Trending in endo & adenomyosis research

Endometriosis is a common inflammatory disease characterized by the presence of tissue outside the uterus that resembles endometrium, mainly on pelvic organs and tissues. It affects ~5-10% of women in their reproductive years - translating to 176 million women worldwide - and is associated with pelvic pain and infertility. Diagnosis is reliably established only through surgical visualization with histological verification, although ovarian endometrioma and deep nodular forms of disease can be detected through ultrasonography and MRI. Retrograde menstruation is regarded as an important origin of the endometrial deposits, but other factors are involved, including a favourable endocrine and metabolic environment, epithelial-mesenchymal transition and altered immunity and inflammatory responses in genetically susceptible women. Current treatments are dictated by the primary indication (infertility or pelvic pain) and are limited to surgery and hormonal treatments and analgesics with many adverse effects that rarely provide long-term relief. Endometriosis substantially affects the quality of life of women and their families and imposes costs on society similar to those of other chronic conditions such as type 2 diabetes mellitus, Crohn's disease and rheumatoid arthritis. Future research must focus on understanding the pathogenesis, identifying disease subtypes, developing non-invasive diagnostic methods and targeting non-hormonal treatments that are acceptable to women who wish to conceive.

IMPORTANCE: Endometriosis is a chronic, estrogen-dependent, inflammatory disease defined by endometrial-like tissue (lesions) outside the uterine lining. It affects up to 10% of women worldwide, and 9 million women in the US, during reproductive years. OBSERVATIONS: Endometriosis has varying clinical presentations; however, 90% of people with endometriosis report pelvic pain, including dysmenorrhea, nonmenstrual pelvic pain, and dyspareunia, and 26% report infertility. Risk factors for endometriosis include younger age at menarche, shorter menstrual cycle length, lower body mass index, nulliparity, and congenital obstructive müllerian anomalies such as obstructed hemivagina. Although definitive diagnosis requires surgical visualization of lesions, a suspected clinical diagnosis can be made based on symptoms, supported by physical examination findings and imaging with transvaginal ultrasound and/or pelvic magnetic resonance imaging; normal physical examination and imaging do not exclude the diagnosis. The diagnosis is often delayed, averaging 5 to 12 years after onset of symptoms, with most women consulting 3 or more clinicians prior to diagnosis. Hormonal medications, such as combined oral contraceptives and progestin-only options, are first-line treatment and should be offered to symptomatic premenopausal women who do not currently desire pregnancy. In a network meta-analysis (n = 1680, 15 clinical trials), hormonal treatments including combined oral contraceptives, progestins, and gonadotropin-releasing hormone (GnRH) agonists led to clinically significant pain reduction compared with placebo, with mean differences ranging between 13.15 and 17.6 points (0-100 visual analog scale) with little difference in effectiveness among options. However, 11% to 19% of individuals with endometriosis have no pain reduction with hormonal medications and 25% to 34% experience recurrent pelvic pain within 12 months of discontinuing hormonal treatment. Surgical removal of lesions, usually with laparoscopy, should be considered if first-line hormonal therapies are ineffective or contraindicated. Second-line hormone therapies include GnRH agonists and antagonists, and third-line treatments include aromatase inhibitors. Hysterectomy with surgical removal of lesions may be considered when initial treatments are ineffective. However, approximately 25% of patients who undergo hysterectomy for endometriosis experience recurrent pelvic pain and 10% undergo additional surgery, such as lysis of adhesions, to treat pain. CONCLUSIONS AND RELEVANCE: Endometriosis is a common cause of pelvic pain affecting approximately 10% of reproductive-age women. Hormonal suppression with combined estrogen-progestin contraceptives or progestins is first-line treatment for women who are not seeking immediate pregnancy. Surgical removal of endometriosis lesions may be performed if hormonal therapies are ineffective or contraindicated, and hysterectomy may be considered if medical treatments and surgical removal of lesions do not relieve symptoms.

Endometriosis affects approximately 190 million women and people assigned female at birth worldwide. It is a chronic, inflammatory, gynecologic disease marked by the presence of endometrial-like tissue outside the uterus, which in many patients is associated with debilitating painful symptoms. Patients with endometriosis are also at greater risk of infertility, emergence of fatigue, multisite pain, and other comorbidities. Thus, endometriosis is best understood as a condition with variable presentation and effects at multiple life stages. A long diagnostic delay after symptom onset is common, and persistence and recurrence of symptoms despite treatment is common. This review discusses the potential genetic, hormonal, and immunologic factors that lead to endometriosis, with a focus on current diagnostic and management strategies for gynecologists, general practitioners, and clinicians specializing in conditions for which patients with endometriosis are at higher risk. It examines evidence supporting the different surgical, pharmacologic, and non-pharmacologic approaches to treating patients with endometriosis and presents an easy to adopt step-by-step management strategy. As endometriosis is a multisystem disease, patients with the condition should ideally be offered a personalized, multimodal, interdisciplinary treatment approach. A priority for future discovery is determining clinically informative sub-classifications of endometriosis that predict prognosis and enhance treatment prioritization.

Endometriosis is a chronic inflammatory disease defined as the presence of endometrial tissue outside the uterus, which causes pelvic pain and infertility. This disease should be viewed as a public health problem with a major effect on the quality of life of women as well as being a substantial economic burden. In light of the considerable progress with diagnostic imaging (for example, transvaginal ultrasound and MRI), exploratory laparoscopy should no longer be used to diagnose endometriotic lesions. Instead, diagnosis of endometriosis should be based on a structured process involving the combination of patient interviews, clinical examination and imaging. Notably, a diagnosis of endometriosis often leads to immediate surgery. Therefore, rethinking the diagnosis and management of endometriosis is warranted. Instead of assessing endometriosis on the day of the diagnosis, gynaecologists should consider the patient's 'endometriosis life'. Medical treatment is the first-line therapeutic option for patients with pelvic pain and no desire for immediate pregnancy. In women with infertility, careful consideration should be made regarding whether to provide assisted reproductive technologies prior to performing endometriosis surgery. Modern endometriosis management should be individualized with a patient-centred, multi-modal and interdisciplinary integrated approach.

OBJECTIVE: To assess the impact of endometriosis on health-related quality of life (HRQoL) and work productivity. DESIGN: Multicenter cross-sectional study with prospective recruitment. SETTING: Sixteen clinical centers in ten countries. PATIENT(S): A total of 1,418 premenopausal women, aged 18-45 years, without a previous surgical diagnosis of endometriosis, having laparoscopy to investigate symptoms or to be sterilized. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Diagnostic delay, HRQoL, and work productivity. RESULT(S): There was a delay of 6.7 years, principally in primary care, between onset of symptoms and a surgical diagnosis of endometriosis, which was longer in centers where women received predominantly state-funded health care (8.3 vs. 5.5 years). Delay was positively associated with the number of pelvic symptoms (chronic pelvic pain, dysmenorrhoea, dyspareunia, and heavy periods) and a higher body mass index. Physical HRQoL was significantly reduced in affected women compared with those with similar symptoms and no endometriosis. Each affected woman lost on average 10.8 hours (SD 12.2) of work weekly, mainly owing to reduced effectiveness while working. Loss of work productivity translated into significant costs per woman/week, from US$4 in Nigeria to US$456 in Italy. CONCLUSION(S): Endometriosis impairs HRQoL and work productivity across countries and ethnicities, yet women continue to experience diagnostic delays in primary care. A higher index of suspicion is needed to expedite specialist assessment of symptomatic women. Future research should seek to clarify pain mechanisms in relation to endometriosis severity.

BACKGROUND: Fibrosis is an important pathological feature of endometriotic lesions of all subtypes. Fibrosis is present in and around endometriotic lesions, and a central role in its development is played by myofibroblasts, which are cells derived mainly after epithelial-to-mesenchymal transition (EMT) and fibroblast-to-myofibroblast transdifferentiation (FMT). Transforming growth factor-β (TGF-β) has a key role in this myofibroblastic differentiation. Myofibroblasts deposit extracellular matrix (ECM) and have contracting abilities, leading to a stiff micro-environment. These aspects are hypothesized to be involved in the origin of endometriosis-associated pain. Additionally, similarities between endometriosis-related fibrosis and other fibrotic diseases, such as systemic sclerosis or lung fibrosis, indicate that targeting fibrosis could be a potential therapeutic strategy for non-hormonal therapy for endometriosis. OBJECTIVE AND RATIONALE: This review aims to summarize the current knowledge and to highlight the knowledge gaps about the role of fibrosis in endometriosis. A comprehensive literature overview about the role of fibrosis in endometriosis can improve the efficiency of fibrosis-oriented research in endometriosis. SEARCH METHODS: A systematic literature search was performed in three biomedical databases using search terms for 'endometriosis', 'fibrosis', 'myofibroblasts', 'collagen', and 'α-smooth muscle actin'. Original studies were included if they reported about fibrosis and endometriosis. Both preclinical in vitro and animal studies, as well as research concerning human subjects were included. OUTCOMES: Our search yielded 3441 results, of which 142 studies were included in this review. Most studies scored a high to moderate risk of bias according to the bias assessment tools. The studies were divided in three categories: human observational studies, experimental studies with human-derived material, and animal studies. The observational studies showed details about the histologic appearance of fibrosis in endometriosis and the co-occurrence of nerves and immune cells in lesions. The in vitro studies identified several pro-fibrotic pathways in relation to endometriosis. The animal studies mainly assessed the effect of potential therapeutic strategies to halt or regress fibrosis, for example targeting platelets or mast cells. WIDER IMPLICATIONS: This review shows the central role of fibrosis and its main cellular driver, the myofibroblast, in endometriosis. Platelets and TGF-β have a pivotal role in pro-fibrotic signaling. The presence of nerves and neuropeptides is closely associated with fibrosis in endometriotic lesions, and is likely a cause of endometriosis-associated pain. The process of fibrotic development after EMT and FMT shares characteristics with other fibrotic diseases, so exploring similarities in endometriosis with known processes in diseases like systemic sclerosis, idiopathic pulmonary fibrosis or liver cirrhosis is relevant and a promising direction to explore new treatment strategies. The close relationship with nerves appears rather unique for endometriosis-related fibrosis and is not observed in other fibrotic diseases. REGISTRATION NUMBER: N/A.

