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1.
Trends Mol Med ; 2024 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-38991858

RESUMO

Endometriosis is a common disorder associated with pain, gastrointestinal and urinary symptoms, infertility, and fatigue. It is defined by the presence of endometrial-like lesions found predominantly in the pelvis. Mechanisms that contribute to disease aetiology include changes in hormonal, inflammatory, and pain pathways. In this article, we focus on recent developments in imaging technologies, on our improved understanding of mechanisms contributing to infertility, on drug therapies that are in clinical trials, and on insights from studies on the gut that offer potential to support self-management strategies. We postulate that improvements in the quality of life of patients will be accelerated by reframing endometriosis as a multi-system disorder and learning from treatments targeting symptoms shared between endometriosis, neuroinflammatory, and gastrointestinal disorders.

2.
Cell Rep Med ; 5(6): 101596, 2024 Jun 18.
Artigo em Inglês | MEDLINE | ID: mdl-38897171

RESUMO

Endometriosis is a chronic disorder with debilitating symptoms that is difficult to diagnose and treat. Advances in imaging technologies and strategies for the management of symptoms are improving the quality of life of patients by reducing the time taken for diagnosis and offering a more balanced approach to therapy.


Assuntos
Endometriose , Endometriose/diagnóstico , Endometriose/terapia , Endometriose/patologia , Humanos , Feminino , Qualidade de Vida
3.
Reprod Fertil ; 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38739749

RESUMO

Endometriosis is a chronic inflammatory condition affecting one in 10 women and those assigned female at birth, defined by the presence of endometrial-like tissue outside the uterus. It is commonly associated with pain, infertility, and mood disorders, and often comorbid with other chronic pain conditions, such as irritable bowel syndrome. Recent research has identified a key role for the microbiota-gut-brain axis in health and a range of inflammatory and neurological disorders, prompting an exploration of its potential mechanistic role in endometriosis. Increased awareness of the impact of the gut microbiota within the patient community, combined with the often-detrimental side effects of current therapies, has motivated many to utilise self-management strategies, such as dietary modification and supplements, despite a lack of robust clinical evidence. Current research has characterised the gut microbiota in endometriosis patients and animal models. However, small cohorts and differing methodology has resulted in little consensus in the data. In this narrative review, we summarise research studies that have investigated the role of gut microbiota and their metabolic products in the development and progression of endometriosis lesions, before summarising insights from research into co-morbid conditions and discussing the reported impact of self-management strategies on symptoms of endometriosis. Finally, we suggest ways in which this promising field of research could be expanded to explore the role of specific bacteria, improve access to 'microbial' phenotyping, and to develop personalised patient advice for reduction of symptoms such as chronic pain and bloating.

4.
bioRxiv ; 2024 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-38746109

RESUMO

KIR3DL1 is a polymorphic inhibitory Natural Killer (NK) cell receptor that recognizes Human Leukocyte Antigen (HLA) class I allotypes that contain the Bw4 motif. Structural analyses have shown that in addition to residues 77-83 that span the Bw4 motif, polymorphism at other sites throughout the HLA molecule can influence the interaction with KIR3DL1. Given the extensive polymorphism of both KIR3DL1 and HLA class I, we built a machine learning prediction model to describe the influence of allotypic variation on the binding of KIR3DL1 to HLA class I. Nine KIR3DL1 tetramers were screened for reactivity against a panel of HLA class I molecules which revealed different patterns of specificity for each KIR3DL1 allotype. Separate models were trained for each of KIR3DL1 allotypes based on the full amino sequence of exons 2 and 3 encoding the α1 and α2 domains of the class I HLA allotypes, the set of polymorphic positions that span the Bw4 motif, or the positions that encode α1 and α2 but exclude the connecting loops. The Multi-Label-Vector-Optimization (MLVO) model trained on all alpha helix positions performed best with AUC scores ranging from 0.74 to 0.974 for the 9 KIR3DL1 allotype models. We show that a binary division into binder and non-binder is not precise, and that intermediate levels exist. Using the same models, within the binder group, high- and low-binder categories can also be predicted, the regions in HLA affecting the high vs low binder being completely distinct from the classical Bw4 motif. We further show that these positions affect binding affinity in a nonadditive way and induce deviations from linear models used to predict interaction strength. We propose that this approach should be used in lieu of simpler binding models based on a single HLA motif.

