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15 pages, 4169 KiB

Open AccessArticle

A Reassessment of the Therapeutic Potential of a Dopamine Receptor 2 Agonist (D2-AG) in Endometriosis by Comparison against a Standardized Antiangiogenic Treatment

by Miguel Á. Tejada, Ana I. Santos-Llamas, María José Fernández-Ramírez, Juan J. Tarín, Antonio Cano and Raúl Gómez

Biomedicines 2021, 9(3), 269; https://doi.org/10.3390/biomedicines9030269 - 8 Mar 2021

Cited by 12 | Viewed by 2317

Abstract

Dopamine receptor 2 agonists (D2-ags) have been shown to reduce the size of tumors by targeting aberrant angiogenesis in pathological tissue. Because of this, the use of a D2-ag was inferred for endometriosis treatment. When assayed in mouse models however, D2-ags have been [...] Read more.

Dopamine receptor 2 agonists (D2-ags) have been shown to reduce the size of tumors by targeting aberrant angiogenesis in pathological tissue. Because of this, the use of a D2-ag was inferred for endometriosis treatment. When assayed in mouse models however, D2-ags have been shown to cause a shift of the immature vessels towards a more mature phenotype but not a significant reduction in the amount of vascularization and size of lesions. These has raised concerns on whether the antiangiogenic effects of these compounds confer a therapeutic value for endometriosis. In the belief that antiangiogenic effects of D2-ags in endometriosis were masked due to non-optimal timing of pharmacological interventions, herein we aimed to reassess the antiangiogenic therapeutic potential of D2-ags in vivo by administering compounds at a timeframe in which vessels in the lesions are expected to be more sensitive to antiangiogenic stimuli. To prove our point, immunodeficient (NU/NU) mice were given a D2-ag (cabergoline), anti-VEGF (CBO-P11) or vehicle (saline) compounds (n = 8 per group) starting 5 days after implantation of a fluorescently labeled human lesion. The effects on the size of the implants was estimated by monitoring the extent of fluorescence emitted by the lesion during the three-week treatment period. Subsequently mice were sacrificed and lesions excised and fixed for quantitative immunohistochemical/immunofluorescent analysis of angiogenic parameters. Lesion size, vascular density and innervation were comparable in D2-ag and anti-VEGF groups and significantly decreased when compared to control. These data suggest that D2-ags are as powerful as standard antiangiogenic compounds in interfering with angiogenesis and lesion size. Our preliminary study opens the way to further exploration of the mechanisms beneath the antiangiogenic effects of D2-ags for endometriosis treatment in humans. Full article

(This article belongs to the Special Issue Advanced Research in Endometriosis)

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13 pages, 5024 KiB

Open AccessArticle

Novel Medicine for Endometriosis and Its Therapeutic Effect in a Mouse Model

by Young Sang Kim, Yu Jin Kim, Myung Joo Kim, Sang Jin Lee, Hwang Kwon and Jae Ho Lee

Biomedicines 2020, 8(12), 619; https://doi.org/10.3390/biomedicines8120619 - 16 Dec 2020

Cited by 13 | Viewed by 10115

Abstract

Current therapeutic medicines for endometriosis cannot be administered during assisted reproductive technology (ART) because they have bad effects during pregnancy. In this study, we created an animal model of endometriosis and evaluated the therapeutic effect of progestin (Dienogest), dopamine agonist (Cabergoline), and their [...] Read more.

Current therapeutic medicines for endometriosis cannot be administered during assisted reproductive technology (ART) because they have bad effects during pregnancy. In this study, we created an animal model of endometriosis and evaluated the therapeutic effect of progestin (Dienogest), dopamine agonist (Cabergoline), and their combination (Dienogest + Cabergoline). We established a mouse model mimicking human endometriosis. The mice with endometriosis were then treated with a single drug (Dienogest or Cabergoline) or both drugs (Dienogest + Cabergoline) for 14 days. An immunohistological study was then performed to analyze inflammatory lesions in the recipient mice. Real-time polymerase chain reaction (RT-PCR) and Western blotting were also performed to determine the levels of genes and proteins in inflammatory lesions to assess the recovery of endometriosis. Histologic staining showed that all medication groups showed a clear decrease in the inflammatory phenotype in the uterus, peritoneum, and intestine. Gene and protein expression analysis showed a therapeutic effect in all medication groups. In conclusion, Cabergoline had a therapeutic effect similar to that of Dienogest and could be used as an alternative to Dienogest during ART for patients with infertility; compared to the individual drugs, the combination treatment has a synergistic effect on endometriosis. Full article