Endometriosis is defined as the presence of endometrial-type mucosa outside the uterine cavity. Of the proposed pathogenic theories (retrograde menstruation, coelomic metaplasia and Müllerian remnants), none explain all the different types of endometriosis. According to the most convincing model, the retrograde menstruation hypothesis, endometrial fragments reaching the pelvis via transtubal retrograde flow, implant onto the peritoneum and abdominal organs, proliferate and cause chronic inflammation with formation of adhesions. The number and amount of menstrual flows together with genetic and environmental factors determines the degree of phenotypic expression of the disease. Endometriosis is estrogen-dependent, manifests during reproductive years and is associated with pain and infertility. Dysmenorrhoea, deep dyspareunia, dyschezia and dysuria are the most frequently reported symptoms. Standard diagnosis is carried out by direct visualization and histologic examination of lesions. Pain can be treated by excising peritoneal implants, deep nodules and ovarian cysts, or inducing lesion suppression by abolishing ovulation and menstruation through hormonal manipulation with progestins, oral contraceptives and gonadotropin-releasing hormone agonists. Medical therapy is symptomatic, not cytoreductive; surgery is associated with high recurrence rates. Although lesion eradication is considered a fertility-enhancing procedure, the benefit on reproductive performance is moderate. Assisted reproductive technologies constitute a valid alternative. Endometriosis is associated with a 50% increase in the risk of epithelial ovarian cancer, but preventive interventions are feasible.

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.

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The IDEA (International Deep Endometriosis Analysis group) statement is a consensus opinion on terms, definitions and measurements that may be used to describe the sonographic features of the different phenotypes of endometriosis. Currently, it is difficult to compare results between published studies because authors use different terms when describing the same structures and anatomical locations. We hope that the terms and definitions suggested herein will be adopted in centers around the world. This would result in consistent use of nomenclature when describing the ultrasound location and extent of endometriosis. We believe that the standardization of terminology will allow meaningful comparisons between future studies in women with an ultrasound diagnosis of endometriosis and should facilitate multicenter research. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

The MUSA (Morphological Uterus Sonographic Assessment) statement is a consensus statement on terms, definitions and measurements that may be used to describe and report the sonographic features of the myometrium using gray-scale sonography, color/power Doppler and three-dimensional ultrasound imaging. The terms and definitions described may form the basis for prospective studies to predict the risk of different myometrial pathologies, based on their ultrasound appearance, and thus should be relevant for the clinician in daily practice and for clinical research. The sonographic features and use of terminology for describing the two most common myometrial lesions (fibroids and adenomyosis) and uterine smooth muscle tumors are presented.

A healthy 25-year-old woman presents with worsening dysmenorrhea, pain of recent onset in the left lower quadrant, and dyspareunia. She has regular menstrual cycles, and her last menstrual period was 3 weeks before presentation. How should this patient be evaluated and treated?

Pelvic endometriosis is a complex syndrome characterized by an estrogen-dependent chronic inflammatory process that affects primarily pelvic tissues, including the ovaries. It is caused when shed endometrial tissue travels retrograde into the lower abdominal cavity. Endometriosis is the most common cause of chronic pelvic pain in women and is associated with infertility. The underlying pathologic mechanisms in the intracavitary endometrium and extrauterine endometriotic tissue involve defectively programmed endometrial mesenchymal progenitor/stem cells. Although endometriotic stromal cells, which compose the bulk of endometriotic lesions, do not carry somatic mutations, they demonstrate specific epigenetic abnormalities that alter expression of key transcription factors. For example, GATA-binding factor-6 overexpression transforms an endometrial stromal cell to an endometriotic phenotype, and steroidogenic factor-1 overexpression causes excessive production of estrogen, which drives inflammation via pathologically high levels of estrogen receptor-β. Progesterone receptor deficiency causes progesterone resistance. Populations of endometrial and endometriotic epithelial cells also harbor multiple cancer driver mutations, such as KRAS, which may be associated with the establishment of pelvic endometriosis or ovarian cancer. It is not known how interactions between epigenomically defective stromal cells and the mutated genes in epithelial cells contribute to the pathogenesis of endometriosis. Endometriosis-associated pelvic pain is managed by suppression of ovulatory menses and estrogen production, cyclooxygenase inhibitors, and surgical removal of pelvic lesions, and in vitro fertilization is frequently used to overcome infertility. Although novel targeted treatments are becoming available, as endometriosis pathophysiology is better understood, preventive approaches such as long-term ovulation suppression may play a critical role in the future.

Originally described over three hundred years ago, endometriosis is classically defined by the presence of endometrial glands and stroma in extrauterine locations. Endometriosis is an inflammatory, estrogen-dependent condition associated with pelvic pain and infertility. This work reviews the disease process from theories regarding origin to the molecular basis for disease sequelae. A thorough understanding of the histopathogenesis and pathophysiology of endometriosis is essential to the development of novel diagnostic and treatment approaches for this debilitating condition.

Endometriosis can have a profound impact on women's lives, including associated pain, infertility, decreased quality of life, and interference with daily life, relationships, and livelihood. The first step in alleviating these adverse sequelae is to diagnose the underlying condition. For many women, the journey to endometriosis diagnosis is long and fraught with barriers and misdiagnoses. Inherent challenges include a gold standard based on an invasive surgical procedure (laparoscopy) and diverse symptomatology, contributing to the well-established delay of 4-11 years from first symptom onset to surgical diagnosis. We believe that remedying the diagnostic delay requires increased patient education and timely referral to a women's healthcare provider and a shift in physician approach to the disorder. Endometriosis should be approached as a chronic, systemic, inflammatory, and heterogeneous disease that presents with symptoms of pelvic pain and/or infertility, rather than focusing primarily on surgical findings and pelvic lesions. Using this approach, symptoms, signs, and clinical findings of endometriosis are anticipated to become the main drivers of clinical diagnosis and earlier intervention. Combining these factors into a practical algorithm is expected to simplify endometriosis diagnosis and make the process accessible to more clinicians and patients, culminating in earlier effective management. The time has come to bridge disparities and to minimize delays in endometriosis diagnosis and treatment for the benefit of women worldwide.

Endometriosis, an estrogen-dependent chronic inflammatory disease characterized by the growth of endometrium-like tissues outside the uterine cavity, affects 10% of reproductive-age women. Although the pathogenesis of endometriosis is uncertain, it is widely accepted that retrograde menstruation results in ectopic endometrial tissue implantation. Given that not all women with retrograde menstruation develop endometriosis, immune factors have been hypothesized to affect the pathogenesis of endometriosis. In this review, we demonstrate that the peritoneal immune microenvironment, including innate immunity and adaptive immunity, plays a central role in the pathogenesis of endometriosis. Current evidence supports the fact that immune cells, such as macrophages, natural killer (NK) cells, dendritic cells (DCs), neutrophils, T cells, and B cells, as well as cytokines and inflammatory mediators, contribute to the vascularization and fibrogenesis of endometriotic lesions, accelerating the implantation and development of ectopic endometrial lesions. Endocrine system dysfunction influences the immune microenvironment through overexpressed estrogen and progesterone resistance. In light of the limitations of hormonal therapy, we describe the prospects for potential diagnostic biomarkers and nonhormonal therapy based on the regulation of the immune microenvironment. Further studies are warranted to explore the available diagnostic biomarkers and immunological therapeutic strategies for endometriosis.

[For a first-person account of endometriosis, see www.cmaj.ca/lookup/doi/10.1503/cmaj.230215][1] KEY POINTS Endometriosis is a chronic condition defined by the presence of endometrial-like tissue outside of the uterus, which can lead to estrogen-driven inflammation. The extent of disease can be

INTRODUCTION: Endometriosis is a common gynecological disorder affecting approximately 10-15% of women of reproductive age. The main complaints of patients with endometriosis are pain and fertility problems. Symptoms of endometriosis can impact the psychological functioning of the patients and significantly compromise their mental health. METHODS: The aim of this review was to assess the prevalence of depressive and anxiety symptoms and quality of life in endometriosis patients. For this systematic review, we searched the PubMed, MEDLINE, ProQuest, EMBASE, Cochrane, CINAHL, Google Scholar, Scopus, and ScienceDirect electronic databases up to March 2023 to identify potentially relevant studies. The systematic review in the present paper is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance. RESULTS: Of four records identified, 18 were eligible to be reviewed on the association between endometriosis and symptoms of depression and anxiety. Of 8,901 records identified, 28 were reviewed on the association between endometriosis and quality of life. The reviewed articles showed a prevalence ranging from 9.8 to 98.5% for depressive symptoms and 11.5 to 87.5% for anxiety. The quality of life in patients with endometriosis was significantly impaired, regardless of the tool used for evaluation. DISCUSSION: This systematic review shows that endometriosis is associated with depressive and anxiety symptoms and impaired HRQoL. Broad correlating factors modulate mental health outcomes, indicating the complex relationship between the disease and the psychological health of the patients.

Advances in preoperative diagnostics as well as in surgical techniques for the treatment of endometriosis, especially for deep endometriosis, call for a classification system, that includes all aspects of the disease such as peritoneal endometriosis, ovarian endometriosis, deep endometriosis, and secondary adhesions. The widely accepted revised American Society for Reproductive Medicine classification (rASRM) has certain limitations because of its incomplete description of deep endometriosis. In contrast, the Enzian classification, which has been implemented in the last decade, has proved to be the most suitable tool for staging deep endometriosis, but does not include peritoneal or ovarian disease or adhesions. To overcome these limitations, a comprehensive classification system for complete mapping of endometriosis, including anatomical location, size of the lesions, adhesions and degree of involvement of the adjacent organs, that can be used with both diagnostic and surgical methods, has been created through a consensus process and will be described in detail-the #Enzian classification.

This review emphasizes the participation of estrogen and inflammation in the development of endometriosis. A feedback cycle in which prostaglandins and aromatase activity are prominent allows for the persistence of endometriotic tissue. Knowledge of this cycle has important implications for the treatment of endometriosis.

