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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.

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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.

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.

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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. Enfoque sistemático para la evaluación ecográfica de la pelvis en mujeres con posible endometriosis, incluyendo términos, definiciones y mediciones: una opinión consensuada del Grupo Internacional de Análisis de la Endometriosis Profunda La declaración del Grupo Internacional de Análisis de la Endometriosis Profunda (IDEA, por sus siglas en inglés) es una opinión basada en un consenso sobre los términos, definiciones y medidas que se pueden utilizar para describir las características ecográficas de los distintos fenotipos de la endometriosis. Actualmente es difícil comparar los resultados entre los estudios publicados porque los autores utilizan términos diferentes para describir las mismas estructuras y localizaciones anatómicas. Esperamos que los términos y definiciones propuestas en este documento se adopten en centros de investigación de todo el mundo. Esto resultaría en un uso uniforme de la nomenclatura para describir la ubicación y el alcance de la endometriosis en la evaluación ecográfica. Creemos que la normalización de la terminología permitirá realizar comparaciones significativas entre futuros estudios de mujeres con diagnóstico de endometriosis mediante ecografía y debería facilitar la investigación entre múltiples centros de investigación. Endometriosis is a common gynecological problem, affecting approximately 5% of women1. The disease can be found in many sites throughout the pelvis, in particular the ovaries, pelvic peritoneum, pouch of Douglas (POD), rectum, rectosigmoid, rectovaginal septum (RVS), uterosacral ligaments (USLs), vagina and urinary bladder. Correct site-specific diagnosis is fundamental in defining the optimal treatment strategy for endometriosis. Non-invasive imaging methods are required to map accurately the location and extent of endometriotic lesions. The recent consensus statement produced by the World Endometriosis Society recommended the establishment of centers of expertise for the management of higher-stage disease2. This recommendation requires a reliable preoperative system of triage which enables immediate understanding of the location and severity of disease. Increasingly, endometriosis is being managed medically and surgery can be avoided or delayed in a growing proportion of cases. Transvaginal sonography (TVS) is the first-line imaging technique in the diagnosis of pelvic endometriosis and in particular for deep infiltrating endometriosis (DIE)3. It is important to note, however, that there is substantial heterogeneity in the reported sensitivity and specificity of TVS with regard to detection of DIE, irrespective of its location4, 5. Adding ultrasound examination by an experienced operator to history and pelvic examination improves the accuracy of diagnosis of pelvic endometriosis6, 7. In their meta-analysis, Hudelist et al.8 concluded that TVS with or without the use of prior bowel preparation is an accurate test for non-invasive, presurgical detection of DIE of the rectosigmoid. Although the diagnostic performance of ultrasound for detecting DIE reported by individual units is excellent for certain anatomical locations9-11, the lack of standardized definitions in the sonographic classification and diagnosis of DIE is a general cause for concern. This lack of uniformity when classifying anatomical location and extent of disease contributes to the considerable variation in the reported diagnostic accuracy of TVS in the diagnosis of endometriosis. The aim of this consensus opinion is to ensure that the ultrasound examination of a woman with potentially underlying endometriosis is performed in a standardized manner, that the measurement of endometriotic lesions is standardized and that the terminology used when describing the location of DIE and the sonographic features of DIE and other manifestations of endometriosis (endometriomas, adenomyosis, pelvic adhesions) is uniform. This consensus opinion should be useful in clinical practice as well as in research. We believe that careful definition of ultrasound-detected DIE will facilitate interpretation of research and lead to improved clinical care. This work is based on the opinion of a panel of clinicians, gynecological sonologists, advanced laparoscopic surgeons and radiologists (International Deep Endometriosis Analysis (IDEA) group) with expertise in diagnosis and management of endometriosis. Criteria used to invite the experts to participate in this consensus process included their having significant peer-reviewed publications in the field of diagnosis and management of endometriosis. An initial statement was presented in 2011 at the ISUOG congress in Copenhagen12, incorporating several suggestions from all participants. A first draft was written in December 2014 by a joint effort of the two first authors (S.G. and G.C.) and sent to all coauthors. All coauthors had the opportunity to comment within a fixed time limit. Reply was mandatory for coauthorship. Taking all comments into account, a revised draft was then sent to all coauthors. In case of conflicting opinions, a consensus was proposed after discussion between the two first authors and the last author (D.T.). This pathway was repeated until a consensus between all authors was reached. The consensus also included ultrasound images/videos and schematic drawings to illustrate the text. After 13 revisions, the manuscript was deemed ready for submission. In addition to terms, definitions and measurements to describe the sonographic features of DIE, adhesions, adenomyosis and endometriomas, this consensus opinion includes recommendations regarding how to take a history, how to perform a clinical examination, how to perform an ultrasound examination and which ultrasound modality to use when examining patients with suspected or known endometriosis. DIE anatomical locations in this consensus were modified from Chapron's anatomical distribution of pelvic DIE13. A detailed clinical history should be taken for all women with suspected endometriosis, with particular emphasis on symptoms which could be attributed to endometriosis14, 15. The following should be noted specifically: age; height; weight; ethnic origin; parity; bleeding pattern (regular, irregular or absent); last menstrual period; previous surgery for endometriosis (type, effect); previous myomectomy or Cesarean delivery (these entail increased risk of DIE in the bladder); family history of endometriosis; previous non-surgical treatment for endometriosis (type, duration, effect); subfertility including duration of subfertility; treatment for infertility and outcome of fertility treatment; pain (dysmenorrhea, dyspareunia, dysuria, dyschezia, chronic pelvic pain); hematochezia and/or hematuria. The onset and duration of symptoms should be noted and, if possible, the intensity of the pain recorded by letting the patient use a visual analog scale or investigating it with a 0–10 narrative numeric rating scale. A pelvic examination should be performed either before or after the pelvic ultrasound scan, with the aim of defining the presence or absence of vaginal and/or low rectal endometriosis7. The pelvic examination should include speculum examination (direct visualization of vaginal or cervical DIE) and vaginal palpation. Mobility, fixation and/or tenderness of the uterus should be evaluated carefully. Site-specific tenderness in the pelvis should also be evaluated. The purpose of performing an ultrasound examination in a woman with suspected endometriosis is to try to explain underlying symptoms, map the disease location and assess the severity of disease prior to medical therapy or surgical intervention. Various ultrasound approaches have been published, but to date none has been externally validated16, 17. We propose four basic sonographic steps when examining women with suspected or known endometriosis, as shown in Figure 1. Note that these steps can be adopted in this or any order as long as ALL four steps are performed to confirm/exclude the different forms of endometriosis. Using TVS as the first-line imaging tool, the operator should examine the uterus and the adnexa. The mobility of the uterus should be evaluated: normal, reduced or fixed (‘question mark sign’)18. Sonographic signs of adenomyosis should be searched for and described using the terms and definitions published in the Morphological Uterus Sonographic Assessment consensus opinion19. The presence or absence of endometriomas (Figure S1a), their size, measured systematically in three orthogonal planes (see ‘Measurement of lesions’, below), the number of endometriomas and their ultrasound appearance should be noted20. The sonographic characteristics of any endometrioma should be described using the International Ovarian Tumor Analysis terminology21. An atypical endometrioma (Figure S1b) is defined as a unilocular-solid mass with ground glass echogenicity with a papillary projection, a color score of 1 or 2 and no flow inside the papillary projection20. Ovarian endometriomas are associated frequently with other endometriotic lesions, such as adhesions and The (Figure that there are pelvic bowel and endometriosis are in women with without and may in in which case can be with an on ultrasound examination (Figure presence of other endometriotic lesions may facilitate a diagnosis of endometrioma in and the risk of The is to for sonographic