(This article belongs to the Special Issue Advanced Research in Endometriosis)

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21 pages, 5091 KiB

Open AccessArticle

Endometriosis Is Associated with a Significant Increase in hTERC and Altered Telomere/Telomerase Associated Genes in the Eutopic Endometrium, an Ex-Vivo and In Silico Study

by Rafah Alnafakh, Fiona Choi, Alice Bradfield, Meera Adishesh, Gabriele Saretzki and Dharani K. Hapangama

Biomedicines 2020, 8(12), 588; https://doi.org/10.3390/biomedicines8120588 - 9 Dec 2020

Cited by 11 | Viewed by 3250

Abstract

Telomeres protect chromosomal ends and they are maintained by the specialised enzyme, telomerase. Endometriosis is a common gynaecological disease and high telomerase activity and higher hTERT levels associated with longer endometrial telomere lengths are characteristics of eutopic secretory endometrial aberrations of women with [...] Read more.

Telomeres protect chromosomal ends and they are maintained by the specialised enzyme, telomerase. Endometriosis is a common gynaecological disease and high telomerase activity and higher hTERT levels associated with longer endometrial telomere lengths are characteristics of eutopic secretory endometrial aberrations of women with endometriosis. Our ex-vivo study examined the levels of hTERC and DKC1 RNA and dyskerin protein levels in the endometrium from healthy women and those with endometriosis (n = 117). The in silico study examined endometriosis-specific telomere- and telomerase-associated gene (TTAG) transcriptional aberrations of secretory phase eutopic endometrium utilising publicly available microarray datasets. Eutopic secretory endometrial hTERC levels were significantly increased in women with endometriosis compared to healthy endometrium, yet dyskerin mRNA and protein levels were unperturbed. Our in silico study identified 10 TTAGs (CDKN2A, PML, ZNHIT2, UBE3A, MCCC2, HSPC159, FGFR2, PIK3C2A, RALGAPA1, and HNRNPA2B1) to be altered in mid-secretory endometrium of women with endometriosis. High levels of hTERC and the identified other TTAGs might be part of the established alteration in the eutopic endometrial telomerase biology in women with endometriosis in the secretory phase of the endometrium and our data informs future research to unravel the fundamental involvement of telomerase in the pathogenesis of endometriosis. Full article

(This article belongs to the Special Issue Advanced Research in Endometriosis)

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15 pages, 3692 KiB

Open AccessArticle

The Potential Effect of Fucoidan on Inhibiting Epithelial-to-Mesenchymal Transition, Proliferation, and Increase in Apoptosis for Endometriosis Treatment: In Vivo and In Vitro Study

by Li-Chun Chang, Yi-Fen Chiang, Hsin-Yuan Chen, Yun-Ju Huang, An-Chieh Liu and Shih-Min Hsia

Biomedicines 2020, 8(11), 528; https://doi.org/10.3390/biomedicines8110528 - 22 Nov 2020

Cited by 10 | Viewed by 4594

Abstract

Endometriosis is common in reproductive-age women and its pathology is to increase proliferation and migration to enhance epithelial-to-mesenchymal transition progression (EMT). However, treatments are currently limited, so it is important to explore new therapeutic drugs. Hence, in this study, we investigate the therapeutic [...] Read more.