Endometriosis, which affects approximately 10% of women of reproductive age, is a complex inflammatory disease with significant immune system disturbances caused by an inadequate immune response to retrograde menstruation and leading to the establishment of immune evasion mechanisms by ectopic tissue. This review provides an analysis of the immunopathogenetic mechanisms of endometriosis based on 198 high-quality publications selected from 1,209 potentially relevant articles in the PubMed, Scopus, Web of Science, and Google Scholar databases for the period 1927-2025. The study revealed that endometriosis is associated with profound alterations in both innate and adaptive immunity. Key pathogenetic mechanisms include macrophage dysfunction with a shift to the M2 phenotype, reduced cytotoxic activity of NK cells, complement system activation with proinflammatory and proangiogenic effects, a predominant Th2 response with an increase in Treg cells, and B-lymphocyte activation with autoantibody production. The cytokine profile is characterized by a concurrent increase in both pro-inflammatory mediators (IL-1β, IL-6, TNF-α) and immunosuppressive factors (IL-10, TGF-β). The complement system contributes to pathogenesis through C3a/C5a-mediated inflammation, angiogenesis promotion, and interactions with dysbiotic endometrial microbiota. Different forms of endometriosis have specific immunological features: ovarian endometriosis combines local immunosuppression with systemic inflammation, adenomyosis is characterized by pro-inflammatory changes with a Treg cell deficiency, and deep infiltrating endometriosis is distinguished by the activation of the IDO1/COX-2/MMP-9 signaling pathway and complement-mediated tissue destruction. Understanding the specifics of immunopathogenesis opens new avenues for developing targeted immunotherapy, which may include modulating immune cell functions, using cytokine inhibitors, blocking immune checkpoints, and employing nanotechnological approaches.

Endometriosis is a complex gynecological disorder characterized by endometrial-like tissue growing outside the uterus, leading to chronic pain, infertility, and reduced quality of life. Its pathophysiology involves genetic, epigenetic, immune, and molecular factors. Theories such as retrograde menstruation, coelomic metaplasia, and stem cell involvement explain lesion formation. Endometrial mesenchymal stem cells (eMSCs) and epithelial progenitors (eEPs) contribute to lesion establishment by adhering to peritoneal surfaces, proliferating, and differentiating into ectopic tissue. Aberrant adhesion molecules, inflammatory cytokines, and molecular pathways like PI3K/Akt and Wnt/β-catenin drive proliferation, angiogenesis, and resistance to apoptosis. Elevated estrogen levels and progesterone resistance further promote lesion growth and immune evasion. Immune dysfunction, including altered macrophage activity and reduced natural killer (NK) cell function, contributes to inflammation and lesion persistence. Pain is linked to prostaglandin E2 (PGE2) and nerve infiltration, emphasizing the need for targeted pain management. Current therapies, such as GnRH agonists, suppress ovarian hormone production but face limitations in long-term efficacy and side effects. Integrating molecular insights into clinical practice may advance diagnostics and treatment, with emerging approaches focusing on molecular pathways, immune modulation, and hormonal regulation for more effective, personalized therapies. Future research should unravel the complex mechanisms driving endometriosis to improve patient outcomes.

BACKGROUND: This study aimed to calculate costs and health-related quality of life of women with endometriosis-associated symptoms treated in referral centres. METHODS: A prospective, multi-centre, questionnaire-based survey measured costs and quality of life in ambulatory care and in 12 tertiary care centres in 10 countries. The study enrolled women with a diagnosis of endometriosis and with at least one centre-specific contact related to endometriosis-associated symptoms in 2008. The main outcome measures were health care costs, costs of productivity loss, total costs and quality-adjusted life years. Predictors of costs were identified using regression analysis. RESULTS: Data analysis of 909 women demonstrated that the average annual total cost per woman was €9579 (95% confidence interval €8559-€10 599). Costs of productivity loss of €6298 per woman were double the health care costs of €3113 per woman. Health care costs were mainly due to surgery (29%), monitoring tests (19%) and hospitalization (18%) and physician visits (16%). Endometriosis-associated symptoms generated 0.809 quality-adjusted life years per woman. Decreased quality of life was the most important predictor of direct health care and total costs. Costs were greater with increasing severity of endometriosis, presence of pelvic pain, presence of infertility and a higher number of years since diagnosis. CONCLUSIONS: Our study invited women to report resource use based on endometriosis-associated symptoms only, rather than drawing on a control population of women without endometriosis. Our study showed that the economic burden associated with endometriosis treated in referral centres is high and is similar to other chronic diseases (diabetes, Crohn's disease, rheumatoid arthritis). It arises predominantly from productivity loss, and is predicted by decreased quality of life.

BACKGROUND: Adenomyosis is a benign uterine disorder where endometrial glands and stroma are pathologically demonstrated within the uterine myometrium. The pathogenesis involves sex steroid hormone abnormalities, inflammation, fibrosis and neuroangiogenesis, even though the proposed mechanisms are not fully understood. For many years, adenomyosis has been considered a histopathological diagnosis made after hysterectomy, classically performed in perimenopausal women with abnormal uterine bleeding (AUB) or pelvic pain. Until recently, adenomyosis was a clinically neglected condition. Nowadays, adenomyosis may also be diagnosed by non-invasive techniques, because of imaging advancements. Thus, a new epidemiological scenario has developed with an increasing number of women of reproductive age with ultrasound (US) or magnetic resonance imaging (MRI) diagnosis of adenomyosis. This condition is associated with a wide variety of symptoms (pelvic pain, AUB and/or infertility), but it is also recognised that some women are asymptomatic. Furthermore, adenomyosis often coexists with other gynecological comorbidities, such as endometriosis and uterine fibroids, and the diagnostic criteria are still not universally agreed. Therefore, the diagnostic process for adenomyosis is challenging. OBJECTIVE AND RATIONALE: We present a comprehensive review on the diagnostic criteria of adenomyosis, including clinical signs and symptoms, ultrasound and MRI features and histopathological aspects of adenomyotic lesions. We also briefly summarise the relevant theories on adenomyosis pathogenesis, in order to provide the pathophysiological background to understand the different phenotypes and clinical presentation. The review highlights the controversies of multiple existing criteria, summarising all of the available evidences on adenomyosis diagnosis. The review aims also to underline the future perspective for diagnosis, stressing the importance of an integrated clinical and imaging approach, in order to identify this gynecological disease, so often underdiagnosed. SEARCH METHODS: PubMed and Google Scholar were searched for all original and review articles related to diagnosis of adenomyosis published in English until October 2018. OUTCOMES: The challenge in diagnosing adenomyosis starts with the controversies in the available pathogenic theories. The difficulties in understanding the way the disease arises and progresses have an impact also on the specific diagnostic criteria to use for a correct identification. Currently, the diagnosis of adenomyosis may be performed by non-invasive methods and the clinical signs and symptoms, despite their heterogeneity and poor specificity, may guide the clinician for a suspicion of the disease. Imaging techniques, including 2D and 3D US as well as MRI, allow the proper identification of the different phenotypes of adenomyosis (diffuse and/or focal). From a histological point of view, if the diagnosis of diffuse adenomyosis is straightforward, in more limited disease, the diagnosis has poor inter-observer reproducibility, leading to extreme variations in the prevalence of disease. Therefore, an integrated non-invasive diagnostic approach, considering risk factors profile, clinical symptoms, clinical examination and imaging, is proposed to adequately identify and characterise adenomyosis. WIDER IMPLICATIONS: The development of the diagnostic tools allows the physicians to make an accurate diagnosis of adenomyosis by means of non-invasive techniques, representing a major breakthrough, in the light of the clinical consequences of this disease. Furthermore, this technological improvement will open a new epidemiological scenario, identifying different groups of women, with a dissimilar clinical and/or imaging phenotypes of adenomyosis, and this should be object of future research.

Endometriosis is a chronic, inflammatory disease affecting more than 170 million women worldwide and up to 10% of women of reproductive age. As a consequence of inflammatory reaction and infiltration of anatomic structures, endometriosis can cause "pain symptoms" including dysmenorrhea, dyspareunia, dyschezia, dysuria, and chronic pelvic pain. In this review, we summarized the impact of endometriosis on quality of life in all its aspects including sexual life, work, and social relationships. The data research was conducted using web-based search engines and/or various electronic research databases querying for all articles related to endometriosis and quality of life from the inception of the database up to February 2020. Endometriosis has not only physical but also psychological effects, causing depression, anxiety, and compromising social relationships. Furthermore, endometriosis negatively impacts sexual life and social relationships. At last, the economic burden of endometriosis should not be underestimated, both individually and for the community, as this pathology leads to a loss of productivity at work and large use of health resources. Thus, endometriosis-related symptoms control women's lives compromising the quality of life in all aspects. In this review, we summarized the impact of endometriosis on various aspects of women's lives.

BACKGROUND Endometriosis is a chronic condition affecting between 2 and 17% of women of reproductive age. Common symptoms are chronic pelvic pain, fatigue, congestive dysmenorrhoea, heavy menstrual bleeding and deep dyspareunia. Studies have demonstrated the considerable negative impact of this condition on women's quality of life (QoL), especially in the domains of pain and psychosocial functioning. The impact of endometriosis is likely to be exacerbated by the absence of an obvious cause and the likelihood of chronic, recurring symptoms. The aims of this paper are to review the current body of knowledge on the social and psychological impact of endometriosis on women's lives; to provide insights into women's experience of endometriosis; to provide a critical commentary on the current state of knowledge and to make recommendations for future psycho-social research. METHODS The review draws on a method of critical narrative synthesis to discuss a heterogeneous range of both quantitative and qualitative studies from several disciplines. This included a systematic search, a structured process for selecting and collecting data and a systematic thematic analysis of results. RESULTS A total of 42 papers were included in the review; 23 used quantitative methods, 16 used qualitative methods and 3 were mixed methods studies. The majority of papers came from just four countries: UK (10), Australia (8), Brazil (6) and the USA (5). Key categories of impact identified in the thematic analysis were diagnostic delay and uncertainty; 'QoL' and everyday activities; intimate relationships; planning for and having children; education and work; mental health and emotional wellbeing and medical management and self-management. CONCLUSIONS Endometriosis has a significant social and psychological impact on the lives of women across several domains. Many studies have methodological limitations and there are significant gaps in the literature especially in relation to a consideration of the impact on partners and children. We recommend additional prospective and longitudinal research utilizing mixed methods approaches and endometriosis-specific instruments to explore the impact of endometriosis in more diverse populations and settings. Furthermore, there is an urgent need to develop and evaluate interventions for supporting women and partners living with this chronic and often debilitating condition.

Endometriosis is a chronic inflammatory condition affecting women of reproductive age. A relevant feature of endometriosis is the presence of fibrotic tissue inside and around the lesions, thus contributing to the classic endometriosis-related symptoms, pain, and infertility. The molecular mechanisms responsible for the development of fibrosis in endometriosis are not yet defined. The present review aimed to examine the biological mechanisms and signalling pathways involved in fibrogenesis of endometriotic lesions, highlighting the difference between deep infiltrating and ovarian endometriosis. The main cell types involved in the development of fibrosis are platelets, myofibroblasts, macrophages, and sensory nerve fibers. Members of the transforming growth factor (TGF) -β family, as well as the receptor Notch, or the bioactive sphingolipid sphingosine 1-phosphate (S1P), play a role in the development of tissue fibrosis, resulting in their metabolism and/or their signalling pathways altered in endometriotic lesions. It is relevant the knowledge of the molecular mechanisms that guide and support fibrosis in endometriosis, to identify new drug targets and provide new therapeutic approaches to patients.