5.
Cell Rep Med ; 4(11): 101288, 2023 11 21.
Artigo em Inglês | MEDLINE | ID: mdl-37992677

RESUMO

Patients with endometriosis often report gastrointestinal symptoms in addition to those usually considered hallmarks of the disorder (pain and infertility). Yang et al.1 identify genetic risk factors that can contribute to a shared disease etiology, providing new opportunities for improvements in disease management.


Assuntos
Endometriose , Gastroenteropatias , Infertilidade Feminina , Feminino , Humanos , Endometriose/genética , Endometriose/complicações , Endometriose/diagnóstico , Infertilidade Feminina/etiologia , Gastroenteropatias/genética , Gastroenteropatias/complicações
6.
Cell Rep Med ; 4(9): 101192, 2023 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-37729869

RESUMO

Endometriosis is a common chronic pain condition with no known cure and limited treatment options. Digital technologies, ranging from smartphone apps to wearable sensors, have shown potential toward facilitating chronic pain assessment and management; however, to date, many of these tools have not been specifically deployed or evaluated in patients with endometriosis-associated pain. Informed by previous studies in related chronic pain conditions, we discuss how digital technologies may be used in endometriosis to facilitate objective, continuous, and holistic symptom tracking. We postulate that these pervasive and increasingly affordable technologies present promising opportunities toward developing decision-support tools assisting healthcare professionals and empowering patients with endometriosis to make better-informed choices about symptom management.


Assuntos
Dor Crônica , Endometriose , Feminino , Humanos , Endometriose/diagnóstico , Tecnologia Digital , Pessoal de Saúde
7.
Commun Biol ; 6(1): 780, 2023 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-37587191

RESUMO

Endometriosis is a leading cause of pain and infertility affecting millions of women globally. Herein, we characterize variation in DNA methylation (DNAm) and its association with menstrual cycle phase, endometriosis, and genetic variants through analysis of genotype data and methylation in endometrial samples from 984 deeply-phenotyped participants. We estimate that 15.4% of the variation in endometriosis is captured by DNAm and identify significant differences in DNAm profiles associated with stage III/IV endometriosis, endometriosis sub-phenotypes and menstrual cycle phase, including opening of the window for embryo implantation. Menstrual cycle phase was a major source of DNAm variation suggesting cellular and hormonally-driven changes across the cycle can regulate genes and pathways responsible for endometrial physiology and function. DNAm quantitative trait locus (mQTL) analysis identified 118,185 independent cis-mQTLs including 51 associated with risk of endometriosis, highlighting candidate genes contributing to disease risk. Our work provides functional evidence for epigenetic targets contributing to endometriosis risk and pathogenesis. Data generated serve as a valuable resource for understanding tissue-specific effects of methylation on endometrial biology in health and disease.


Assuntos
Endometriose , Feminino , Humanos , Endometriose/genética , Metilação de DNA , Dor , Implantação do Embrião
8.
Nat Immunol ; 24(7): 1052-1053, 2023 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-37308666
9.
Cells ; 12(12)2023 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-37371074

RESUMO

The liver performs a multitude of bodily functions, whilst retaining the ability to regenerate damaged tissue. In this review, we discuss sex steroid biology, regulation of mammalian liver physiology and the development of new model systems to improve our understanding of liver biology in health and disease. A major risk factor for the development of liver disease is hepatic fibrosis. Key drivers of this process are metabolic dysfunction and pathologic activation of the immune system. Although non-alcoholic fatty liver disease (NAFLD) is largely regarded as benign, it does progress to non-alcoholic steatohepatitis in a subset of patients, increasing their risk of developing cirrhosis and hepatocellular carcinoma. NAFLD susceptibility varies across the population, with obesity and insulin resistance playing a strong role in the disease development. Additionally, sex and age have been identified as important risk factors. In addition to the regulation of liver biochemistry, sex hormones also regulate the immune system, with sexual dimorphism described for both innate and adaptive immune responses. Therefore, sex differences in liver metabolism, immunity and their interplay are important factors to consider when designing, studying and developing therapeutic strategies to treat human liver disease. The purpose of this review is to provide the reader with a general overview of sex steroid biology and their regulation of mammalian liver physiology.