Endometriosis is common in reproductive-age women and its pathology is to increase proliferation and migration to enhance epithelial-to-mesenchymal transition progression (EMT). However, treatments are currently limited, so it is important to explore new therapeutic drugs. Hence, in this study, we investigate the therapeutic effect of fucoidan (FC) on the progression and mechanisms of endometriosis. The cell viability of endometrial cell lines End1/E6E7 and Vk2/E6E7 treated with different concentrations of FC were assessed by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and cell counting. Cell migration was evaluated using wound-healing assay. In an in vivo experiment, female Balb/c mice received surgically induced endometriosis followed by different concentrations of fucoidan for 6 weeks. High-frequency ultrasound imaging was applied to detect subsequent lesion growth. The results demonstrated that fucoidan inhibited the viability and migration ability of End1/E6E7 and Vk2/E6E7 cells. Additionally, the administration of fucoidan reduced the volume and weight of endometriotic lesions, decreased inflammatory cytokines and vascular endothelial growth factor (VEGF) of serum and lesions, and improved EMT proliferation and apoptosis-related protein expression. For the first time, fucoidan indicated anti-proliferative and anti-inflammatory effects as well as inhibited EMT progression and induced apoptosis, improving endometriosis. Full article

(This article belongs to the Special Issue Advanced Research in Endometriosis)

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23 pages, 3064 KiB

Open AccessArticle

Three-Dimensional Biofabrication Models of Endometriosis and the Endometriotic Microenvironment

by Jillian R. H. Wendel, Xiyin Wang, Lester J. Smith and Shannon M. Hawkins

Biomedicines 2020, 8(11), 525; https://doi.org/10.3390/biomedicines8110525 - 21 Nov 2020

Cited by 18 | Viewed by 4758

Abstract

Endometriosis occurs when endometrial-like tissue grows outside the uterine cavity, leading to pelvic pain, infertility, and increased risk of ovarian cancer. The present study describes the optimization and characterization of cellular spheroids as building blocks for Kenzan scaffold-free method biofabrication and proof-of-concept models [...] Read more.

Endometriosis occurs when endometrial-like tissue grows outside the uterine cavity, leading to pelvic pain, infertility, and increased risk of ovarian cancer. The present study describes the optimization and characterization of cellular spheroids as building blocks for Kenzan scaffold-free method biofabrication and proof-of-concept models of endometriosis and the endometriotic microenvironment. The spheroid building blocks must be of a specific diameter (~500 μm), compact, round, and smooth to withstand Kenzan biofabrication. Under optimized spheroid conditions for biofabrication, the endometriotic epithelial-like cell line, 12Z, expressed high levels of estrogen-related genes and secreted high amounts of endometriotic inflammatory factors that were independent of TNFα stimulation. Heterotypic spheroids, composed of 12Z and T-HESC, an immortalized endometrial stromal cell line, self-assembled into a biologically relevant pattern, consisting of epithelial cells on the outside of the spheroids and stromal cells in the core. 12Z spheroids were biofabricated into large three-dimensional constructs alone, with HEYA8 spheroids, or as heterotypic spheroids with T-HESC. These three-dimensional biofabricated constructs containing multiple monotypic or heterotypic spheroids represent the first scaffold-free biofabricated in vitro models of endometriosis and the endometriotic microenvironment. These efficient and innovative models will allow us to study the complex interactions of multiple cell types within a biologically relevant microenvironment. Full article

(This article belongs to the Special Issue Advanced Research in Endometriosis)

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13 pages, 2414 KiB

Open AccessArticle

Relaxin-2 May Suppress Endometriosis by Reducing Fibrosis, Scar Formation, and Inflammation

by Osamu Yoshino, Yosuke Ono, Masako Honda, Kyoko Hattori, Erina Sato, Takehiro Hiraoka, Masami Ito, Mutsumi Kobayashi, Kenta Arai, Hidekazu Katayama, Hiroyoshi Tsuchida, Kaori Yamada-Nomoto, Shunsuke Iwahata, Yoshiyuki Fukushi, Shinichiro Wada, Haruko Iwase, Kaori Koga, Yutaka Osuga, Michio Iwaoka and Nobuya Unno

Biomedicines 2020, 8(11), 467; https://doi.org/10.3390/biomedicines8110467 - 31 Oct 2020

Cited by 8 | Viewed by 3988

Abstract

Background: Relaxin (RLX)-2, produced by the corpus luteum and placenta, is known to be potentially effective in fibrotic diseases of the heart, lungs, kidneys, and bladder; however, its effectiveness in endometriosis has not yet been investigated. In the present study, we conducted a [...] Read more.

