandra Camboni and Etienne Marbaix

Int. J. Mol. Sci. 2021, 22(20), 10974; https://doi.org/10.3390/ijms222010974 - 11 Oct 2021

Cited by 17 | Viewed by 9180

Abstract

Endometriosis and adenomyosis are two frequent diseases closely linked, characterized by ectopic endometrium. Despite their benign nature, endometriosis and adenomyosis impair women’s quality of life by causing pain and infertility and an increase in the incidence of gynecological malignancies has been reported. Since the first description of ectopic endometrium in 1860, different attempts have been made to describe, classify and understand the origin of these diseases. Several theories have been proposed to describe the pathogenic mechanism leading to the development of adenomyosis or endometriosis. However, all the hypotheses show some limitations in explaining all the different aspects and manifestations of these diseases. Despite the remarkable progress made over recent years, the pathogeneses of endometriosis and adenomyosis remain unclear. Moreover, because of the lack of standardized protocols and diagnostic criteria in pathology practice it is difficult to study and to classify these disorders. The goal of this review is to summarize the pathological aspects of adenomyosis and endometriosis, spanning a historical perspective to newly reported data. Full article

(This article belongs to the Special Issue Endometriosis: Biological Targets and New Therapeutical Approaches)

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18 pages, 2778 KiB

Open AccessReview

New Therapeutics in Endometriosis: A Review of Hormonal, Non-Hormonal, and Non-Coding RNA Treatments

by Geraldine Brichant, Ines Laraki, Laurie Henry, Carine Munaut and Michelle Nisolle

Int. J. Mol. Sci. 2021, 22(19), 10498; https://doi.org/10.3390/ijms221910498 - 28 Sep 2021

Cited by 34 | Viewed by 8241

Abstract

Endometriosis is defined as endometrial-like tissue outside the uterine cavity. It is a chronic inflammatory estrogen-dependent disease causing pain and infertility in about 10% of women of reproductive age. Treatment nowadays consists of medical and surgical therapies. Medical treatments are based on painkillers and hormonal treatments. To date, none of the medical treatments have been able to cure the disease and symptoms recur as soon as the medication is stopped. The development of new biomedical targets, aiming at the cellular and molecular mechanisms responsible for endometriosis, is needed. This article summarizes the most recent medications under investigation in endometriosis treatment with an emphasis on non-coding RNAs that are emerging as key players in several human diseases, including cancer and endometriosis. Full article

(This article belongs to the Special Issue Endometriosis: Biological Targets and New Therapeutical Approaches)

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16 pages, 754 KiB

Open AccessReview

Genetics and Inflammation in Endometriosis: Improving Knowledge for Development of New Pharmacological Strategies

by Elisa Giacomini, Sabrina Minetto, Letizia Li Piani, Luca Pagliardini, Edgardo Somigliana and Paola Viganò

Int. J. Mol. Sci. 2021, 22(16), 9033; https://doi.org/10.3390/ijms22169033 - 21 Aug 2021

Cited by 43 | Viewed by 5008

Abstract

According to a rich body of literature, immune cell dysfunctions, both locally and systemically, and an inflammatory environment characterize all forms of endometriosis. Alterations in transcripts and proteins involved in the recruitment of immune cells, in the interaction between cytokines and their receptors, cellular adhesion and apoptosis have been demonstrated in endometriotic lesions. The objective of this narrative review is to provide an overview of the components and mechanisms at the intersection between inflammation and genetics that may constitute vanguard therapeutic approaches in endometriosis. The GWAS technology and pathway-based analysis highlighted the role of the MAPK and the WNT/β-catenin cascades in the pathogenesis of endometriosis. These signaling pathways have been suggested to interfere with the disease establishment via several mechanisms, including apoptosis, migration and angiogenesis. Extracellular vesicle-associated molecules may be not only interesting to explain some aspects of endometriosis progression, but they may also serve as therapeutic regimens per se. Immune/inflammatory dysfunctions have always represented attractive therapeutic targets in endometriosis. These would be even more interesting if genetic evidence supported the involvement of functional pathways at the basis of these alterations. Targeting these dysfunctions through next-generation inhibitors can constitute a therapeutic alternative for endometriosis. Full article