site-specific tenderness and fixed The presence of the of endometriosis and between the uterus and can assess if the is fixed to the uterus to the pelvic or to the The presence of adhesions can also be suspected on with the and/or with the the or the uterus to be fixed to structures and/or there is pelvic of may be between the or without and the uterus or the of the there are endometriomas or pelvic endometriosis, the are frequently in the disease may the and of the by endometriotic or adhesions may also a a may these and should be searched for and The is to assess the of the using the In order to assess the when the uterus is (Figure is the using the to the the of the and vaginal the rectal the is for this location The then the in order to the uterus between the and the is in the other to assess the bowel the of the it the is also in this the is found to be in of these anatomical and the is recorded as being on TVS it is that either the rectal or the the or the at of the locations has a then the is recorded as and describing the in a uterus is different (Figure is the with the to the the the the is to be for this location The then the in order to the uterus between the and is in the other to assess the the it the is also to be in this long as the is found to be in of these anatomical the and the the is recorded as The is to for DIE in the and assess the the is in the of the endometriosis is suspected on the of symptoms, patients should be to their before the ultrasound A of the of the and detection and of endometriotic the is in the of the vagina and the vagina to allow visualization of the authors the use of bowel preparation on the before the pelvic and the use of a rectal within an before the ultrasound examination to and in the this is and there are no published studies TVS with and without bowel preparation for the diagnosis of bowel In a recent meta-analysis, either with or without bowel was found to be an accurate of The includes the following anatomical urinary and DIE frequently in the and in the The is if it a of because this Although et described two and propose the ultrasound into four (Figure the which within of the is a by the two and the (Figure the which and and to the vagina and the (Figure the which to the and is (Figure and the (Figure Figure and the location of endometriotic the ultrasound the appearance of DIE in the can be including or lesions, with or without the or of the The of the should be measured in three orthogonal DIE is if the of the is lesions the disease. of the can be evaluated using the the is in the and the uterus is between the and of the operator the the the then the is and the is as the the then the is and the is as (Figure in the pelvic are in of women with a previous Cesarean and are a of pelvic The should be using the The can be found by the in the and the the pelvic The of the is and its to it the and then to the pelvic and to the of the of the common It is to for to as this as long with a from the of the the common of the to endometriosis is by either or and the from the to the should be measured (Figure of the at the time of surgery is important in all in which is In all women with DIE, a of the to for is because the of endometriotic lesions in the urinary may be and women with DIE the may be The of should be and using ultrasound with of should be for of a to of to et the common sites of DIE in the vaginal and Sonographic of the should aim at the and anatomical location of DIE affecting these DIE lesions as of the of the bowel or or as which may in and have or irregular studies have defined the TVS diagnosis of DIE in the as absence of the appearance of the between the vagina and to the presence of a DIE have used the terms and DIE to describe DIE in the The is an individual anatomical with a DIE DIE in the rectovaginal The rectovaginal includes the the and the there is in the definition of DIE in the DIE has been described as endometriotic lesions which the and the vaginal with into the have used the to describe which the with into the vagina and/or endometriosis is We propose that of the should be suspected when a DIE is on TVS in the rectovaginal the the of the of the the (Figure DIE is (Figure DIE is an of vaginal (Figure rectal (Figure or vaginal and rectal (Figure The use of improves the detection of vaginal and The of the DIE should be recorded in three orthogonal planes and the between the of the and the should be This should be the DIE is in the vagina or in the rectum, or the and lesions, when managed are associated with including We propose that of the vaginal and/or vaginal should be suspected when a DIE is on TVS in the rectovaginal the the of the of the of the pouch of and the the of the of the the in Figure vaginal or endometriosis is suspected if the vaginal is or if a is found in the of the vaginal (Figure The may be or with or without (Figure and there may or may be the Figure is an ultrasound vaginal The of the vaginal DIE should be measured in three orthogonal or when DIE lesions in the vaginal into the rectal (Figure the of the DIE in the rectal is the same as the in the vaginal (Figure is a but between these two of the lesions are the of the and are on are on ultrasound (Figure DIE lesions can be in the of the uterus (Figure these are by the in the vaginal in the in the and then the to the are to be by DIE when a with or irregular is within the the The may be or may be of a into the vagina or into other The of a can be measured in the at the of the on the that the can be from structures (Figure In the DIE the is at the (Figure it is as a of the The of the DIE should be recorded in three orthogonal DIE the rectum, and/or all of which can be using Figure a schematic of a DIE within the DIE can take the of an or can be lesions affecting the same and/or lesions affecting several bowel and/or Although TVS can be used to rectal DIE (Figure there are no published its and imaging can be used to and bowel bowel endometriosis is defined as the presence of and in the bowel at the this and This results in of the bowel and of the bowel rectal can be on the rectal is as a the is with the and by a the is and the is (Figure DIE on TVS as a of the or as with or without (Figure with The of bowel should be described to Figure bowel lesions are and in a or a is noted at a (Figure The appearance of the of the or is by a of with and adhesions, in the or (Figure the of these lesions can We propose that bowel DIE lesions noted on TVS be described to the of the or in which with DIE lesions the of the of the on the being as rectal DIE lesions, this being as at rectal DIE lesions, at the of the being as DIE lesions and the of the being as DIE lesions (Figure The of the rectal and/or DIE should be recorded in three orthogonal planes and the between the of the and the should be measured using bowel DIE may the bowel at different other bowel lesions should be for when there is a DIE affecting the (Figure or rectosigmoid. that rectal DIE lesions may be associated with a in of diagnosis of has been in this The can be as or on or or a an experienced operator can the of in an it is at the of the uterus and/or and, in a it is at the uterus and/or We propose that endometrioma and DIE should be measured systematically in three orthogonal to the and (Figure This of in three planes to DIE lesions in the and rectosigmoid. in of endometriosis in the it is important to the between the and a DIE which a the can be by either or the is the of the should be at this and the other at the for measurement (Figure In of bowel DIE lesions the of the bowel from to should be measured (Figure It is important to be that the within DIE lesions can result in an of the of the and an of the of the (Figure This has been described as the on and can also be noted on In of DIE lesions in the bowel or it is important to the between the and the (Figure It is to the from the to the bowel using the into the and the of the the endometriotic can be on the at the of the and a used to the from the on the to the of the when the has been TVS can also be used to the from the to the of the bowel there are bowel lesions, then the between the and the bowel is Figure 13 an of and locations for deep infiltrating endometriosis. 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Currently, it is difficult to compare results between published because authors use different terms when describing the same structures and 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 should allow meaningful comparisons between future studies in women with an ultrasound diagnosis of endometriosis and should facilitate multicenter Figure Transvaginal sonographic a endometrioma with and ground glass echogenicity of and an atypical endometrioma within the with ground glass echogenicity of Figure two endometriomas are fixed to other by adhesions in the pouch of Figure ultrasound of endometrioma in Figure drawings deep infiltrating endometriosis of of of bladder. Figure and ultrasound location of endometriotic Figure location of the the then the is and the is as Figure measurement of from to of in of deep infiltrating endometriosis in the by is Figure drawings and ultrasound location and different of deep infiltrating endometriosis in vaginal A ultrasound is shown for by increased of vaginal of of Figure and ultrasound of deep infiltrating endometriosis in vaginal into rectal Figure and schematic drawings deep infiltrating endometriosis of the uterosacral ligaments and are on of DIE in the of DIE in the in of DIE at the in a the Figure drawings and ultrasound deep infiltrating endometriotic rectal lesions. 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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.