Endometriosis is an estrogen-dependent disease characterized by the growth of endometrial-like tissue outside the uterus. Progestins are currently the most commonly used treatment for endometriosis because of their excellent therapeutic effects and limited side effects. However, progestins have been unsuccessful in some symptomatic patients. The inability of the endometrium to respond properly to progesterone is known as progesterone resistance. An increasing body of evidence suggests the loss of progesterone signaling and the existence of progesterone resistance in endometriosis. The mechanisms of progesterone resistance have received considerable scholarly attention in recent years. Abnormal PGR signaling, chronic inflammation, aberrant gene expression, epigenetic alterations, and environmental toxins are considered potential molecular causes of progesterone resistance in endometriosis. The general objective of this review was to summarize the evidence and mechanisms of progesterone resistance. A deeper understanding of how these mechanisms contribute to progesterone resistance may help develop a novel therapeutic regimen for women with endometriosis by reversing progesterone resistance.

Copyright © 2017 Massachusetts Medical Society. BACKGROUND Endometriosis is a chronic, estrogen-dependent condition that causes dysmenorrhea and pelvic pain. Elagolix, an oral, nonpeptide, gonadotropin-releasing hormone (GnRH) antagonist, produced partial to nearly full estrogen suppression in previous studies. METHODS We performed two similar, double-blind, randomized, 6-month phase 3 trials (Elaris Endometriosis I and II [EM-I and EM-II]) to evaluate the effects of two doses of elagolix-150 mg once daily (lower-dose group) and 200 mg twice daily (higher-dose group)-as compared with placebo in women with surgically diagnosed endometriosis and moderate or severe endometriosis-associated pain. The two primary efficacy end points were the proportion of women who had a clinical response with respect to dysmenorrhea and the proportion who had a clinical response with respect to nonmenstrual pelvic pain at 3 months. Each of these end points was measured as a clinically meaningful reduction in the pain score and a decreased or stable use of rescue analgesic agents, as recorded in a daily electronic diary. RESULTS A total of 872 women underwent randomization in Elaris EM-I and 817 in Elaris EM-II; of these women, 653 (74.9%) and 632 (77.4%), respectively, completed the intervention. At 3 months, a significantly greater proportion of women who received each elagolix dose met the clinical response criteria for the two primary end points than did those who received placebo. In Elaris EM-I, the percentage of women who had a clinical response with respect to dysmenorrhea was 46.4% in the lower-dose elagolix group and 75.8% in the higher-dose elagolix group, as compared with 19.6% in the placebo group; in Elaris EM-II, the corresponding percentages were 43.4% and 72.4%, as compared with 22.7% (P<0.001 for all comparisons). In Elaris EM-I, the percentage of women who had a clinical response with respect to nonmenstrual pelvic pain was 50.4% in the lower-dose elagolix group and 54.5% in the higher-dose elagolix group, as compared with 36.5% in the placebo group (P<0.001 for all comparisons); in Elaris EM-II, the corresponding percentages were 49.8% and 57.8%, as compared with 36.5% (P = 0.003 and P<0.001, respectively). The responses with respect to dysmenorrhea and nonmenstrual pelvic pain were sustained at 6 months. Women who received elagolix had higher rates of hot flushes (mostly mild or moderate), higher levels of serum lipids, and greater decreases from baseline in bone mineral density than did those who received placebo; there were no adverse endometrial findings. CONCLUSIONS Both higher and lower doses of elagolix were effective in improving dysmenorrhea and nonmenstrual pelvic pain during a 6-month period in women with endometriosis-associated pain. The two doses of elagolix were associated with hypoestrogenic adverse effects.

PURPOSE OF REVIEW: Endometriosis is a disease of adolescents and reproductive-aged women characterized by the presence of endometrial tissue outside the uterine cavity and commonly associated with chronic pelvic pain and infertility. Here we review the epidemiology of endometriosis as well as potential biomarkers for detection and with the goal of highlighting risk factors that could be used in combination with biomarkers to identify and treat women with endometriosis earlier.. RECENT FINDINGS: Early age at menarche, shorter menstrual length, and taller height are associated with a higher risk of endometriosis while parity, higher body mass index (BMI) and smoking are associated with decreased risk. Endometriosis often presents as infertility or continued pelvic pain despite treatment with analgesics and cyclic oral contraceptive pills. SUMMARY: Despite a range of symptoms, diagnosis of endometriosis is often delayed due to lack of non-invasive, definitive and consistent biomarkers for diagnosis of endometriosis. Hormone therapy and analgesics are used for treatment of symptomatic endometriosis. However, the efficacy of these treatments are limited as endometriosis often recurs. In this review, we describe potential diagnostic biomarkers and risk factors that may be used as early non-invasive in vitro tools for identification of endometriosis to minimize diagnostic delay and improve reproductive health of patients.

BACKGROUND: Endometriosis is a common cause of pelvic pain in women, for which current treatment options are suboptimal. Relugolix, an oral gonadotropin-releasing hormone receptor antagonist, combined with estradiol and a progestin, was evaluated for treatment of endometriosis-associated pain. METHODS: In these two replicate, phase 3, multicentre, randomised, double-blind, placebo-controlled trials at 219 community and hospital research centres in Africa, Australasia, Europe, North America, and South America, we randomly assigned women aged 18-50 years with surgically or directly visualised endometriosis with or without histological confirmation, or with histological diagnosis alone. Participants were eligible if they had moderate to severe endometriosis-associated pain and, during the 35-day run-in period, a dysmenorrhoea Numerical Rating Scale (NRS) score of 4·0 or higher on two or more days and a mean non-menstrual pelvic pain NRS score of 2·5 or higher, or a mean score of 1·25 or higher that included a score of 5 or more on 4 or more days. Women received (1:1:1) once-daily oral placebo, relugolix combination therapy (relugolix 40 mg, estradiol 1 mg, norethisterone acetate 0·5 mg), or delayed relugolix combination therapy (relugolix 40 mg monotherapy followed by relugolix combination therapy, each for 12 weeks) for 24 weeks. During the double-blind randomised treatment and follow-up period, all patients, investigators, and sponsor staff or representatives involved in the conduct of the study were masked to treatment assignment. The co-primary endpoints were responder rates at week 24 for dysmenorrhoea and non-menstrual pelvic pain, both based on NRS scores and analgesic use. Efficacy and safety were analysed in the modified intent-to-treat population (randomised patients who received ≥1 study drug dose). The studies are registered at ClinicalTrials.gov (SPIRIT 1 [NCT03204318] and SPIRIT 2 [NCT03204331]) and EudraCT (SPIRIT 1 [2017-001588-19] and SPIRIT 2 [2017-001632-19]). Eligible patients who completed the SPIRIT studies could enrol in a currently ongoing 80-week open-label extension study (SPIRIT EXTENSION [NCT03654274, EudraCT 2017-004066-10]). Database lock for the on-treatment duration has occurred, and post-treatment follow-up for safety, specificially for bone mineral density and menses recovery, is ongoing at the time of publication. FINDINGS: 638 patients were enrolled into SPIRIT 1 and randomly assigned between Dec 7, 2017, and Dec 4, 2019, to receive relugolix combination therapy (212 [33%]), placebo (213 [33%]), or relugolix delayed combination therapy (213 [33%]). 623 patients were enrolled into SPIRIT 2 and were randomly assigned between Nov 1, 2017 and Oct 4, 2019, to receive relugolix combination therapy (208 [33%]), placebo (208 [33%]), or relugolix delayed combination therapy (207 [33%]). 98 (15%) patients terminated study participation early in SPIRIT 1 and 115 (18%) in SPIRIT 2. In SPIRIT 1, 158 (75%) of 212 patients in the relugolix combination therapy group met the dysmenorrhoea responder criteria compared with 57 (27%) of 212 patients in the placebo group (treatment difference 47·6% [95% CI 39·3-56·0]; p<0·0001). In SPIRIT 2, 155 (75%) of 206 patients in the relugolix combination therapy group were dysmenorrhoea responders compared with 62 (30%) of 204 patients in the placebo group (treatment difference 44·9% [95% CI 36·2-53·5]; p<0·0001). In SPIRIT 1, 124 (58%) of 212 patients in the relugolix combination therapy group met the non-menstrual pelvic pain responder criteria versus 84 (40%) patients in the placebo group (treatment difference 18·9% [9·5-28·2]; p<0·0001). In SPIRIT 2, 136 (66%) of 206 patients were non-menstrual pelvic pain responders in the relugolix combination therapy group compared with 87 (43%) of 204 patients in the placebo group (treatment difference 23·4% [95% CI 13·9-32·8]; p<0·0001). The most common adverse events were headache, nasopharyngitis, and hot flushes. There were nine reports of suicidal ideation across both studies (two in the placebo run-in, two in the placebo group, two in the relugolix combination therapy group, and three in the delayed relugolix combination therapy group). No deaths were reported. Least squares mean percentage change in lumbar spine bone mineral density in the relugolix combination therapy versus placebo groups was -0·70% versus 0·21% in SPIRIT 1 and -0·78% versus 0·02% in SPIRIT 2, and in the delayed relugolix combination group was -2·0% in SPIRIT 1 and -1·9% in SPIRIT 2. Decreases in opioid use were seen in treated patients as compared with placebo. INTERPRETATION: Once-daily relugolix combination therapy significantly improved endometriosis-associated pain and was well tolerated. This oral therapy has the potential to address the unmet clinical need for long-term medical treatment for endometriosis, reducing the need for opioid use or repeated surgical treatment. FUNDING: Myovant Sciences.

Despite the clinically recognized association between endometriosis and infertility, the mechanisms implicated in endometriosis-associated infertility are not fully understood. Endometriosis is a multifactorial and systemic disease that has pleiotropic direct and indirect effects on reproduction. A complex interaction between endometriosis subtype, pain, inflammation, altered pelvic anatomy, adhesions, disrupted ovarian reserve/function, and compromised endometrial receptivity as well as systemic effects of the disease define endometriosis-associated infertility. The population of infertile women with endometriosis is heterogeneous, and diverse patients' phenotypes can be observed in the clinical setting, thus making difficult to establish a precise diagnosis and a single mechanism of endometriosis related infertility. Moreover, clinical management of infertility associated with endometriosis can be challenging due to this heterogeneity. Innovative non-invasive diagnostic tools are on the horizon that may allow us to target the specific dysfunctional alteration in the reproduction process. Currently the treatment should be individualized according to the clinical situation and to the suspected level of impairment. Here we review the etiology of endometriosis related infertility as well as current treatment options, including the roles of surgery and assisted reproductive technologies.

