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McMaster University Health Sciences Center, Hamilton, Ontario, Canada
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Endometriosis is a chronic disease associated with debilitating pain that affects many people assigned female at birth, from menarche through menopause, not just causing pain and infertility but also negatively impacting quality of life, participation in daily activities, productivity, and income. It is associated with increased incidence of obstetric and neonatal complications, anxiety, other chronic diseases, and substantial healthcare costs. Despite the profound negative impact of endometriosis on quality of life, current treatment options remain suboptimal and many patients express dissatisfaction with current care. The prevailing acute-care, single-provider model in which the provider works in relative isolation and thus with limited diagnostic and therapeutic strategies readily available proves inadequate for treating endometriosis. Patients would benefit from earlier diagnosis and referral to a center capable of providing a comprehensive and multimodal management plan that utilizes a chronic care model. Often this can only be achieved through multidisciplinary teams of providers with expertise in endometriosis. The authors acknowledge that many low- and middle-income countries do not have the resources to support such centers but could still benefit from any breakthroughs in treatment they bring about. Researchers need to agree on standardized core outcome measures, relevant to patients with endometriosis and the healthcare system as a whole. Only through increased societal and healthcare provider education and recognition of endometriosis as a chronic disease can we achieve better treatment outcomes.
Lay summary
Endometriosis is a disease that affects about one out of every women. It occurs when tissue like that which is normally located inside the uterus is present outside the uterus. The body’s reaction to this tissue causes inflammation and pain, usually so severe that it disrupts daily activities. Our current medical system does not serve these patients well. Patients with endometriosis often must see many different doctors over many years before learning of their disease and getting treatment. We need to increase awareness of endometriosis and think of it as a chronic disease like diabetes or heart disease. We can improve care by creating centers where experienced teams work together to treat patients and study treatment impacts on quality of life. It is time to adopt a new model for caring for patients with endometriosis.
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Departamento de Ginecologia, Universidade Federal de São Paulo, São Paulo, Brazil
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Biobehavioral Pediatric Pain Lab, Department of Psychiatry, Boston Children’s Hospital, Boston, Massachusetts, USA
Pain and Affective Neuroscience Center, Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Children’s Hospital, Massachusetts, USA
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Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK
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Endometriosis is a chronic condition that affects ~10% of women globally. Its symptoms include chronic pelvic pain, heavy periods and tiredness/fatigue, which have been associated with poorer quality of life and mental health. We aim to explore the impact of the COVID-19 pandemic on pain and fatigue symptoms and their interactions with the impact on mental health in people with endometriosis. This global cross-sectional online survey study collected data from 4717 adults with self-reported surgical/radiological diagnosis of endometriosis between May and June 2020. The survey included questions on the current status and changes of endometriosis symptoms (pelvic pain, tiredness/fatigue, and bleeding patterns), mental health, pain catastrophising, and the impact of the COVID-19 pandemic on the respondents’ lives. Compared to 6 months earlier, Respondents reported a marked worsening of their endometriosis symptoms (endometriosis-associated pain (39.3%; 95% CI: 37.7, 40.5), tiredness/fatigue (49.9%; 95% CI: 48.4, 51.2) and bleeding patterns (39.6%; 95% CI: 38.2, 41)) and mental health (38.6%; 95% CI: 37.2, 39.9). Those with a pre-existing mental health diagnosis (38.8%) were more likely to report their symptoms worsening. Worsening of pain and tiredness/fatigue was significantly correlated with worsening of mental health (P < 0.001). The relationship between changes in mental health and (a) change in pain and (b) change in fatigue was found to be weakly mediated by pain catastrophising scores (pain: B = 0.071, lower limit of confidence interval (LLCI) = 0.060, upper limit of confidence interval (ULCI) = 0.082, tiredness/fatigue: B = 0.050, LLCI = 0.040, ULCI = 0.060). This study demonstrates that stressful experiences impact the physical and mental health of people with endometriosis. The findings highlight the need to consider psychological approaches in the holistic management of people with endometriosis.
Lay summary
Endometriosis is a chronic condition in which tissue similar to that of the lining of the womb grows outside it. It affects around 10% of women globally, and the symptoms often include persistent pelvic pain, heavy periods and tiredness/fatigue. These symptoms are associated with impaired mental health and life quality. This study used an online questionnaire to assess the experiences of people with endometriosis during the first months of the pandemic. Results from 4717 adults revealed that pelvic pain, tiredness/fatigue and bleeding worsened in more than 39% of the participants. Poor mental health was also exacerbated and associated with worsening in tiredness/fatigue. Further analysis revealed that this relationship could be partially explained by ‘pain catastrophising’, which measures how participants think about their pain. Our results suggest that stressful experiences like the pandemic negatively impact the already burdened mental health of people with endometriosis, who could benefit from psychological interventions.