[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

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.

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A healthy 25-year-old woman presents with worsening dysmenorrhea, new-onset left lower quadrant pain, 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?

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.

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.

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.

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: This study aimed to explore women's experiences of the impact of endometriosis and whether there are differences across three age groups. METHODS: A qualitative descriptive design was conducted using semi-structured focus group discussions with 35 Australian women with endometriosis, in three age groups. All tape-recorded discussions were transcribed verbatim and read line by line to extract meaningful codes and categories using NVivo 9 software through a thematic analysis approach. Categories were then clustered into meaningful themes. RESULTS: Participants' ages ranged from 17 to 53 years and had a history of 2 to 40 years living with endometriosis, with an average delay time to diagnosis of 8.1 years. Two main themes emerged: (1) experiences of living with endometriosis, and (2) impact of endometriosis on women's lives, with 14 discrete categories. The results showed similarities and differences of the impact between the three age groups. The most highlighted impacts were on marital/sexual relationships, social life, and on physical and psychological aspects in all three age groups, but with different orders of priority. Education was the second most highlighted for the 16-24 years, life opportunities and employment for the 25-34 years; and financial impact for those 35 years and above. CONCLUSIONS: Our findings show that endometriosis impacts negatively on different aspects of women's lives. A better understanding of these findings could help to decrease the negative impact of endometriosis by guiding service delivery and future research to meet more effectively the needs of women and teenagers with this condition.