IMPORTANCE: Endometriosis has been associated with an increased risk of ovarian cancer; however, the associations between endometriosis subtypes and ovarian cancer histotypes have not been well-described. OBJECTIVE: To evaluate the associations of endometriosis subtypes with incidence of ovarian cancer, both overall and by histotype. DESIGN, SETTING, AND PARTICIPANTS: Population-based cohort study using data from the Utah Population Database. The cohort was assembled by matching 78 893 women with endometriosis in a 1:5 ratio to women without endometriosis. EXPOSURES: Endometriosis cases were identified via electronic health records and categorized as superficial endometriosis, ovarian endometriomas, deep infiltrating endometriosis, or other. MAIN OUTCOMES AND MEASURES: Estimated adjusted hazard ratios (aHRs), adjusted risk differences (aRDs) per 10 000 women, and 95% CIs for overall ovarian cancer, type I ovarian cancer, and type II ovarian cancer comparing women with each type of endometriosis with women without endometriosis. Models accounted for sociodemographic factors, reproductive history, and past gynecologic operations. RESULTS: In this Utah-based cohort, the mean (SD) age at first endometriosis diagnosis was 36 (10) years. There were 597 women with ovarian cancer. Ovarian cancer risk was higher among women with endometriosis compared with women without endometriosis (aHR, 4.20 [95% CI, 3.59-4.91]; aRD, 9.90 [95% CI, 7.22-12.57]), and risk of type I ovarian cancer was especially high (aHR, 7.48 [95% CI, 5.80-9.65]; aRD, 7.53 [95% CI, 5.46-9.61]). Ovarian cancer risk was highest in women with deep infiltrating endometriosis and/or ovarian endometriomas for all ovarian cancers (aHR, 9.66 [95% CI, 7.77-12.00]; aRD, 26.71 [95% CI, 20.01-33.41]), type I ovarian cancer (aHR, 18.96 [95% CI, 13.78-26.08]; aRD, 19.57 [95% CI, 13.80-25.35]), and type II ovarian cancer (aHR, 3.72 [95% CI, 2.31-5.98]; aRD, 2.42 [95% CI, -0.01 to 4.85]). CONCLUSIONS AND RELEVANCE: Ovarian cancer risk was markedly increased among women with ovarian endometriomas and/or deep infiltrating endometriosis. This population may benefit from counseling regarding ovarian cancer risk and prevention and could be an important population for targeted screening and prevention studies.

OBJECTIVE: To assess patient response rates to medical therapies used to treat endometriosis-associated pain. DESIGN: A systematic review with the use of Medline and Embase. SETTING: Not applicable. PATIENT(S): Women receiving medical therapy to treat endometriosis. INTERVENTIONS(S): None. MAIN OUTCOME MEASURE(S): The proportions of patients who: experienced no reduction in endometriosis-associated pain symptoms; had pain symptoms remaining at the end of the treatment period; had pain recurrence after treatment cessation; experienced an increase or no change in disease score during the study; were satisfied with treatment; and discontinued therapy owing to adverse events or lack of efficacy. The change in pain symptom severity experienced during and after treatment, as measured on the visual analog scale, was also assessed. RESULT(S): In total, 58 articles describing 125 treatment arms met the inclusion criteria. Data for the response of endometriosis-associated pain symptoms to treatment were presented in only 29 articles. The median proportions of women with no reduction in pain were 11%-19%; at the end of treatment, 5%-59% had pain remaining; and after follow-up, 17%-34% had experienced recurrence of pain symptoms after treatment cessation. After median study durations of 2-24 months, the median discontinuation rates due to adverse events or lack of efficacy were 5%-16%. CONCLUSION(S): Few studies of medical therapies for endometriosis report outcomes that are relevant to patients, and many women gain only limited or intermittent benefit from treatment.

BACKGROUND: Although surgery for endometriosis can improve pain and fertility, the risk of disease recurrence is high. There is little consensus regarding the benefit of medical therapy in preventing recurrence of endometriosis following surgery. OBJECTIVE AND RATIONALE: We performed a review of prospective observational studies and randomised controlled trials (RCTs) to evaluate the risk of endometriosis recurrence in patients undergoing post-operative hormonal suppression, compared to placebo/expectant management. SEARCH METHODS: The following databases were searched from inception to March 2020 for RCTs and prospective observational cohort studies: MEDLINE, Embase, Cochrane CENTRAL and Web of Science. We included English language full-text articles of pre-menopausal women undergoing conservative surgery (conserving at least one ovary) and initiating hormonal suppression within 6 weeks post-operatively with either combined hormonal contraceptives (CHC), progestins, androgens, levonorgesterel-releasing intra-uterine system (LNG-IUS) or GnRH agonist or antagonist. We excluded from the final analysis studies with <12 months of follow-up, interventions of diagnostic laparoscopy, experimental/non-hormonal treatments or combined hormonal therapy. Risk of bias was assessed using the Cochrane Risk of Bias Tool for RCTs and the Newcastle-Ottawa Scale (NOS) for observational studies. OUTCOMES: We included 17 studies (13 RCTs and 4 cohort studies), with 2137 patients (1189 receiving post-operative suppression and 948 controls), which evaluated various agents: CHC (6 studies, n = 869), progestin (3 studies, n = 183), LNG-IUS (2 studies, n = 94) and GnRH agonist (9 studies, n = 1237). The primary outcome was post-operative endometriosis recurrence, determined by imaging or recurrence of symptoms, at least 12 months post-operatively. The secondary outcome was change in endometriosis-related pain. Mean follow up of included studies ranged from 12 to 36 months, and outcomes were assessed at a median of 18 months. There was a significantly decreased risk of endometriosis recurrence in patients receiving post-operative hormonal suppression compared to expectant management/placebo (relative risk (RR) 0.41, 95% CI: 0.26 to 0.65), 14 studies, 1766 patients, I2 = 68%, random effects model). Subgroup analysis on patients treated with CHC and LNG-IUS as well as sensitivity analyses limited to RCTs and high-quality studies showed a consistent decreased risk of endometriosis recurrence. Additionally, the patients receiving post-operative hormonal suppression had significantly lower pain scores compared to controls (SMD -0.49, 95% CI: -0.91 to -0.07, 7 studies, 652 patients, I2 = 68%). WIDER IMPLICATIONS: Hormonal suppression should be considered for patients not seeking pregnancy immediately after endometriosis surgery in order to reduce disease recurrence and pain. Various hormonal agents have been shown to be effective, and the exact treatment choice should be individualised according to each woman's needs.

OBJECTIVE: To describe the current evidence-based diagnosis and management of adenomyosis. TARGET POPULATION: All patients with a uterus of reproductive age. OPTIONS: Diagnostic options include transvaginal sonography and magnetic resonance imaging. Treatment options should be tailored to symptoms (heavy menstrual bleeding, pain, and/or infertility) and include medical options (non-steroidal anti-inflammatory drugs, tranexamic acid, combined oral contraceptives, levonorgestrel intrauterine system, dienogest, other progestins, gonadotropin-releasing analogues), interventional options (uterine artery embolization), and surgical options (endometrial ablation, excision of adenomyosis, hysterectomy). OUTCOMES: Outcomes of interest include reduction in heavy menstrual bleeding, reduction in pelvic pain (dysmenorrhea, dyspareunia, chronic pelvic pain), and improvement in reproductive outcomes (fertility, miscarriage, adverse pregnancy outcomes). BENEFITS, HARMS, AND COSTS: This guideline will benefit patients with gynaecological complaints that may be caused by adenomyosis, especially those patients who wish to preserve their fertility, by presenting diagnostic methods and management options. It will also benefit practitioners by improving their knowledge of various options. EVIDENCE: Databases searched were MEDLINE Reviews, MEDLINE ALL, Cochrane, PubMed, EMBASE. The initial search was completed in 2021 and updated with relevant articles in 2022. Search terms included adenomyosis, adenomyoses, endometritis (used/indexed as adenomyosis before 2012), (endometrium AND myometrium) uterine adenomyosis/es, symptom/s/matic adenomyosis] AND [diagnosis, symptoms, treatment, guideline, outcome, management, imaging, sonography, pathogenesis, fertility, infertility, therapy, histology, ultrasound, review, meta-analysis, evaluation]. Articles included randomized controlled trials, meta-analyses, systematic reviews, observational studies, and case reports. Articles in all languages were searched and reviewed. VALIDATION METHODS: The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. See online Appendix A (Table A1 for definitions and Table A2 for interpretations of strong and conditional [weak] recommendations). INTENDED AUDIENCE: Obstetrician-gynaecologists, radiologists, family physicians, emergency physicians, midwives, registered nurses, nurse practitioners, medical students, residents, and fellows. TWEETABLE ABSTRACT: Adenomyosis is common in reproductive-aged women. There are diagnostic and management options that preserve fertility available. SUMMARY STATEMENTS: RECOMMENDATIONS.

OBJECTIVE: To conduct a systematic review of the literature on patients with extrapelvic deep endometriosis. DATA SOURCES: A thorough search of the PubMed/Medline, Embase, and Cochrane databases was performed. METHODS OF STUDY SELECTION: Studies in the last 20 years that reported on primary extrapelvic endometriosis were included (PROSPERO registration number CRD42019125370). TABULATION, INTEGRATION, AND RESULTS: The initial search identified 5465 articles, and 179 articles, mostly case reports and series, were included. A total of 230 parietal (PE), 43 visceral (VE), 628 thoracic (TE), 6 central nerve system, 12 extrapelvic muscle or nerve, and 1 nasal endometriosis articles were identified. Abdominal endometriosis was divided into PE and VE. PE lesions involved primary lesions of the abdominal wall, groin, and perineum. When present, symptoms included a palpable mass (99%), cyclic pain (71%) and cyclic bleeding (48%). Preoperative clinical suspicion was low, the use of tissue diagnosis was indeterminate (25%), and a few (8%) malignancies were suspected. Surgical treatment for PE included wide local excision (97%), with 5% recurrence and no complications. Patients with VE involving abdominal organs - kidneys, liver, pancreas, and biliary tract - were treated surgically (86%) with both conservative (51%) and radical resection (49%), with 15% recurrence and 2 major complications reported. In patients with TE involving the diaphragm, pleura, and lung, isolated and concomitant lesions occurred and favored the right side (80%). Patients with TE presented with the triad of catamenial pain, pneumothorax, and hemoptysis. Thoracoscopy with resection followed by pleurodesis was the most common procedure performed, with 29% recurrence. Adjuvant medical therapy with gonadotropin-releasing hormone was administered in 15% of cases. Preoperative magnetic resonance imaging was performed in all cases of nonthoracic and nonabdominal endometriosis. Common symptoms were paresthesia and cyclic pain with radiation. Surgical resection was reported in 84%, with improvement of symptoms. CONCLUSION: Extrapelvic endometriosis, traditionally thought to be rare, has been reported in a considerable number of cases. Heightened awareness and clinical suspicion of the disease and a multidisciplinary approach are recommended to achieve a prompt diagnosis and optimize patient outcomes. Currently, there are no comparative studies to provide recommendations regarding optimal diagnostic methods, treatment options, and outcomes for endometriosis involving extrapelvic sites.