Background: Relaxin (RLX)-2, produced by the corpus luteum and placenta, is known to be potentially effective in fibrotic diseases of the heart, lungs, kidneys, and bladder; however, its effectiveness in endometriosis has not yet been investigated. In the present study, we conducted a comprehensive study on the effect of RLX-2 on endometriosis. We checked the expressions of LGR-7, a primary receptor of RLX-2, in endometriomas using immunohistochemistry. Endometriotic stromal cells (ESCs) purified from surgical specimens were used in in vitro experiments. The effects of RLX-2 on ESCs were evaluated by quantitative-PCR, ELISA, and Western blotting. Gel contraction assay was used to assess the contraction suppressive effect of RLX-2. The effect of RLX-2 was also examined in the endometriosis mouse model. LGR-7 was expressed in endometriotic lesions. In ESCs, RLX-2 increased the production of cAMP and suppressed the secretion of interleukin-8, an inflammatory cytokine, by 15% and mRNA expression of fibrosis-related molecules, plasminogen activator inhibitor-1 (PAI-1), and collagen-I by approximately 50% (p < 0.05). In the gel contraction assay, RLX-2 significantly suppressed the contraction of ESCs, which was cancelled by removing RLX-2 from the medium or by adding H89, a Protein Kinase A (PKA) inhibitor. In ESCs stimulated with RLX-2, p38 MAPK phosphorylation was significantly suppressed. In the endometriosis mouse model, administration of RLX-2 significantly decreased the area of the endometriotic-like lesion with decreasing fibrotic component compared to non-treated control (p = 0.01). RLX-2 may contribute to the control of endometriotic lesion by suppressing fibrosis, scar formation, and inflammation. Full article

(This article belongs to the Special Issue Advanced Research in Endometriosis)

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14 pages, 2748 KiB

Open AccessArticle

Iron-Storage Protein Ferritin Is Upregulated in Endometriosis and Iron Overload Contributes to a Migratory Phenotype

by Jeong-Hwa Woo, Youn Seok Choi and Jung-Hye Choi

Biomedicines 2020, 8(11), 454; https://doi.org/10.3390/biomedicines8110454 - 27 Oct 2020

Cited by 24 | Viewed by 6790

Abstract

High levels of iron in the peritoneal cavity during menstruation have been implicated in the pathogenesis of endometriosis. However, whether iron directly affects the growth or migration of human endometriotic cells is poorly understood. This study demonstrated the presence of increased levels of [...] Read more.

High levels of iron in the peritoneal cavity during menstruation have been implicated in the pathogenesis of endometriosis. However, whether iron directly affects the growth or migration of human endometriotic cells is poorly understood. This study demonstrated the presence of increased levels of the iron storage protein, ferritin, in the endometriotic tissues of patients with endometriosis. Furthermore, iron treatment stimulated the migration and epithelial–mesenchymal transition (EMT), but not growth, of 12Z human endometriotic cells. The expression of matrix metalloproteinase (MMP)-2/-9 was markedly increased through iron treatment in 12Z cells. Interestingly, intracellular reactive oxygen species (ROS) levels were significantly increased by iron in 12Z cells, and N-acetyl-L-cysteine significantly reduced iron-induced migration and MMP-2/-9 expression. Additionally, iron stimulated the activation of the NFκB pathway, and the activation was associated with iron-induced migration and MMP-2/-9 expression in 12Z cells. Moreover, iron markedly increased EMT and MMP-2/-9 expression in endometriotic lesions in an endometriosis mouse model. Taken together, these results suggest that iron may contribute to the migration abilities of human endometriotic cells via MMP expression through the ROS–NFκB pathway. Full article

(This article belongs to the Special Issue Advanced Research in Endometriosis)

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14 pages, 3510 KiB

Open AccessArticle

miR-142-3p Reduces the Size, Migration, and Contractility of Endometrial and Endometriotic Stromal Cells by Targeting Integrin- and Rho GTPase-Related Pathways That Regulate Cytoskeletal Function

by Christin S. Börschel, Anna Stejskalova, Sebastian D. Schäfer, Ludwig Kiesel and Martin Götte

Biomedicines 2020, 8(8), 291; https://doi.org/10.3390/biomedicines8080291 - 18 Aug 2020

Cited by 14 | Viewed by 6692

Abstract

Downregulated microRNA-142-3p signaling contributes to the pathogenesis of endometriosis, an invasive disease where the lining of the uterus grows at ectopic locations, by yet incompletely understood mechanisms. Using bioinformatics and in vitro assays, this study identifies cytoskeletal regulation and integrin signaling as two [...] Read more.