(No abstract on file for this paper.)

INTRODUCTION: No prior study of endometriosis has investigated the psychological impact of having asymptomatic endometriosis versus endometriosis with pelvic pain in a systematic way. This study aimed at examining the impact of endometriosis on quality of life, anxiety and depression by comparing asymptomatic endometriosis, endometriosis with pelvic pain, and healthy, pain-free controls. The psychological impact of different types of endometriosis pain was also tested. METHODS: One hundred and ten patients with surgically diagnosed endometriosis (78 with pelvic pain and 32 without pain symptoms) and 61 healthy controls completed two psychometric tests assessing quality of life, anxiety and depression. Endometriosis participants indicated on a numerical rating scale the intensity of four types of pain (dysmenorrhea, dyspareunia, non-menstrual pelvic pain and dyschezia). RESULTS: Endometriosis patients with pelvic pain had poorer quality of life and mental health as compared with those with asymptomatic endometriosis and the healthy controls. No significant differences were found between asymptomatic endometriosis and the control group. Dysmenorrhea had significant effects only on physical quality of life; non-menstrual pelvic pain affected all the variables; no significant effects were found for dyspareunia and dyschezia. CONCLUSIONS: Pain significantly affects women's experience of endometriosis. The medical treatment of endometriosis with pain may not be sufficient and psychological intervention is recommended.

IMPORTANCE: Chronic pelvic pain (CPP) is a challenging condition that affects an estimated 26% of the world's female population. Chronic pelvic pain accounts for 40% of laparoscopies and 12% of hysterectomies in the US annually even though the origin of CPP is not gynecologic in 80% of patients. Both patients and clinicians are often frustrated by a perceived lack of treatments. This review summarizes the evaluation and management of CPP using recommendations from consensus guidelines to facilitate clinical evaluation, treatment, improved care, and more positive patient-clinician interactions. OBSERVATIONS: Chronic pelvic pain conditions often overlap with nonpelvic pain disorders (eg, fibromyalgia, migraines) and nonpain comorbidities (eg, sleep, mood, cognitive impairment) to contribute to pain severity and disability. Musculoskeletal pain and dysfunction are found in 50% to 90% of patients with CPP. Traumatic experiences and distress have important roles in pain modulation. Complete assessment of the biopsychosocial factors that contribute to CPP requires obtaining a thorough history, educating the patient about pain mechanisms, and extending visit times. Training in trauma-informed care and pelvic musculoskeletal examination are essential to reduce patient anxiety associated with the examination and to avoid missing the origin of myofascial pain. Recommended treatments are usually multimodal and require an interdisciplinary team of clinicians. A single-organ pathological examination should be avoided. Patient involvement, shared decision-making, functional goal setting, and a discussion of expectations for long-term care are important parts of the evaluation process. CONCLUSIONS AND RELEVANCE: Chronic pelvic pain is like other chronic pain syndromes in that biopsychosocial factors interact to contribute and influence pain. To manage this type of pain, clinicians must consider centrally mediated pain factors as well as pelvic and nonpelvic visceral and somatic structures that can generate or contribute to pain.