Adenomyosis is a common disorder of the uterus, and is associated with an enlarged uterus, heavy menstrual bleeding (HMB), pelvic pain, and infertility. It is characterized by endometrial epithelial cells and stromal fibroblasts abnormally found in the myometrium where they elicit hyperplasia and hypertrophy of surrounding smooth muscle cells. While both the mechanistic processes and the pathogenesis of adenomyosis are uncertain, several theories have been put forward addressing how this disease develops. These include intrinsic or induced (1) microtrauma of the endometrial-myometrial interface; (2) enhanced invasion of endometrium into myometrium; (3) metaplasia of stem cells in myometrium; (4) infiltration of endometrial cells in retrograde menstrual effluent into the uterine wall from the serosal side; (5) induction of adenomyotic lesions by aberrant local steroid and pituitary hormones; and (6) abnormal uterine development in response to genetic and epigenetic modifications. Dysmenorrhea, HMB, and infertility are likely results of inflammation, neurogenesis, angiogenesis, and contractile abnormalities in the endometrial and myometrial components. Elucidating mechanisms underlying the pathogenesis of adenomyosis raise possibilities to develop targeted therapies to ameliorate symptoms beyond the current agents that are largely ineffective. Herein, we address these possible etiologies and data that support underlying mechanisms.

Endometriosis is a gynecologic condition often described as the "chameleon of gynecology" because of its elusive symptoms. The World Health Organization acknowledges its severe impact on quality of life due to pain, fatigue, depression, and infertility. There is limited literature on the prevalence of endometriosis, knowledge of which is essential for effective prevention, treatment strategies, and funding. We aim to structure and present the published data on endometriosis prevalence, synthesizing the discrepancy between health insurance and clinical data. PubMed, Cochrane CENTRAL, and LIVIVO were researched for peer-reviewed articles published between January 2000 and July 2023 on women of reproductive age. Health insurance companies argue that few women (~1%) are affected by endometriosis. Interestingly, the prevalence of clinical data studies (6.8%), population-based surveys/self-reported studies (6.6%), and symptomatic patient data (21%) revealed a different picture. Based on the data gathered, a multi-layered prevalence model has been proposed to illustrate the large discrepancy in the prevalence numbers, leading to the disease being underestimated and underfunded. This variability may be influenced by the heterogeneity in designs and the analyzed data, and clinical complexity. In summary, this narrative review reveals that the prevalence of endometriosis is higher than health insurance and other stakeholders might have previously assumed.

STUDY QUESTION: What is the prevalence of adenomyosis in a population of women attending a general gynaecological clinic? SUMMARY ANSWER: Adenomyosis was present in 206 of 985 [20.9%; 95% confidence interval (CI): 18.5-23.6%] women included in the study. WHAT IS KNOWN ALREADY: Previous studies of occurrence of adenomyosis have been limited to women who underwent hysterectomy, which is likely to overestimate its prevalence compared with the general population of women. There are no large prospective studies on the prevalence of adenomyosis, either in the general population of women or in a general gynaecology clinic setting. STUDY DESIGN, SIZE, DURATION: This was a prospective observational study set in the general gynaecology clinic of a university teaching hospital between January 2009 and January 2010. PARTICIPANTS/MATERIALS, SETTING, METHODS: There were 985 consecutive women who attended the clinic and underwent structured clinical and transvaginal ultrasound examination in accordance with the study protocol. Morphological features of adenomyosis were systematically recorded with the ultrasound scan to determine its prevalence and factors which may affect its occurrence. MAIN RESULTS AND THE ROLE OF CHANCE: Adenomyosis was present in 206/985 [20.9% (95% CI: 18.5-23.6%)] women included in the study. Multivariate analysis showed that the prevalence of adenomyosis was significantly associated with women's age, gravidity and pelvic endometriosis (P< 0.001). In women who subsequently underwent hysterectomy, there was a good level of agreement between the ultrasound and histological diagnosis of adenomyosis [κ = 0.62 (P = 0.001), 95% CI (0.324, 0.912)]. LIMITATIONS, REASONS FOR CAUTION: Our estimate of prevalence of adenomyosis is likely to be higher than in the general population as we studied symptomatic women attending a gynaecology clinic. WIDER IMPLICATIONS OF THE FINDINGS: Better estimates of the prevalence of adenomyosis can improve our understanding of the burden of the disease, help to identify women at high risk of developing the condition and facilitate the development of preventative strategies and effective treatment. STUDY FUNDING/COMPETING INTEREST(S): The authors have no competing interests to declare. The study was not supported by an external grant.

Adenomyosis, characterized by the presence of endometrial glands and stroma within the myometrium, can have a substantial impact on the quality of women's lives. Despite this, the epidemiologic research on this condition lags considerably behind that of other noncancerous reproductive health conditions. The lack of progress and knowledge is due in part to the challenges in designing valid epidemiologic studies, since the diagnosis of adenomyosis historically has been limited to the examination of uterine specimens from hysterectomy. This review describes the available data on the frequency of this condition and the epidemiologic investigation thus far into the risk factors for disease-highlighting the methodologic and inference challenges primarily around study sample selection. We conclude with providing recommendations for approaches to future epidemiologic study that capitalize on the advancements in imaging technology to detect adenomyosis and provide a fuller picture of the occurrence and risk factors for disease.

The association between nutrition and endometriosis is controversial. This umbrella review aimed to investigate whether specific dietetic strategies are useful for reducing endometriosis risk/symptoms. Systematic reviews on diet therapies for endometriosis were analyzed using the Joanna Briggs Institute (JBI) Manual for Evidence Synthesis methodology, and an umbrella review was implemented using Jamovi software. The 10 included systematic reviews comprised observational studies (cohort, case-control, cross-sectional) and interventional trials (randomized, non-randomized). A mild (class IV, lowest strength on evidence quartile) protective effect on vegetables (RR 0.590; 95% CI 0.49-0.71 p < 0.001), cheese (OR 0.840; 95% CI 0.74-0.96 p = 0.011), total dairy (RR 0.874; 95% CI 0.81-0.95 p = 0.001), and high-fat dairy (RR 0.590; 95% CI 0.81-0.99 p = 0.025) was found. Butter (RR 1.266; 95% CI 1.03-1.55 p = 0.024) and high caffeine (>300 mg/day) (RR 1.303; 95% CI 1.05-1.62 p = 0.019) consumption increased the risk of endometriosis. Other food groups had low-quality evidence due to limited studies. A higher intake of vegetables and dairy products may reduce the risk and/or symptoms of endometriosis, while a high intake of caffeine and butter may increase the risk. However, the heterogeneity across studies is significant, and the overall quality of the findings is low. Therefore, it is crucial to conduct new research in this field, focusing on well-designed randomized trials.

BACKGROUND & OBJECTIVES: Endometriosis is one of the causes of female infertility, but the prevalence of endometriosis is not exactly known. We conducted a systematic review and meta-analysis to provide an estimate of the prevalence of endometriosis in women considering the stage of disease, diagnostic method, geographical distribution, clinical symptoms and sample size. METHODS: MEDLINE, Web of Science, Google Scholar, Scopus and Cumulative Index of Nursing and Allied Health were searched to identify peer-reviewed studies published from January 1990 to December 2018 reporting the prevalence of endometriosis. Relevant additional articles were identified from the lists of the retrieved articles. Studies with cross-sectional design were included in the meta-analysis. RESULTS: The overall prevalence of endometriosis was 18 per cent [95% confidence interval (CI): 16-20] and the prevalence of endometriosis by stage ranged from two per cent (95% CI: 1-4) for stage 4 to 20 per cent (95% CI: 11-28) for stage 1. The prevalence levels of endometriosis in women with infertility, chronic pelvic pain and asymptomatic were 31 (95% CI: 15-48), 42 (95% CI: 25-58) and 23 per cent (95% CI: 19-26), respectively. INTERPRETATION & CONCLUSIONS: The results of this study showed that the prevalence of endometriosis in developing countries was high. Future studies are needed to explore other factors affecting the prevalence of endometriosis worldwide, which may help develop future prevention programmes.