(This article belongs to the Special Issue Endometriosis: Biological Targets and New Therapeutical Approaches)

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18 pages, 16613 KiB

Open AccessReview

Can Endometriosis-Related Oxidative Stress Pave the Way for New Treatment Targets?

by Luciana Cacciottola, Jacques Donnez and Marie-Madeleine Dolmans

Int. J. Mol. Sci. 2021, 22(13), 7138; https://doi.org/10.3390/ijms22137138 - 1 Jul 2021

Cited by 54 | Viewed by 10926

Abstract

Endometriosis is a disease of reproductive age characterized by chronic pelvic pain and infertility. Its pathogenesis is complex and still partially unexplained. However, there is increasing evidence of the role of chronic inflammation, immune system dysregulation, and oxidative stress in its development and progression. The latter appears to be involved in multiple aspects of the disease. Indeed, disease progression sustained by a hyperproliferative phenotype can be related to reactive oxygen species (ROS) imbalance, as numerous experiments using drugs to counteract hyperproliferation have shown in recent years. Chronic pelvic pain is also associated with cell function dysregulation favoring chronic inflammation and oxidative stress, specifically involving macrophages and mast cell activation. Moreover, there is increasing evidence of a role for ROS and impaired mitochondrial function not only as deleterious effectors of the ovarian reserve in patients with endometriomas but also in terms of oocyte quality and, hence, embryo development impairment. Targeting oxidative stress looks to be a promising strategy to both curb endometriotic lesion progression and alleviate endometriosis-associated symptoms of chronic pain and infertility. More investigations are nevertheless needed to develop effective therapeutic strategies for clinical application. Full article

(This article belongs to the Special Issue Endometriosis: Biological Targets and New Therapeutical Approaches)

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23 pages, 4720 KiB

Open AccessReview

Intricate Connections between the Microbiota and Endometriosis

by Irene Jiang, Paul J. Yong, Catherine Allaire and Mohamed A. Bedaiwy

Int. J. Mol. Sci. 2021, 22(11), 5644; https://doi.org/10.3390/ijms22115644 - 26 May 2021

Cited by 86 | Viewed by 24431

Abstract

Imbalances in gut and reproductive tract microbiota composition, known as dysbiosis, disrupt normal immune function, leading to the elevation of proinflammatory cytokines, compromised immunosurveillance and altered immune cell profiles, all of which may contribute to the pathogenesis of endometriosis. Over time, this immune dysregulation can progress into a chronic state of inflammation, creating an environment conducive to increased adhesion and angiogenesis, which may drive the vicious cycle of endometriosis onset and progression. Recent studies have demonstrated both the ability of endometriosis to induce microbiota changes, and the ability of antibiotics to treat endometriosis. Endometriotic microbiotas have been consistently associated with diminished Lactobacillus dominance, as well as the elevated abundance of bacterial vaginosis-related bacteria and other opportunistic pathogens. Possible explanations for the implications of dysbiosis in endometriosis include the Bacterial Contamination Theory and immune activation, cytokine-impaired gut function, altered estrogen metabolism and signaling, and aberrant progenitor and stem-cell homeostasis. Although preliminary, antibiotic and probiotic treatments have demonstrated efficacy in treating endometriosis, and female reproductive tract (FRT) microbiota sampling has successfully predicted disease risk and stage. Future research should aim to characterize the “core” upper FRT microbiota and elucidate mechanisms behind the relationship between the microbiota and endometriosis. Full article

(This article belongs to the Special Issue Endometriosis: Biological Targets and New Therapeutical Approaches)

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