Downregulated microRNA-142-3p signaling contributes to the pathogenesis of endometriosis, an invasive disease where the lining of the uterus grows at ectopic locations, by yet incompletely understood mechanisms. Using bioinformatics and in vitro assays, this study identifies cytoskeletal regulation and integrin signaling as two relevant categories of miR-142-3p targets. qPCR revealed that miR-142-3p upregulation in St-T1b cells downregulates Rho-associated protein kinase 2 (ROCK2), cofilin 2 (CFL2), Ras-related C3 botulinum toxin substrate 1 (RAC1), neural Wiskott-Aldrich syndrome protein (WASL), and integrin α-V (ITGAV). qPCR and Western-blotting showed miR-142-3p effect on WASL and ITGAV was significant also in primary endometriotic stroma cells. Luciferase reporter assays in ST-T1b cells then confirmed direct regulation of ITGAV and WASL. On the functional side, miR-142-3p upregulation significantly reduced ST-T1b cell size, the size of vinculin plaques, migration through fibronectin-coated transwell filters, and the ability of ST-T1b and primary endometriotic stroma cells to contract collagen I gels. These results suggest that miR-142-3p has a strong mechanoregulatory effect on endometrial stroma cells and its external administration reduces the invasive endometrial phenotype. Within the limits of an in vitro investigation, our study provides new mechanistic insights into the pathogenesis of endometriosis and provides a perspective for the development of miR-142-3p based drugs for inhibiting invasive growth of endometriotic cells. Full article

(This article belongs to the Special Issue Advanced Research in Endometriosis)

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Review

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22 pages, 1900 KiB

Open AccessReview

Getting to Know Endometriosis-Related Infertility Better: A Review on How Endometriosis Affects Oocyte Quality and Embryo Development

by Mara Simopoulou, Anna Rapani, Sokratis Grigoriadis, Agni Pantou, Petroula Tsioulou, Evangelos Maziotis, Despina Tzanakaki, Olga Triantafyllidou, Theodoros Kalampokas, Charalampos Siristatidis, Panagiotis Bakas and Nikolaos Vlahos

Biomedicines 2021, 9(3), 273; https://doi.org/10.3390/biomedicines9030273 - 9 Mar 2021

Cited by 23 | Viewed by 6672

Abstract

Endometriosis-related infertility describes a case of deteriorated fecundity when endometriosis is diagnosed. Numerous mechanisms have been proposed in an effort to delineate the multifaceted pathophysiology that induces impairment of reproductive dynamics in patients with endometriosis. In this critical analysis, authors present the plethora [...] Read more.

Endometriosis-related infertility describes a case of deteriorated fecundity when endometriosis is diagnosed. Numerous mechanisms have been proposed in an effort to delineate the multifaceted pathophysiology that induces impairment of reproductive dynamics in patients with endometriosis. In this critical analysis, authors present the plethora of molecular events that are entailed and elaborate on how they potentially impair the oocyte’s and embryo’s competence in patients with endometriosis. Reactive oxygen species, dysregulation of the immune system and cellular architectural disruption constitute the crucial mechanisms that detrimentally affect oocyte and embryo developmental potential. The molecular level impairment of the reproductive tissue is discussed, since differentiation, proliferation and apoptosis constitute focal regulatory cellular functions that appear severely compromised in cases of endometriosis. Mapping the precise molecular mechanisms entailed in endometriosis-related infertility may help delineate the complex nature of the disorder and bring us a step closer to a more personalized approach in understanding, diagnosing and managing endometriosis-related infertility. Full article

(This article belongs to the Special Issue Advanced Research in Endometriosis)

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18 pages, 852 KiB

Open AccessReview

Inflammatory Mediators and Pain in Endometriosis: A Systematic Review

by Nikolaos Machairiotis, Sofia Vasilakaki and Nikolaos Thomakos

Biomedicines 2021, 9(1), 54; https://doi.org/10.3390/biomedicines9010054 - 8 Jan 2021

Cited by 80 | Viewed by 8208

Abstract

Background: pain is one of the main symptoms of endometriosis and it has a deleterious effect on a patients’ personal and social life. To date, the clinical management of pain includes prolonged medication use and, in some cases, surgery, both of which are [...] Read more.