In 2015, the international Morphological Uterus Sonographic Assessment (MUSA) group published a consensus on which terminology to use when describing myometrial lesions seen on ultrasonography1. The use of MUSA terminology to describe ultrasound images of fibroids, including their location according to the International Federation of Gynecology and Obstetrics (FIGO), is relatively straightforward to implement2, 3. However, even though the MUSA consensus statement suggests which terms should be used to describe ultrasound images of adenomyosis, it does not provide guidelines on how to classify morphological types or the extent of adenomyosis1. We propose a uniform reporting system for ultrasound findings of adenomyosis. The opinion presented herein is based on a thorough discussion among all authors, including a Delphi procedure (Appendix S1). Images and videos of cases typical of the different morphological variations of adenomyosis were used in the debates. The gold standard for the diagnosis of adenomyosis is histological examination of a hysterectomy specimen. Because only a small, selected group of women undergo hysterectomy, an accurate estimation of the prevalence of the disease cannot be established4. The introduction of imaging techniques such as transvaginal sonography and magnetic resonance imaging (MRI) has allowed non-invasive diagnosis of adenomyosis5-8. Ultrasound imaging is widely available in an office setting, is relatively inexpensive, requires no preparation, has no contraindications and is relatively accurate in expert hands, making it the imaging modality of choice in gynecology7. Although adenomyosis is usually diagnosed in women between 40 and 60 years of age, it is also described in younger women, in whom any surgery performed on the uterus might adversely affect child-bearing9. The treatment of choice for adenomyosis is primarily hormonal (e.g. levonorgestrel intrauterine device; oral progestins)10. Patient management is often based on ultrasound diagnosis alone. This highlights the importance of a uniform, reproducible and clinically relevant reporting system for ultrasound findings of adenomyosis. Uniform reporting also facilitates studies on the prevalence, etiology and clinical implications of adenomyosis and on the effectiveness of therapies. There are various theories about the pathogenesis of adenomyosis. It is commonly thought to originate from direct contact between the endometrium and the underlying myometrium, which allows the formation of ectopic endometrial glands and stroma. However, the precise pathophysiological pathway is not known. Reported risk factors for adenomyosis include multiparity11, 12 and previous uterine surgery13-16 (curettage and Cesarean delivery), suggesting a possible role of damage to the endometrial–myometrial junction. Such damage allowing the growth of ectopic endometrial glands and stroma into the myometrium may explain ultrasound findings of subendometrial lines and buds with expansion to hyperechogenic islands in the myometrium (Figure 1)1. On the other hand, Kishi et al.17 reported infiltration of endometriosis from outside the uterus, with disruption of the serosa and infiltration of the external myometrium inducing another subtype of adenomyosis. Extrauterine adenomyosis has also been reported, for example in the rectovaginal septum18. Other theories involve infolding of endometrium which then penetrates into the myometrium, basement membrane damage through single nucleotide polymorphisms, and initiation/progression of adenomyosis modulated by vascular factors and estrogen receptors18-20. The histologic diagnosis of adenomyosis is made by observing the presence of endometrial stroma and glands in the myometrium. However, there is no consensus among pathologists, and various histopathological definitions have been reported, including: (1) disruption of the normal boundary between the endometrium and myometrium21, 22, (2) presence of ectopic endometrium that is basal-type non-secretory tissue with a direct connection to the basalis layer5, (3) myometrial invasion by endometrium > 4 mm below the basalis layer23, (4) myometrial invasion by endometrium > 2.5 mm below the basalis layer5, (5) endometrial invasion to > 25% of the thickness of the uterine musculature, as measured from the endometrial–myometrial junction18. On histology, adenomyosis is classified as focal if there are circumscribed nodular aggregates of endometrial glands and stroma surrounded by normal myometrium, and diffuse if there are endometrial glands and stroma distributed diffusely throughout the myometrium24. Adenomyomas are a subgroup of focal adenomyosis surrounded by hypertrophic myometrium25. Different histological disease severity classifications have been suggested, but without international consensus17, 26-30. The ultrasound characteristics of adenomyosis reflect the histological features. Different morphological types, seen on ultrasound examination or histological examination, may reflect different stages in the development of the disease, and may have different clinical significance with respect to symptomatology, fertility, obstetric outcome and therapeutic options. Clearly, there is a need for an internationally accepted, uniform classification of adenomyosis that, preferably, can be achieved using ultrasound. Seven items should be assessed when examining and describing a uterus with adenomyosis. First, the myometrium should be classified as normal or as abnormal, and, in the latter case, according to whether it manifests signs of adenomyosis, myoma or sarcoma, using MUSA terminology1. Other myometrial lesions to be considered in the differential diagnosis are accessory cavitated uterine masses, also reported as juvenile cystic adenomyoma, and postoperative uterine scarring, including focal loss of myometrium and fistulae31. MUSA features typical of a uterus with adenomyosis include an enlarged globular uterus, asymmetrical thickening of the myometrium, myometrial cysts, echogenic subendometrial lines and buds, hyperechogenic islands, fan-shaped shadowing, an irregular or interrupted junctional zone and translesional vascularity on color Doppler ultrasound examination (Figure 2)1. The definitions of these features can be found in the MUSA Consensus Opinion1. The location of the adenomyosis should be described as anterior, posterior, lateral left, lateral right or fundal. To determine the exact location, the uterus should be examined in both sagittal and transverse planes. The additional value of three-dimensional ultrasound to examine the coronal plane of the uterus needs to be established in future studies. In each location, it should be determined whether the adenomyosis is focal or diffuse, by estimating the relative proportions of the lesion and the surrounding normal myometrium on a sagittal section through the uterus where the adenomyotic lesion appears to be at its largest (Figure 3). We propose that an adenomyotic lesion should be defined as focal if > 25% of the circumference of the lesion is surrounded by normal myometrium. Adenomyosis is classified as diffuse if < 25% of the lesion is surrounded by normal myometrium. If it is difficult to differentiate focal from diffuse adenomyosis, the lesion should be reported as diffuse. If there is both diffuse and focal adenomyosis in different locations in the uterus, this should be classified as ‘mixed-type adenomyosis’. Futures studies are needed to determine the value of using the transverse and/or coronal planes for discriminating between focal and diffuse adenomyosis. When focal adenomyosis is demarcated distinctly and surrounded by hypertrophic myometrium, it is called an adenomyoma8 (Figure 3). Adenomyosis should be classified as cystic or non-cystic (Figure 4). Presence of cysts should be reported for all types of adenomyosis (focal, diffuse, mixed-type and adenomyoma). Adenomyosis is defined as cystic in the presence of measurable myometrial cysts, i.e. with largest diameter ≥ 2 mm. Cystic fluid is usually anechoic or of low-level echogenicity, and cysts may be surrounded by an echogenic rim. It is sufficient to measure the largest diameter of the largest cyst only, and whether the rim is echogenic should be recorded. We propose that involvement of the uterine layers, not only the junctional zone but also the other layers of the myometrium and serosa, should be evaluated, and speculate that the number and type of layers involved might depend on the etiology of adenomyosis and be associated with the clinical presentation. Adenomyosis may involve one or more of three uterine layers: the junctional zone (the inner myometrium, also called the subendometrial layer, consisting of longitudinal and circular, closely packed, smooth-muscle fibers); the middle myometrium (the myometrium between the vascular arcade and the junctional zone, consisting of crisscrossing muscle fibers); and the outer myometrium (the subserosal layer, i.e. the layer between the serosa and the vascular arcade)17, 28, 32-34 (Figure 5). If the outer myometrium is involved, the serosal layer may be intact or interrupted. To help identify serosal involvement of adenomyosis, the presence of sliding of or fixed viscera32 (bowels) against the uterus should always be recorded. Discussion of ultrasound examination with regard to concomitant superficial or deep endometriosis35 is beyond the scope of this Opinion. Involvement of one of the three layers is recorded as Type 1, 2 or 3, as appropriate (Figure 5). If more than one layer is involved, the type is recorded and described, for example, as Type 1–2, Type 2–3 or Type 1–3. To differentiate between involvement of the subserosal layer and middle myometrial layer, it may help to use color Doppler and estimate the location in relation to the vascular arcade. Future studies are needed to determine whether it is feasible to differentiate between the three muscle layers, and if there is any clinical value in differentiating between the middle and outer myometrium. The extent of the disease should be assessed subjectively, based on the estimated proportion of the uterine corpus that is affected by adenomyosis, and classified as: mild ( 50% affected). If there are adenomyotic lesions in different locations, the sum of volumes of the different lesions should be estimated when describing the extent of the disease. The estimated extent of the disease might not be associated with the type or severity of symptoms, but may be useful for research purposes. The largest diameter of the adenomyosis lesion(s) should be measured. In clinical situations, this should be done in the plane of the largest diameter of the largest lesion. In the research setting, we advise measurement of the largest diameter of each focal lesion. In the case of a diffuse lesion, the myometrial wall thickness should be measured and the site involved noted. Future studies are needed to estimate the additional value of assessing lesion size in all three orthogonal planes. We propose a consensus-based practical classification of adenomyosis, on the basis of ultrasound findings (Figure 6), that consists of: (1) identification of the presence of adenomyosis, using the MUSA criteria1; (2) determination of location of the adenomyosis; (3) differentiation between focal and diffuse disease; (4) discrimination between cystic and non-cystic lesion; (5) determination of myometrial layer involvement; (6) classification of disease extent as mild, moderate or severe; (7) measurement of size of lesion. Cycle day and current hormonal use should always be recorded. Several examples of classification are given in Table 1. Sliding viscera: yes JZ (inner myometrium) and middle myometrium (Type 1–2) 2 cm Focal Type-1–2 cystic adenomyosis in anterior wall Extent: mild Max diam: 2 cm Sliding viscera: no JZ (inner myometrium), middle myometrium and outer myometrium (subserosa)(Type 1–3) Diffuse Type-1–3 cystic adenomyosis in posterior wall Extent: moderate Max diam: 3 cm Diffuse Type-1–2 adenomyosis in anterior wall Extent: severe Max diam: 7 cm Mixed-type cystic adenomyosis: Type-1–2 adenomyoma in anterior wall and Type-3 focal adenomyosis in left lateral side Extent: mild Max diam: 1. Adenomyoma: 3 cm 2. Focal lesion: 2 cm Mixed-type cystic adenomyosis: Type-2 focal adenomyosis in left lateral wall and diffuse Type-1–3 adenomyosis in anterior wall Extent: Severe Max diam: 1. Focal lesion: 4 cm 2. Diffuse lesion: 7 cm Although this consensus was developed using MUSA terms and definitions, we have proposed some changes. For example, using the original MUSA terminology, an ‘ill-defined lesion’ may be localized or diffuse, the latter being a lesion involving at least 50% of the total uterine volume1. We suggest reporting adenomyosis as focal or diffuse in each location. For example, it should be possible to report focal adenomyosis in the anterior wall and diffuse adenomyosis in the posterior wall, using the definition of focal disease outlined above. A second slight adjustment is the specification of the myometrial layer involved. This classification should facilitate consistent reporting of adenomyosis, but it needs to be validated and refined in future studies. For example, the feasibility and reproducibility of the differentiation between the middle and outer myometrial layers using power Doppler needs to be assessed. Likewise, the additional value of the use of transverse and/or coronal planes (the latter using three-dimensional ultrasound) for the assessment of location, extent and size of adenomyotic lesions needs to be investigated further. Research is also needed to assess the accuracy of ultrasound examination in the diagnosis of focal vs diffuse adenomyosis. In a prospective case series assessing uterine lesions in hysterectomy specimens, some adenomyosis lesions appeared to be much more extensive than was suspected at ultrasonography or on macroscopic examination36. The possibility of diffuse disease not being detected at ultrasound examination should be borne in mind when planning management of patients with adenomyosis and when planning studies. Several recent studies have shown that the number of morphological features of adenomyosis is associated with clinical symptoms and success of fertility treatment37-39. However, more research is needed to evaluate the importance of different ultrasound features. In our clinical experience, some women with small lesions may present with severe symptoms of pain and uterine bleeding, whereas others with larger lesions may be asymptomatic. Clearly, the classification we have suggested cannot be used on its own to decide on treatment. The proposed classification might need to be amended after external validation and based on the results of future studies evaluating the relationships between ultrasound features, clinical symptoms, histological findings and possibly also MRI findings. There are still uncertainties regarding the clinical importance of myometrial cysts, the relevance of discriminating between the uterine layers and the reliability of estimating disease extent. A study addressing the intra- and interobserver variability using the proposed reporting is also needed. Our suggested approach should be considered only as a first step towards an internationally accepted classification and reporting system. Finally, we recognize that some aspects of the suggested reporting and classification system might require extensive ultrasound skills. After validation and optimization of this proposed classification, it would be reasonable to develop an e-learning program for less experienced ultrasonographers. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