Assuntos
Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Animais , Humanos , Feminino , Masculino , Hepatopatia Gordurosa não Alcoólica/metabolismo , Cirrose Hepática/patologia , Hormônios Esteroides Gonadais , Esteroides , Mamíferos
11.
Int J Mol Sci ; 24(3)2023 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-36768741

RESUMO

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.


Assuntos
Dor Crônica , Endometriose , Dor Visceral , Animais , Feminino , Humanos , Endometriose/complicações , Endometriose/diagnóstico , Pesquisa Translacional Biomédica , Dor Crônica/complicações , Modelos Animais
12.
Front Endocrinol (Lausanne) ; 13: 1027164, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36465608

RESUMO

Decidualization is the hormone-dependent process of endometrial remodeling that is essential for fertility and reproductive health. It is characterized by dynamic changes in the endometrial stromal compartment including differentiation of fibroblasts, immune cell trafficking and vascular remodeling. Deficits in decidualization are implicated in disorders of pregnancy such as implantation failure, intra-uterine growth restriction, and pre-eclampsia. Androgens are key regulators of decidualization that promote optimal differentiation of stromal fibroblasts and activation of downstream signaling pathways required for endometrial remodeling. We have shown that androgen biosynthesis, via 5α-reductase-dependent production of dihydrotestosterone, is required for optimal decidualization of human stromal fibroblasts in vitro, but whether this is required for decidualization in vivo has not been tested. In the current study we used steroid 5α-reductase type 1 (SRD5A1) deficient mice (Srd5a1-/- mice) and a validated model of induced decidualization to investigate the role of SRD5A1 and intracrine androgen signaling in endometrial decidualization. We measured decidualization response (weight/proportion), transcriptomic changes, and morphological and functional parameters of vascular development. These investigations revealed a striking effect of 5α-reductase deficiency on the decidualization response. Furthermore, vessel permeability and transcriptional regulation of angiogenesis signaling pathways, particularly those that involved vascular endothelial growth factor (VEGF), were disrupted in the absence of 5α-reductase. In Srd5a1-/- mice, injection of dihydrotestosterone co-incident with decidualization restored decidualization responses, vessel permeability, and expression of angiogenesis genes to wild type levels. Androgen availability declines with age which may contribute to age-related risk of pregnancy disorders. These findings show that intracrine androgen signaling is required for optimal decidualization in vivo and confirm a major role for androgens in the development of the vasculature during decidualization through regulation of the VEGF pathway. These findings highlight new opportunities for improving age-related deficits in fertility and pregnancy health by targeting androgen-dependent signaling in the endometrium.


Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase , Decídua , Remodelação Vascular , Animais , Feminino , Camundongos , Gravidez , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , 3-Oxo-5-alfa-Esteroide 4-Desidrogenase/metabolismo , Androgênios/farmacologia , Colestenona 5 alfa-Redutase/genética , Colestenona 5 alfa-Redutase/metabolismo , Decídua/efeitos dos fármacos , Decídua/metabolismo , Di-Hidrotestosterona/farmacologia , Endométrio/efeitos dos fármacos , Endométrio/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Remodelação Vascular/efeitos dos fármacos , Remodelação Vascular/genética , Remodelação Vascular/fisiologia
13.
Elife ; 112022 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-36524724