Background: pain is one of the main symptoms of endometriosis and it has a deleterious effect on a patients’ personal and social life. To date, the clinical management of pain includes prolonged medication use and, in some cases, surgery, both of which are disruptive events for patients. Hence, there is an urgency for the development of a sufficient non-invasive medical treatment. Inflammation is one of the causative factors of pain in endometriosis. It is well established that inflammatory mediators promote angiogenesis and interact with the sensory neurons inducing the pain signal; the threshold of pain varies and it depends on the state and location of the disease. The inhibition of inflammatory mediators’ synthesis might offer a novel and effective treatment of the pain that is caused by inflammation in endometriosis. Objectives: patients with endometriosis experience chronic pelvic pain, which is moderate to severe in terms of intensity. The objective of this systematic review is to highlight the inflammatory mediators that contribute to the induction of pain in endometriosis and present their biological mechanism of action. In addition, the authors aim to identify new targets for the development of novel treatments for chronic pelvic pain in patients with endometriosis. Data Sources: three databases (PubMed, Scopus, and Europe PMC) were searched in order to retrieve articles with the keywords ‘inflammation, pain, and endometriosis’ between the review period of 1 January 2016 to 31 December 2020. This review has been registered with PROSPERO (registry number: CRD42020171018). Eligibility Criteria: only original articles that presented the regulation of inflammatory mediators and related biological molecules in endometriosis and their contribution in the stimulation of pain signal were included. Data Extraction: two authors independently extracted data from articles, using predefined criteria. Results: the database search yielded 1871 articles, which were narrowed down to 56 relevant articles of interest according to the eligibility criteria. Conclusions: inflammatory factors that promote angiogenesis and neuroangiogenesis are promising targets for the treatment of inflammatory pain in endometriosis. Specifically, CXC chemokine family, chemokine fractalkine, and PGE₂ have an active role in the induction of pain. Additionally, IL-1β appears to be the primary interleukin (IL), which stimulates the majority of the inflammatory factors that contribute to neuroangiogenesis along with IL-6. Finally, the role of Ninj1 and BDNF proteins needs further investigation. Full article

(This article belongs to the Special Issue Advanced Research in Endometriosis)

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12 pages, 2309 KiB

Open AccessReview

Ovariopexy—Before and after Endometriosis Surgery

by Juhi Dhanawat, Julian Pape, Damaris Freytag, Nicolai Maass and Ibrahim Alkatout

Biomedicines 2020, 8(12), 533; https://doi.org/10.3390/biomedicines8120533 - 25 Nov 2020

Cited by 9 | Viewed by 6651

Abstract

Endometriosis surgery is often very challenging. Key to complete resection of endometriosis is access to the retroperitoneum. Endometriosis can involve the ureter and uterine vessels, and ovary on the lateral pelvic wall makes retroperitoneal access difficult. Primary and post-surgical adhesions prevalence in endometriosis [...] Read more.

Endometriosis surgery is often very challenging. Key to complete resection of endometriosis is access to the retroperitoneum. Endometriosis can involve the ureter and uterine vessels, and ovary on the lateral pelvic wall makes retroperitoneal access difficult. Primary and post-surgical adhesions prevalence in endometriosis is very high. Ovariopexy, transposition of ovaries temporarily, is done for better surgical access and to reduce postoperative adhesions. We concluded that although limited evidence, ovariopexy is an excellent tool to aid endometriosis surgery and prevent postoperative adhesions. It is cost effective, simple and complication rate almost nil. More robust trials are required to substantiate evidence for its impact on preventing postoperative adhesions and its effect on fertility. In this review, we describe our technique of ovariopexy supplemented with a video, with the aim to put light on this useful and important technique, which is beneficial both for surgeons and patients. Full article

(This article belongs to the Special Issue Advanced Research in Endometriosis)

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