BACKGROUND AND OBJECTIVE: Endometriosis is associated with pain and impaired health-related quality of life (HRQoL). Psychosocial factors have been associated with pain and HRQoL in other conditions, suggesting their potential relevance in Endometriosis. However, the role of psychosocial factors in this population has not been systematically explored yet. This systematic review aims to explore the association of psychosocial factors with pain intensity/severity and HRQoL in women with Endometriosis. DATABASES AND DATA TREATMENT: Observational and experimental studies that explored the association of psychosocial factors with pain and HRQoL in women with Endometriosis were eligible. The following databases were searched: Medline, Embase, Cochrane library, Web of Science, PsychInfo and Cumulative index of nursing and allied health literature. The methodological quality was assessed, and findings were synthesized using narrative synthesis. RESULTS: Twenty-seven studies were eligible for inclusion, which included 5419 women with Endometriosis. Catastrophising and anxiety were the factors most consistently associated with greater pain, whilst depression, anxiety and stress were related to worse HRQoL. Findings regarding depression and pain were mixed, and research on social factors was limited. CONCLUSIONS: This systematic review highlights the role of psychosocial factors in Endometriosis. Anxiety, depression and catastrophising are suggested as potential treatment targets. The review also indicates the lack of research on other potentially important psychosocial factors, such as avoidance, perceived injustice and social support. SIGNIFICANCE: This systematic review explored the role of psychosocial factors in Endometriosis, suggesting that these are associated with pain and health-related quality of life (HRQoL). Among the psychosocial factors included, anxiety, depression and catastrophising were the factors most often associated with pain and HRQoL in Endometriosis. These findings highlight the need to target psychological factors in the treatment of women with Endometriosis.

STUDY QUESTION: What is the role of iron in the pathophysiology of endometriosis? SUMMARY ANSWER: Iron excess is demonstrated wherever endometriotic tissues are found and is associated with oxidative stress, an inflammatory micro-environment, and cell damage; the iron-mediated oxidative stress is independently linked to subfertility, symptom severity, and malignant transformation. WHAT IS KNOWN ALREADY: Iron is found in excess in endometriotic tissues, and multiple mechanisms have been studied and posited to explain this. It is clear that iron excess plays a vital role in promoting oxidative stress and cell damage. The evidence base is large, but no comprehensive reviews exist to summarize our understanding and highlight the overarching themes to further our understanding and suggest future directions of study for the field. STUDY DESIGN SIZE DURATION: This systematic review with a thematic analysis retrieved studies from the PubMed, Embase, Web of Science, and Cochrane Library databases and searches were conducted from inception through to August 2022. Human and animal studies published in the English language were included and identified using a combination of exploded MeSH terms ('Iron' and 'Endometriosis') and free-text search terms ('Iron', 'Ferric', 'Ferrous', 'Endometriosis', 'Endometrioma'). PARTICIPANTS/MATERIALS SETTING METHODS: This review was reported in accordance with the PRISMA guidelines. All studies reporting original data concerning the role of iron or iron complexes in the pathophysiology of endometriosis were included. Studies that did not report original data or provided a review of the field were excluded. Bias analysis was completed for each included study by using the Newcastle-Ottawa scoring system. MAIN RESULTS AND THE ROLE OF CHANCE: There were 776 records identified and these were screened down to 53 studies which met the eligibility criteria, including 6 animal and 47 human studies, with 3556 individual participants. Iron excess is demonstrated in various tissues and fluids, including ovarian endometriomas, ovarian follicles, ectopic endometriotic lesions, and peritoneal fluid. Markers of oxidative stress are strongly associated with high iron levels, and aberrant expression of iron-transport proteins has been demonstrated. Abnormal resistance to ferroptosis is likely. Iron-mediated oxidative stress is responsible for a pro-inflammatory micro-environment and is linked to subfertility, symptom severity, and, possibly, malignant transformation. LIMITATIONS REASONS FOR CAUTION: A minority of the included studies were of objectively low quality with a high risk of bias and may lead to misleading conclusions. Additionally, multiple studies failed to appropriately characterize the included patients by known confounding variables, such as menstrual cycle phase, which may introduce bias to the findings. WIDER IMPLICATIONS OF THE FINDINGS: Current literature depicts a central role of aberrant iron mechanics and subsequent oxidative stress in endometriosis. It is likely that iron excess is at least partly responsible for the persistence and proliferation of ectopic endometriotic lesions. As such, iron mechanics represent an attractive target for novel therapeutics, including iron chelators or effectors of the iron-oxidative stress pathway. There are significant gaps in our current understanding, and this review highlights and recommends several topics for further research. These include the role of iron chelation, resistance to ferroptosis, the relationship between iron excess and localized hypoxia, systemic iron pathophysiology in endometriosis, and the role of oxidative stress in malignant transformation. STUDY FUNDING/COMPETING INTERESTS: J.W. and S.G.P. are supported by clinical fellowships at Liverpool University Hospital NHS Foundation trust. No additional funding was requested or required for the completion of this work. C.J.H. is supported by a Wellbeing of Women project grant (RG2137). D.K.H. is supported by a Wellbeing of Women project grant (RG2137) and an MRC clinical research training fellowship (MR/V007238/1). The authors have no conflicts of interest to declare. REGISTRATION NUMBER: A protocol was prospectively registered with the PROSPERO database in August 2021 (CRD42021272818).

(No abstract on file for this paper.)

OBJECTIVE: To study the pathophysiology of endometriosis. DESIGN: Overview of observations on endometriosis. SETTING: Not applicable. PATIENT(S): None. INTERVENTIONS(S): None. MAIN OUTCOME MEASURE(S): The hypothesis is compatible with all observations. RESULT(S): Endometriosis, endometrium-like tissue outside the uterus, has a variable macroscopic appearance and a poorly understood natural history. It is a hereditary and heterogeneous disease with many biochemical changes in the lesions, which are clonal in origin. It is associated with pain, infertility, adenomyosis, and changes in the junctional zone, placentation, immunology, plasma, peritoneal fluid, and chronic inflammation of the peritoneal cavity. The Sampson hypothesis of implanted endometrial cells following retrograde menstruation, angiogenic spread, lymphogenic spread, or the metaplasia theory cannot explain all observations if metaplasia is defined as cells with reversible changes and an abnormal behavior/morphology due to the abnormal environment. We propose a polygenetic/polyepigenetic mechanism. The set of genetic and epigenetic incidents transmitted at birth could explain the hereditary aspects, the predisposition, and the endometriosis-associated changes in the endometrium, immunology, and placentation. To develop typical, cystic ovarian or deep endometriosis lesions, a variable series of additional transmissible genetic and epigenetic incidents are required to occur in a cell which may vary from endometrial to stem cells. Subtle lesions are viewed as endometrium in a different environment until additional incidents occur. Typical cystic ovarian or deep endometriosis lesions are heterogeneous and represent three different diseases. CONCLUSION(S): The genetic epigenetic theory is compatible with all observations on endometriosis. Implications for treatment and prevention are discussed.

Endometriosis is a chronic disease that affects about 10% of women of reproductive age. It can contribute to pelvic pain, infertility or other conditions such as asthma, cardiovascular disease, breast or ovarian cancer. Research has shown that one of the conditions for the development of endometrial lesions is the dysfunction of the immune system. It appears that immune cells, such as neutrophils, macrophages, NK cells and dendritic cells, may play a specific role in the angiogenesis, growth and invasion of endometriosis cells. Immune cells secrete cytokines and defensins that also affect the endometriosis environment. This review discusses the various components of the immune system that are involved in the formation of endometrial lesions in women.

BACKGROUND: Diagnosis of endometriosis is a challenge. The recent development of a saliva-based micro-ribonucleic acid (miRNA) signature for the diagnosis of endometriosis may enable a timelier and less invasive approach, but this requires external validation. METHODS: The prospective, multicenter validation of the salivary miRNA signature of endometriosis (ENDOmiRNA) study aimed to assess the diagnostic accuracy, validate the biological reproducibility, and evaluate the clinical utility of a saliva miRNA signature of endometriosis. The study population comprised patients 18 to 43 years of age with signs and symptoms suggestive of endometriosis, who were recruited from diverse medical settings. Patients received a diagnosis of endometriosis by imaging, laparoscopic procedure, or both. All patients who were determined to not have endometriosis were classified as controls (and all underwent laparoscopy). Assessment of endometriosis status based on the saliva miRNA signature was established blinded to patients' endometriosis status, as determined by imaging and/or laparoscopy and/or histology. RESULTS: The external validation population was composed of 971 patients, including patients from a prior interim analysis, with an overall endometriosis prevalence of 77%. The saliva miRNA signature had an accuracy (defined as the probability of correct classification for both positive and negative results) of 96.6% (95% confidence interval [CI], 95.2 to 97.6%), a sensitivity of 97.3% (95% CI, 96.4 to 98.0%), a specificity of 94.1% (95% CI, 91.0 to 96.4%), a positive predictive value of 98.2% (95% CI, 97.3 to 98.9%), a negative predictive value of 91.3% (95% CI, 88.3 to 93.4%), a positive likelihood ratio of 16.6 (95% CI, 10.8 to 26.9), and a negative likelihood ratio of 0.03 (95% CI, 0.02 to 0.04). Among patients with surgical confirmation of the diagnosis, misclassification, underestimation, and overestimation rates were 4.6%, 2.4%, and 2.2%, respectively, for the saliva miRNA signature and 27.2%, 15.1%, and 12.2%, respectively, for imaging (either transvaginal ultrasound, magnetic resonance imaging, or both). CONCLUSIONS: This prospective, multicenter external validation study demonstrated the accurate performance of a saliva-based miRNA signature for the diagnosis of endometriosis in this cohort. (Funded by Ziwig; ClinicalTrials.gov number, NCT05244668.).