STUDY QUESTION: What is the global consensus on the classification of endometriosis that considers the views of women with endometriosis? SUMMARY ANSWER: We have produced an international consensus statement on the classification of endometriosis through systematic appraisal of evidence and a consensus process that included representatives of national and international, medical and non-medical societies, patient organizations, and companies with an interest in endometriosis. WHAT IS KNOWN ALREADY: Classification systems of endometriosis, developed by several professional organizations, traditionally have been based on lesion appearance, pelvic adhesions, and anatomic location of disease. One system predicts fertility outcome and none predicts pelvic pain, response to medications, disease recurrence, risks for associated disorders, quality of life measures, and other endpoints important to women and health care providers for guiding appropriate therapeutic options and prognosis. STUDY DESIGN, SIZE, DURATION: A consensus meeting, in conjunction with pre- and post-meeting processes, was undertaken. PARTICIPANTS/MATERIALS, SETTING, METHODS: A consensus meeting was held on 30 April 2014 in conjunction with the World Endometriosis Society's 12th World Congress on Endometriosis. Rigorous pre- and post-meeting processes, involving 55 representatives of 29 national and international, medical and non-medical organizations from a range of disciplines, led to this consensus statement. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 28 consensus statements were made. Of all, 10 statements had unanimous consensus, however none of the statements was made without expression of a caveat about the strength of the statement or the statement itself. Two statements did not achieve majority consensus. The statements covered women's priorities, aspects of classification, impact of low resources, as well as all the major classification systems for endometriosis. Until better classification systems are developed, we propose a classification toolbox (that includes the revised American Society for Reproductive Medicine and, where appropriate, the Enzian and Endometriosis Fertility Index staging systems), that may be used by all surgeons in each case of surgery undertaken for women with endometriosis. We also propose wider use of the World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonisation Project surgical and clinical data collection tools for research to improve classification of endometriosis in the future, of particular relevance when surgery is not undertaken. LIMITATIONS, REASONS FOR CAUTION: This consensus process differed from that of formal guideline development, although based on the same available evidence. A different group of international experts from those participating in this process may have yielded subtly different consensus statements. WIDER IMPLICATIONS OF THE FINDINGS: This is the first time that a large, global, consortium-representing 29 major stake-holding organizations, from 19 countries - has convened to systematically evaluate the best available evidence on the classification of endometriosis and reach consensus. In addition to 21 international medical organizations and companies, representatives from eight national endometriosis organizations were involved, including lay support groups, thus generating and including input from women who suffer from endometriosis in an endeavour to keep uppermost the goal of optimizing quality of life for women with endometriosis. STUDY FUNDING/COMPETING INTERESTS: The World Endometriosis Society convened and hosted the consensus meeting. Financial support for participants to attend the meeting was provided by the organizations that they represented. There was no other specific funding for this consensus process. Mauricio Abrao is an advisor to Bayer Pharma, and a consultant to AbbVie and AstraZeneca; G David Adamson is the Owner of Advanced Reproductive Care Inc and Ziva and a consultant to Bayer Pharma, Ferring, and AbbVie; Deborah Bush has received travel grants from Fisher & Paykel Healthcare and Bayer Pharmaceuticals; Linda Giudice is a consultant to AbbVie, Juniper Pharmaceutical, and NextGen Jane, holds research grant from the NIH, is site PI on a clinical trial sponsored by Bayer, and is a shareholder in Merck and Pfizer; Lone Hummelshoj is an unpaid consultant to AbbVie; Neil Johnson has received conference expenses from Bayer Pharma, Merck-Serono, and MSD, research funding from AbbVie, and is a consultant to Vifor Pharma and Guerbet; Jörg Keckstein has received a travel grant from AbbVie; Ludwig Kiesel is a consultant to Bayer Pharma, AbbVie, AstraZeneca, Gedeon Richter, and Shionogi, and holds a research grant from Bayer Pharma; Luk Rombauts is an advisor to MSD, Merck Serono, and Ferring, and a shareholder in Monash IVF. The following have declared that they have nothing to disclose: Kathy Sharpe Timms; Rulla Tamimi; Hugh Taylor. TRIAL REGISTRATION NUMBER: N/A.

(No abstract on file for this paper.)

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 & 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.

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.

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.

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.

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.

(No abstract on file for this paper.)

Understanding the pathophysiology of endometriosis is changing our diagnosis and treatment. Endometriosis lesions are clones of specific cells, with variable characteristics as aromatase activity and progesterone resistance. Therefore the GE theory postulates GE incidents to start endometriosis, which thus is different from implanted endometrium. The subsequent growth in the specific environment of the peritoneal cavity is associated with angiogenesis, inflammation, immunologic changes and bleeding in the lesions causing fibrosis. Fibrosis will stop the growth and lesions look burnt out. The pain caused by endometriosis lesions is variable: some lesions are not painful while other lesions cause neuroinflammation at distance up to 28 mm. Diagnosis of endometriosis is made by laparoscopy, following an experience guided clinical decision, based on history, symptoms, clinical exam and imaging. Biochemical markers are not useful. For deep endometriosis, imaging is important before surgery, notwithstanding rather poor predictive values when confidence limits, the prevalence of the disease and the absence of stratification of lesions by size, localization and depth of infiltration, are considered. Surgery of endometriosis is based on recognition and excision. Since the surrounding fibrosis belongs to the body with limited infiltration by endometriosis, a rim of fibrosis can be left without safety margins. For deep endometriosis, this results in a conservative excision eventually with discoid excision or short bowel resections. For cystic ovarian endometriosis superficial destruction, if complete, should be sufficient. Understanding pathophysiology is important for the discussion of early intervention during adolescence. Considering neuroinflammation at distance, the indication to explore large somatic nerves should be reconsidered. Also, medical therapy of endometriosis has to be reconsidered since the variability of lesions results in a variable response, some lesions not requiring estrogens for growth and some being progesterone resistant. If the onset of endometriosis is driven by oxidative stress from retrograde menstruation and the peritoneal microbiome, medical therapy could prevent new lesions and becomes indicated after surgery.

Endometriosis is a common and challenging condition of reproductive-aged women that carries a high individual and societal cost. The many molecular dissimilarities between endometriosis lesions and eutopic endometrium create difficulties in the development of new drug therapies and treatments. Surgery remains the gold standard for definitive diagnosis, but it must be weighed against the risks of surgical morbidity and potential decreases in ovarian reserve, especially in the case of endometriomas. Safe and effective surgical techniques are discussed within this article for various presentations of endometriosis. Medical therapy is suppressive rather than curative, and regimens that are long-term and affordable with minimal side effects are recommended. Recurrences are common and often rapid when medical therapy is discontinued. Endometriosis in the setting of infertility is reviewed and appropriate management is discussed, including when and whether surgery is warranted in this at-risk population. In patients with chronic pain, central sensitization and myofascial pain are integral components of a multidisciplinary approach. Endometriosis is associated with an increased risk of epithelial ovarian cancer; however, the risk is low and currently no preventive screening is recommended. Hormone therapy for symptomatic women with postsurgical menopause should not be delayed as a result of concerns for malignancy or recurrence of endometriosis.

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.

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.