RESUMO

The human endometrium experiences repetitive cycles of tissue wounding characterised by piecemeal shedding of the surface epithelium and rapid restoration of tissue homeostasis. In this study, we used a mouse model of endometrial repair and three transgenic lines of mice to investigate whether epithelial cells that become incorporated into the newly formed luminal epithelium have their origins in one or more of the mesenchymal cell types present in the stromal compartment of the endometrium. Using scRNAseq, we identified a novel population of PDGFRb + mesenchymal stromal cells that developed a unique transcriptomic signature in response to endometrial breakdown/repair. These cells expressed genes usually considered specific to epithelial cells and in silico trajectory analysis suggested they were stromal fibroblasts in transition to becoming epithelial cells. To confirm our hypothesis we used a lineage tracing strategy to compare the fate of stromal fibroblasts (PDGFRa+) and stromal perivascular cells (NG2/CSPG4+). We demonstrated that stromal fibroblasts can undergo a mesenchyme to epithelial transformation and become incorporated into the re-epithelialised luminal surface of the repaired tissue. This study is the first to discover a novel population of wound-responsive, plastic endometrial stromal fibroblasts that contribute to the rapid restoration of an intact luminal epithelium during endometrial repair. These findings form a platform for comparisons both to endometrial pathologies which involve a fibrotic response (Asherman's syndrome, endometriosis) as well as other mucosal tissues which have a variable response to wounding.


The human uterus is a formidable organ. From puberty to menopause, it completely sheds off its internal lining every 28 days or so, creating what is in effect a large open wound. Unlike the skin or other parts of the body, however, this tissue can quickly repair itself without scarring. This fascinating process remains poorly understood, partly because human samples and animal models that mimic human menstruation are still lacking. This makes it difficult to grasp how various types of uterine cells get mobilised for healing. To fill this gap, Kirkwood et al. focused on fibroblasts, a heterogenous cell population which helps to support the epithelial cells lining the inside of the uterus. How these cells responded to the advent of menstruation was examined in female mice genetically manipulated to have human-like periods. A method known as single-cell RNAseq was used to track which genes were active in each of these cells before, one day and two days after period onset. This revealed the existence of a subpopulation of cells which only appeared when wound healing was most needed. These 'repair-specific' fibroblasts expressed a mixture of genes; those typical of fibroblasts but also some known to be active in the epithelial cells lining the uterus. This suggests that the cells were in the process of changing their identity so they could remake the uterine layer lost during a period. And indeed, labelling these fibroblasts with a fluorescent tag showed that, during healing, they had migrated from within the uterine tissue to become part of its newly restored internal surface. These results represent the first evidence that fibroblasts play a direct role in repairing the uterus during menstruation. From endometriosis to infertility, the lives of millions of people around the world are impacted by disorders which affect the uterine lining. A better understanding of how the uterus can fix itself month after month could help to find new treatments for these conditions. This knowledge could also be useful for to address abnormal wound healing in the skin and other tissues, as this process often involves fibroblasts.


Assuntos
Endometriose , Células-Tronco Mesenquimais , Feminino , Camundongos , Humanos , Animais , Menstruação/metabolismo , Endométrio , Células-Tronco Mesenquimais/metabolismo , Células Epiteliais/metabolismo , Análise de Sequência de RNA
14.
Front Reprod Health ; 4: 896170, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36303676

RESUMO

Endometrial hyperplasia (EH) is a precursor lesion to endometrial carcinoma (EC). Risks for EC include genetic, hormonal and metabolic factors most notably those associated with obesity: rates are rising and there is concern that cases in pre-menopausal women may remain undetected. Making an accurate distinction between benign and pre-malignant disease is both a challenge for the pathologist and important to the gynecologist who wants to deliver the most appropriate care to meet the needs of the patient. Premalignant change may be recognized by histological changes of endometrial hyperplasia (which may occur with or without atypia) and endometrial intraepithelial neoplasia (EIN). In this study we created a tissue resource of EH samples diagnosed between 2004 and 2009 (n = 125) and used this to address key questions: 1. Are the EIN/WHO2014 diagnostic criteria able to consistently identify premalignant endometrium? 2. Can computer aided image analysis inform identification of EIN? 3. Can we improve diagnosis by incorporating analysis of protein expression using immunohistochemistry. Our findings confirmed the inclusion of EIN in diagnostic criteria resulted in a better agreement between expert pathologists compared with the previous WHO94 criteria used for the original diagnosis of our sample set. A computer model based on assessment of stromal:epithelial ratio appeared most accurate in classification of areas of tissue without EIN. From an extensive panel of putative endometrial protein tissue biomarkers a score based on assessment of HAND2, PTEN, and PAX2 was able to identify four clusters one of which appeared to be more likely to be benign. In summary, our study has highlighted new opportunities to improve diagnosis of pre-malignant disease in endometrium and provide a platform for further research on this important topic.