BACKGROUND: Endometriosis is an often chronic, inflammatory gynaecologic condition affecting 190 million women worldwide. Studies have reported an elevated cancer risk among patients with endometriosis. However, prior research has included methodologic issues that impede valid and robust interpretation. OBJECTIVE AND RATIONALE: We conducted a meta-analysis of studies investigating the association between endometriosis and cancer risk and analysed the results by methodologic characteristics. We discuss the implications of cancer screening in patients and management challenges faced by clinicians. SEARCH METHODS: We searched PubMed and Embase databases for eligible studies from inception through 24 October 2019. We included cohort and case-control studies examining the association between endometriosis and cancer risk; cross-sectional studies and case reports were excluded. Publications had to present risk/rate/odds estimates with 95% CI. Random effects meta-analysis was used to estimate summary relative risks (SRR) and CIs. Heterogeneity across studies was assessed by the Q test and I2 statistics, and publication bias using Egger's and Begg's tests. Risk of bias and quality of the included studies were assessed using the risk of bias in non-randomized studies of interventions (ROBINS-I) tool. OUTCOMES: Forty-nine population-based case-control and cohort studies were included. Twenty-six studies were scored as having a 'serious'/'critical' risk of bias, and the remaining 23 'low'/'moderate'. Cancer-specific analyses showed a positive association between endometriosis and ovarian cancer risk (SRR = 1.93, 95% CI = 1.68-2.22; n = 24 studies) that was strongest for clear cell (SRR = 3.44, 95% CI = 2.82-4.42; n = 5 studies) and endometrioid (SRR = 2.33, 95% CI = 1.82-2.98; n = 5 studies) histotypes (Pheterogeneity < 0.0001), although with significant evidence of both heterogeneity across studies and publication bias (Egger's and Begg's P-values < 0.01). A robust association was observed between endometriosis and thyroid cancer (SRR = 1.39, 95% CI =1.24-1.57; n = 5 studies), a very small association with breast cancer (SRR = 1.04, 95% CI =1.00-1.09; n = 20 studies) and no association with colorectal cancer (SRR = 1.00, 95% CI =0.87-1.16; n = 5 studies). The association with endometrial cancer was not statistically significant (SRR = 1.23, 95% CI =0.97-1.57; n = 17 studies) overall and wholly null when restricted to prospective cohort studies (SRR = 0.99, 95% CI =0.72-1.37; n = 5 studies). The association with cutaneous melanoma was also non-significant (SRR = 1.17, 95% CI =0.97-1.41; n = 7 studies) but increased in magnitude and was statistically significant when restricted to studies with low/moderate risk of bias (SRR = 1.71, 95% CI = 1.24-2.36, n = 2 studies). The most robust finding both in terms of statistical significance and magnitude of effect was an inverse association with cervical cancer (SRR = 0.68, 95% CI =0.56-0.82; n = 4 studies); however, this result has a high potential to reflect heightened access to detection of dysplasia for women who reached an endometriosis diagnosis and is thus likely not causal. Several additional cancer types were explored based on <4 studies. WIDER IMPLICATIONS: Endometriosis was associated with a higher risk of ovarian and thyroid, and minimally (only 4% greater risk) with breast cancer, and with a lower risk of cervical cancer. However, this meta-analysis confirms that: a majority of studies had severe/critical risk of bias; there is impactful heterogeneity across studies-and for ovarian cancer, publication bias; and causal inference requires temporality, which in many studies was not considered. We discuss the implications of these potential associations from the perspectives of patients with endometriosis, clinicians involved in their care, and scientists investigating their long-term health risks.

BACKGROUND: Endometriosis is a chronic inflammatory condition defined as endometrial-like tissue proliferating outside the uterus. It is a common yet frequently under-recognised condition affecting one in nine Australian women. OBJECTIVE: This paper aims to provide a summary of the recommendations for the diagnosis and management of endometriosis-associated pain and infertility from the most recent evidence-based guidelines on endometriosis by the European Society of Human Reproduction and Embryology, the Royal Australian College of Obstetricians and Gynaecologists and the National Institute for Health and Care Excellence. DISCUSSION: Effective management of endometriosis requires prompt diagnosis to enable early multidisciplinary intervention that aligns with patient needs and priorities. Assessment includes a thorough history, pelvic examination where appropriate and referral for transvaginal ultrasound and/or magnetic resonance imaging. If endometriosis is suspected based on clinical symptoms but imaging is negative or empirical treatment is ineffective, individuals should be referred to a gynaecologist for further assessment and consideration of laparoscopy. Management options include hormonal and surgical therapies.