15.
Adv Exp Med Biol ; 1390: 21-39, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36107311

RESUMO

The female reproductive system which consists of the ovaries, uterus (myometrium, endometrium), Fallopian tubes, cervix and vagina is exquisitely sensitive to the actions of steroid hormones. The ovaries play a key role in the synthesis of bioactive steroids (oestrogens, androgens, progestins) that act both within the tissue (intracrine/paracrine) as well as on other reproductive organs following release into the blood stream (endocrine action). Sex steroid receptors encoded by the oestrogen (ESR1, ESR2), progesterone (PR) and androgen (AR) receptor genes, which are members of the superfamily of ligand activated transcription factors are widely expressed within these tissues. These receptors play critical role(s) in regulation of cell proliferation, ovulation, endometrial receptivity, myometrial cell function and inflammatory cell infiltration. Our understanding of their importance has been informed by studies on human tissues and cells, which have employed immunohistochemistry as well as a wide range of molecular and genetic methods to identify which processes are dependent steroid ligand activation. The development of mice with targeted deletions of each of these receptors has provided complementary data that has extended our appreciation of cell-cell interactions in the fine tuning of reproductive tissue function. This large body of work has formed the basis of new and improved therapeutics to treat conditions such as infertility.


Assuntos
Androgênios , Receptores de Esteroides , Animais , Estrogênios/fisiologia , Feminino , Genitália Feminina/metabolismo , Humanos , Ligantes , Camundongos , Progesterona/metabolismo , Progestinas , Receptores de Esteroides/fisiologia
16.
Reprod Fertil ; 3(2): R51-R65, 2022 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-35514537

RESUMO

Endometriosis is a chronic neuro-inflammatory disorder the defining feature of which is the growth of tissue (lesions) that resembles the endometrium outside the uterus. Estimates of prevalence quote rates of ~10% of women of reproductive age, equating to at least 190 million women world-wide. Genetic, hormonal and immunological factors have all been proposed as contributing to risk factors associated with the development of lesions. Twin studies report the heritable component of endometriosis as ~50%. Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) that appear over-represented in patients with endometriosis, particularly those with more extensive disease (stage III/IV). In different sample populations, there has been replication of SNPs near genes involved in oestrogen and other steroid regulated pathways including ESR1 (oestrogen receptor alpha), GREB1, HOXA10, WNT4 and MAPK kinase signalling. Comparisons with GWAS conducted on other patient cohorts have found links with reproductive traits (age at menarche) and disorders (fibroids, endometrial and ovarian cancer) and common co-morbidities (migraine, depression, asthma). In summary, genetic analyses have provided new insights into the hormone-regulated pathways that may contribute to increased risk of developing endometriosis some of which may act in early life. New studies are needed to clarify the relationship between the many SNPs identified, the genes that they regulate and their contribution(s) to development of different forms of endometriosis. We hope that more advanced methods allowing integration between GWAS, epigenetic and tissue expression data will improve risk analysis and reduce diagnositic delay. Lay summary: Endometriosis is a debilitating reproductive disorder affecting ~10% of reproductive-age women, and those assigned female at birth, which causes a range of symptoms including chronic pain and infertility. The reason why some, but not all these individuals, develop the lesions that characterise the disease are poorly understood, but recently attention has focused on genetic risk factors to explain why the incidence is higher in some families. Studies on large cohorts of patients with comparison of their DNA to women without endometriosis or with other disorders have documented changes in genes associated with steroid hormone production or action. The results provide further evidence that endometriosis shares genetic risk factors with other disorders of the reproductive system and a platform for new ideas related to risk, biomarkers and therapies.


Assuntos
Endometriose , Endometriose/etiologia , Endometriose/genética , Estrogênios , Feminino , Estudo de Associação Genômica Ampla , Genômica , Humanos , Polimorfismo de Nucleotídeo Único , Esteroides
17.
Biomedicines ; 10(2)2022 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-35203710

RESUMO

The aim of this study was to develop and refine a heterologous mouse model of endometriosis-associated pain in which non-evoked responses, more relevant to the patient experience, were evaluated. Immunodeficient female mice (N = 24) were each implanted with four endometriotic human lesions (N = 12) or control tissue fat (N = 12) on the abdominal wall using tissue glue. Evoked pain responses were measured biweekly using von Frey filaments. Non-evoked responses were recorded weekly for 8 weeks using a home cage analysis (HCA). Endpoints were distance traveled, social proximity, time spent in the center vs. outer areas of the cage, drinking, and climbing. Significant differences between groups for von Frey response, climbing, and drinking were detected on days 14, 21, and 35 post implanting surgery, respectively, and sustained for the duration of the experiment. In conclusion, a heterologous mouse model of endometriosis-associated evoked a non-evoked pain was developed to improve the relevance of preclinical models to patient experience as a platform for drug testing.

18.
Sci Immunol ; 6(65): eabj2132, 2021 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-34797692

RESUMO

Alveolar macrophages are the most abundant macrophages in the healthy lung where they play key roles in homeostasis and immune surveillance against airborne pathogens. Tissue-specific differentiation and survival of alveolar macrophages rely on niche-derived factors, such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and transforming growth factor­ß (TGF-ß). However, the nature of the downstream molecular pathways that regulate the identity and function of alveolar macrophages and their response to injury remain poorly understood. Here, we identify that the transcription factor EGR2 is an evolutionarily conserved feature of lung alveolar macrophages and show that cell-intrinsic EGR2 is indispensable for the tissue-specific identity of alveolar macrophages. Mechanistically, we show that EGR2 is driven by TGF-ß and GM-CSF in a PPAR-γ­dependent manner to control alveolar macrophage differentiation. Functionally, EGR2 was dispensable for the regulation of lipids in the airways but crucial for the effective handling of the respiratory pathogen Streptococcus pneumoniae. Last, we show that EGR2 is required for repopulation of the alveolar niche after sterile, bleomycin-induced lung injury and demonstrate that EGR2-dependent, monocyte-derived alveolar macrophages are vital for effective tissue repair after injury. Collectively, we demonstrate that EGR2 is an indispensable component of the transcriptional network controlling the identity and function of alveolar macrophages in health and disease.


Assuntos
Proteína 2 de Resposta de Crescimento Precoce/imunologia , Macrófagos Alveolares/imunologia , Animais , Feminino , Humanos , Macrófagos Alveolares/patologia , Masculino , Camundongos , Infecções Pneumocócicas/imunologia , Infecções Pneumocócicas/patologia , Streptococcus pneumoniae/imunologia
19.
Pain ; 162(9): 2349-2365, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34448751