BACKGROUND: The reproductive impact of adenomyosis and endometriosis is widely researched but the extent of these impacts remains elusive. It has been demonstrated that endometriosis, in particular, is known to result in subfertility but endometriosis and adenomyosis are increasingly linked to late pregnancy complications such as those caused by placental insufficiency. At the molecular level, the presence of ectopic endometrium perturbs the endometrial hormonal, cellular, and immunological milieu, negatively influencing decidualization, placentation, and developmental programming of the embryo. It is unclear if and how such early aberrant reproductive development relates to pregnancy outcomes in endometriosis and adenomyosis. OBJECTIVE AND RATIONALE: The aims of this systematic review and meta-analysis were to (i) investigate the association of adenomyosis and endometriosis with fertility, obstetric, and neonatal outcomes of women through both assisted reproduction and natural conception and (ii) determine whether endometriosis disease subtypes have specific impacts on different stages of the reproductive process. SEARCH METHODS: A systematic literature review of NHS evidence electronic databases and the Cochrane database identified all comparative and observational studies between 1980 and December 2018 in any language on adenomyosis and endometriosis with fertility, obstetric, and neonatal outcomes (23 search terms used). A total of 104 papers were selected for data extraction and meta-analysis, with use of Downs and Black standardized checklist to evaluate quality and bias. OUTCOMES: We found that endometriosis consistently leads to reduced oocyte yield and a reduced fertilization rate (FR), in line with current evidence. Milder forms of endometriosis were most likely to affect the fertilization (FR OR 0.77, CI 0.63-0.93) and earlier implantation processes (implantation rate OR 0.76, CI 0.62-0.93). The more severe disease by American Society for Reproductive Medicine staging (ASRM III and IV) influenced all stages of reproduction. Ovarian endometriosis negatively affects the oocyte yield (MD -1.22, CI -1.96, -0.49) and number of mature oocytes (MD -2.24, CI -3.4, -1.09). We found an increased risk of miscarriage in both adenomyosis and endometriosis (OR 3.40, CI 1.41-8.65 and OR 1.30, CI 1.25-1.35, respectively), and endometriosis can be associated with a range of obstetric and fetal complications including preterm delivery (OR 1.38, CI 1.01-1.89), caesarean section delivery (OR 1.98 CI 1.64-2.38), and neonatal unit admission following delivery (OR 1.29, CI 1.07-1.55). WIDER IMPLICATIONS: Adenomyosis and the subtypes of endometriosis may have specific complication profiles though further evidence is needed to be able to draw conclusions. Several known pregnancy complications are likely to be associated with these conditions. The complications are possibly caused by dysfunctional uterine changes leading to implantation and placentation issues and therefore could potentially have far-reaching consequences as suggested by Barker's hypothesis. Our findings would suggest that women with these conditions should ideally receive pre-natal counselling and should be considered higher risk in pregnancy and at delivery, until evidence to the contrary is available. In order to expand our knowledge of these conditions and better advise on future management of these patients in reproductive and maternal medicine, a more unified approach to studying fertility and reproductive outcomes with longer term follow-up of the offspring and attention to the subtype of disease is necessary.

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.

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.

Endometriosis is a benign, chronic, inflammatory condition affecting up to 10 % of women and characterised by the presence of glands and stroma tissue outside the uterus. Epidemiological and clinical studies demonstrate a consistent association between endometriosis and infertility. However, this relationship is far to be clearly understood and several mechanisms are involved. Available data show that patients with endometriosis have an increased estimated risk of infertility between two and four times compared with the general population. On the other hand, the probability of patients with infertility to have endometriosis is reported up to about 50 % of the cases. Future studies should aim to better elucidate the mechanisms behind endometriosis-associated infertility in order to offer the more appropriate and tailored management for the patients.

The objective was to develop recommendations for the diagnosis and treatment of endometriosis and its associated symptoms. A working group was convened comprised of practising gynaecologists and experts in evidence-based medicine from Europe, as well as an endometriosis self-help group representative. After reviewing existing evidence-based guidelines and systematic reviews, the expert panel met on three occasions for a day during which the guideline was developed and refined. Recommendations based solely on the clinical experience of the panel were avoided as much as possible. The entire ESHRE Special Interest Group for Endometriosis and Endometrium was given the opportunity to comment on the draft guideline, after which it was available for comment on the ESHRE website for 3 months. The working group then ratified the guideline by unanimous or near-unanimous voting; finally, it was approved by the ESHRE Executive Committee. The guideline will be updated regularly, and will be made available at http://www.endometriosis.org/guidelines.html with hyperlinks to the supporting evidence, and the relevant references and abstracts. For women presenting with symptoms suggestive of endometriosis, a definitive diagnosis of most forms of endometriosis requires visual inspection of the pelvis at laparoscopy as the 'gold standard' investigation. However, pain symptoms suggestive of the disease can be treated without a definitive diagnosis using a therapeutic trial of a hormonal drug to reduce menstrual flow. In women with laparoscopically confirmed disease, suppression of ovarian function for 6 months reduces endometriosis-associated pain; all hormonal drugs studied are equally effective although their side-effects and cost profiles differ. Ablation of endometriotic lesions reduces endometriosis-associated pain and the smallest effect is seen in patients with minimal disease; there is no evidence that also performing laparoscopic uterine nerve ablation (LUNA) is necessary. In minimal-mild endometriosis, suppression of ovarian function to improve fertility is not effective, but ablation of endometriotic lesions plus adhesiolysis is effective compared to diagnostic laparoscopy alone. There is insufficient evidence available to determine whether surgical excision of moderate-severe endometriosis enhances pregnancy rates. IVF is appropriate treatment especially if there are coexisting causes of infertility and/or other treatments have failed, but IVF pregnancy rates are lower in women with endometriosis than in those with tubal infertility. The management of severe/deeply infiltrating endometriosis is complex and referral to a centre with the necessary expertise is strongly recommended. Patient self-help groups can provide invaluable counselling, support and advice.