RESUMO

ABSTRACT: Endometriosis (ENDO) and interstitial cystitis/bladder pain syndrome (IC/BPS) are chronic pain conditions for which better treatments are urgently needed. Development of new therapies with proven clinical benefit has been slow. We have conducted a review of existing preclinical in vivo models for ENDO and IC/BPS in rodents, discussed to what extent they replicate the phenotype and pain experience of patients, as well as their relevance for translational research. In 1009 publications detailing ENDO models, 41% used autologous, 26% syngeneic, 18% xenograft, and 11% allogeneic tissue in transplantation models. Intraperitoneal injection of endometrial tissue was the subcategory with the highest construct validity score for translational research. From 1055 IC/BPS publications, most interventions were bladder centric (85%), followed by complex mechanisms (8%) and stress-induced models (7%). Within these categories, the most frequently used models were instillation of irritants (92%), autoimmune (43%), and water avoidance stress (39%), respectively. Notably, although pelvic pain is a hallmark of both conditions and a key endpoint for development of novel therapies, only a small proportion of the studies (models of ENDO: 0.5%-12% and models of IC/BPS: 20%-44%) examined endpoints associated with pain. Moreover, only 2% and 3% of publications using models of ENDO and IC/BPS investigated nonevoked pain endpoints. This analysis highlights the wide variety of models used, limiting reproducibility and translation of results. We recommend refining models so that they better reflect clinical reality, sharing protocols, and using standardized endpoints to improve reproducibility. We are addressing this in our project Innovative Medicines Initiative-PainCare/Translational Research in Pelvic Pain.


Assuntos
Cistite Intersticial , Endometriose , Cistite Intersticial/terapia , Feminino , Humanos , Dor Pélvica/terapia , Reprodutibilidade dos Testes , Pesquisa Translacional Biomédica
20.
EBioMedicine ; 69: 103434, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34218053

RESUMO

BACKGROUND: The symptom of heavy menstrual bleeding (HMB) diminishes quality-of-life for many mid-age women and imposes substantial societal burden. We investigated our hypothesis that HMB reflects impaired endometrial vasoconstriction due to endometrial glucocorticoid deficiency. Does reversing this deficiency, by short-term luteal-phase treatment with exogenous glucocorticoid (dexamethasone), ameliorate HMB? METHODS: In our Bayesian response-adaptive parallel-group placebo-controlled randomised trial, five pre-planned interim analyses used primary outcome data to adjust randomisation probabilities to favour doses providing most dose-response information. Participants with HMB, recruited from Lothian (Scotland) NHS clinics and via community invitations/advertisements, were aged over 18 years; reported regular 21-42 day menstrual cycles; and had measured menstrual blood loss (MBL) averaging ≥ 50 mL over two screening periods. Identically encapsulated placebo, or one of six Dexamethasone doses (0·2 mg, 0·4 mg, 0·5 mg, 0·6 mg, 0·75 mg, 0·9 mg), were taken orally twice-daily over five days in the mid-luteal phase of three menstrual cycles. Participants, investigators, and those measuring outcomes were masked to group assignment. Primary outcome, change in average MBL from screening to 'treatment', was analysed by allocated treatment, for all with data. TRIAL REGISTRATION: ClinicalTrials.gov NCT01769820; EudractCT 2012-003,405-98 FINDINGS: Recruitment lasted 29/01/2014 to 25/09/2017; 176 were screened, 107 randomised and 97 provided primary outcome data (n = 24,5,9,21,8,14,16 in the seven arms, placebo to 1·8 mg total daily active dose). In Bayesian normal dynamic linear modelling, 1·8 mg dexamethasone daily showed a 25 mL greater reduction in MBL from screening, than placebo (95% credible interval 1 to 49 mL), and probability 0·98 of benefit over placebo. Adverse events were reported by 75% (58/77) receiving dexamethasone, 58% (15/26) taking placebo. Three serious adverse events occurred, two during screening, one in a placebo participant. No woman withdrew due to adverse effects. INTERPRETATION: Our adaptive trial in HMB showed that dexamethasone 1·8 mg daily reduced menstrual blood loss. The role of dexamethasone in HMB management deserves further investigation. FUNDING: UK MRC DCS/DPFS grant MR/J003611/1.


Assuntos
Dexametasona/administração & dosagem , Glucocorticoides/administração & dosagem , Menorragia/tratamento farmacológico , Adulto , Dexametasona/uso terapêutico , Endométrio/irrigação sanguínea , Feminino , Glucocorticoides/uso terapêutico , Humanos , Menorragia/fisiopatologia , Pessoa de Meia-Idade , Vasoconstrição
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