BACKGROUND: The association between lesion type, disease stage and severity of pain was studied in a large group of women with endometriosis to verify whether endometrial implants at different sites determine specific complaints and to evaluate the validity of the current classification system in women with symptomatic disease. METHODS: A total of 1054 consecutive women with endometriosis undergoing first-line conservative or definitive surgery were included. Data on age at surgery, disease stage according to the revised American Fertility Society (AFS) classification, anatomical characteristics of endometriotic lesions, and type and severity of pain symptoms were collected and analysed by multiple logistic regression. RESULTS: Minimal endometriosis was present in 319 patients, mild in 139, moderate in 292 and severe in 304. A significant inverse relationship was demonstrated between age at surgery and moderate-to-severe dysmenorrhoea, dyspareunia and non-menstrual pain. A strong association was found between posterior cul-de-sac lesions and pain at intercourse [Wald chi (2) = 17.00, P = 0.0001; odds ratio (OR) = 2.64, 95% confidence interval (CI) = 1.68-4.24]. A correlation between endometriosis stage and severity of symptoms was observed only for dysmenorrhoea (Wald chi (2) = 5.14, P = 0.02) and non-menstrual pain (Wald chi (2) = 5.63, P = 0.018). However, the point estimates of ORs were very close to unity (respectively, 1.33, 95% CI = 1.04-1.71, and 1.01, 95% CI = 1.00-1.03). CONCLUSIONS: The association between endometriosis stage and severity of pelvic symptoms was marginal and inconsistent and could be demonstrated only with a major increase in study power.

BACKGROUND: Endometriosis is a chronic gynaecological disorder that affects 2-10% of women of reproductive age. The aetiology of endometriosis is largely under-explored, yet abnormalities in the immune system have been suggested to explain the origin of ectopic endometrial tissues, and an association between endometriosis and autoimmune diseases has been proposed. Evaluation of current evidence investigating the association between endometriosis and autoimmune diseases from population-based studies will facilitate our understanding of the causes and consequences of endometriosis and provide a reference for better healthcare practices population-wide. OBJECTIVE AND RATIONALE: The aim of this study was to systematically review the literature on population-based studies investigating an association between endometriosis and autoimmune diseases and to conduct a meta-analysis of combinable results to investigate the extent and robustness of evidence. SEARCH METHODS: Four electronic databases were searched (MEDLINE, Embase, Web of Science, and CINAHL) from each database inception date until 7 April 2018. Search terms included a combination of database-specific controlled vocabulary terms and free-text terms relating to 'endometriosis' and 'autoimmune diseases'. Study inclusion criteria focused on peer-reviewed published articles that reported an association between endometriosis and autoimmune diseases, excluding case reports/series, review papers, meta-analyses, organizational guidelines, editorial letters, expert opinions, and conference abstracts. Quality assessment of included studies was performed based on GRADE criteria. Key information of eligible studies was abstracted into a standard form. Meta-analysis was performed for autoimmune diseases with combinable study results from at least three studies investigating an association with endometriosis. For cross-sectional studies and case-control studies, raw data from each study were documented to calculate a Mantel-Haenszel odds ratio with 95% CIs. For cohort studies, an inverse variance probability weighted model was used to pool study results to calculate a rate ratio (a hazard ratio or a standardized incidence rate) with 95% CIs. OUTCOMES: A total of 26 published population-based cross-sectional, case-control, and cohort studies that investigated the association between endometriosis and autoimmune diseases met all eligible criteria and were included in the review. The studies quantified an association between endometriosis and several autoimmune diseases, including systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), rheumatoid arthritis (RA), autoimmune thyroid disorder, coeliac disease (CLD), multiple sclerosis (MS), inflammatory bowel disease (IBD), and Addison's disease. However, the quality of the evidence was generally poor due to the high risk of bias in the majority of the chosen study designs and statistical analyses. Only 5 of the 26 studies could provide high-quality evidence, and among these, 4 supported a statistically significant association between endometriosis and at least 1 autoimmune disease: SLE, SS, RA, CLD, MS, or IBD. WIDER IMPLICATIONS: The observed associations between endometriosis and autoimmune diseases suggest that clinicians need to be aware of the potential coexistence of endometriosis and autoimmune diseases when either is diagnosed. Scientists interested in research studies on endometriosis or autoimmune diseases should consider the likelihood of comorbidity when studying these two types of health conditions. Well-designed large prospective cohort studies with confounding control and mediation quantification, as well as genetic and biological studies, are needed to generate further insights into whether endometriosis is a risk factor for, or a consequence of, autoimmune diseases, and whether these two types of disorders share pathophysiological mechanisms even if they arise independently. Such insights may offer opportunities for the development of novel non-hormonal medications such as immuno-modulators or repurposing of existing immunomodulatory therapies for endometriosis.

(No abstract on file for this paper.)

In the healthy endometrium, progesterone and estrogen signaling coordinate in a tightly regulated, dynamic interplay to drive a normal menstrual cycle and promote an embryo-receptive state to allow implantation during the window of receptivity. It is well-established that progesterone and estrogen act primarily through their cognate receptors to set off cascades of signaling pathways and enact large-scale gene expression programs. In endometriosis, when endometrial tissue grows outside the uterine cavity, progesterone and estrogen signaling are disrupted, commonly resulting in progesterone resistance and estrogen dominance. This hormone imbalance leads to heightened inflammation and may also increase the pelvic pain of the disease and decrease endometrial receptivity to embryo implantation. This review focuses on the molecular mechanisms governing progesterone and estrogen signaling supporting endometrial function and how they become dysregulated in endometriosis. Understanding how these mechanisms contribute to the pelvic pain and infertility associated with endometriosis will open new avenues of targeted medical therapies to give relief to the millions of women suffering its effects.

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.

(No abstract on file for this paper.)