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Gynecologic Division, BP – A Beneficencia Portuguesa de Sao Paulo, Sao Paulo, Sao Paulo, Brazil
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Gynecologic Division, BP – A Beneficencia Portuguesa de Sao Paulo, Sao Paulo, Sao Paulo, Brazil
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The objective of this study was to systematically review the literature on the human microbiome in association with endometriosis. PubMed/Medline, Cochrane, and Embase databases were searched for literature published from 1986 to August 2021. All human studies that assessed the microbiome using 16S rRNA sequencing or shotgun sequencing in women with endometriosis were included. Two reviewers independently abstracted data from the selected articles into tables. To assess the quality of included studies, the National Institutes of Health Study Quality Assessment Tools were utilized. This review included 12 case–control studies. Included studies compared the microbiome from various anatomical sources (fecal, vaginal, cervical, peritoneal, endometrial, and intra-lesional) between patients with endometriosis and a heterogeneous set of control patients. Study quality ranged from poor to good, with 8 of 12 studies rated fair. Multiple studies reported a different distribution of bacteria among women with endometriosis across anatomical sites, but the results were highly heterogeneous. Pseudomonas was overrepresented in peritoneal fluid among women with endometriosis across multiple studies but was also observed to be increased in vaginal, endometrial, and intra-lesional samples. Among bacteria noted across different anatomical samples, Gardnerella was found to be increased in cervical but decreased in endometrial, fecal, and vaginal samples of patients with endometriosis, while Atopium was found to be decreased in vaginal and cervical samples from patients with endometriosis. Sphingobium was found to be increased in vagina, endometrium, and peritoneal fluid from patients with endometriosis. Streptococcus was found to be increased in peritoneal, endometrial, and cervical samples from women with endometriosis. Microbiomal comparisons stratified by endometriosis stage or site of endometriosis involvement were limited and highly heterogeneous.
Lay summary
The microbiome, a group of bacteria found in a particular place in the body, has been shown to vary when patients have some diseases, such as cancer or inflammatory bowel disease. Less is known about the microbiome in patients with endometriosis. This review looked at existing studies comparing the bacteria found in patients with endometriosis and others without. Twelve studies were found that assessed the bacteria from swabs collected from different places, including the vagina, cervix, endometrium, peritoneum, feces, and endometriosis lesions themselves. Most of the studies found higher or lower levels of specific bacteria at each of these places, but the findings were often inconsistent. The findings were probably limited by the small numbers of patients involved and variations in the groups studied. More research is needed to find out which bacteria are over- and underrepresented in patients with endometriosis and where they are found.
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Lay summary
Endometriosis is a benign disease that can cause pain and infertility in women. Debate exists over how endometriosis should best be diagnosed. On one hand, endometriosis can be diagnosed by directly examining pelvic anatomy via a surgical procedure known as diagnostic laparoscopy. On the other hand, the disease can be diagnosed via non-surgical means such as using medical imaging, the symptoms described by the patient and whether the patient responds to non-surgical therapies such as medication. In this debate article, we argue in favour of diagnostic laparoscopy. We review the safety of the procedure, compare the ability of diagnostic laparoscopy vs medical imaging to detect endometriosis and consider the benefits of formally diagnosing or ruling out the condition.
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Endometriosis is the most prevalent benign gynaecologic disease with invalidating effects on the quality of life and decreased economic productivity. As pharmacologic and surgical treatment are only partially effective, women look for self-management strategies in order to control their symptoms. Many dietary interventions have been claimed successful. But it is unclear whether these effects are caused by the idea of taking control of the symptoms by adhering to a diet or by the dietary intervention itself. In order to gain more evidence with regard to the mechanisms behind the effect of dietary intervention in the management of endometriosis, a number of issues need to be addressed for future studies. First, we need clearly defined endpoints in our studies. Secondly, we have to be aware of the difference between the effects of diet on the risk of developing endometriosis and the effects of diet on symptoms in women with already established endometriosis. Thirdly, it may be difficult to strictly define the intervention diet and the control or placebo diet. Fourthly, we have to define endometriosis-related as well as patient-related factors that may influence the success of a dietary intervention. Fifthly, we have to understand the biological mechanisms behind the perceived effects of dietary interventions. These issues will be addressed in this opinion paper.
Lay summary
Endometriosis, defined as the presence of endometrium-like tissue located outside the womb, is a gynaecologic disease that affects many women. They experience severe pain, making it difficult for them to go to school or work. Medication or surgery is often not enough to relieve their pain. Therefore, these women look for ways to suppress their pain by changing their way of life. Changing their diet is an option that is often chosen by women with endometriosis. Many women experience that changing their diet helps to suppress pain symptoms. But it is not clear why changing the diet is effective. Processes in the body could be changed by taking or avoiding specific nutrients, but the effect could also be caused by the empowerment that women experience by adhering to a diet. If we want to learn more about the effect of diet on endometriosis, we have to pay attention to the following issues: first, it is important to exactly define the goal of a new study. Secondly, we have to realize that there is a difference between the study of the effect of diet on the risk of developing endometriosis and the effect of diet on endometriosis that has already developed. Thirdly, we have to realize that it can be difficult to define what the diet contains and how a control group should be defined. Fourthly, it is important to define factors that make it difficult to adhere to a diet. Fifthly, we need to try to understand what happens in the body that may cause the effect of a diet in endometriosis. In this opinion paper, these issues will be addressed.
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Lay summary
Transmasculine people are assigned female at birth but identify as male. These patients often are prescribed testosterone therapy as part of their transition. This treatment can affect ovulation and stop menstrual periods. Endometriosis is a common condition that causes pelvic pain in some people born with female pelvic organs. Not a lot is known about transmasculine people and how often endometriosis affects them. Testosterone should help treat if not reduce the incidence of endometriosis. This commentary looks at the current literature in order to help clarify existing knowledge gaps. Transmasculine patients who present for hysterectomy as a surgery to help them affirm themselves in their self-identified gender sometimes report pelvic pain symptoms as well. There are many reasons why patients report pain before surgery, and this can be related to endometriosis, even though this diagnosis is less expected in this group. Providers caring for transmasculine patients should be aware of this.
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Endometriosis has a large impact on the lives of patients, affecting nearly 90% of women with chronic pelvic pain and infertility. Unfortunately, diagnosis for this condition is often delayed by an average of 7 years, with adolescent patients experiencing disproportionate delays. This is in part due to the use of an invasive procedure for primary diagnosis and limited access to subspecialty care. While laparoscopy serves an important purpose in the diagnosis and management of endometriosis, it has been found to be less cost-effective than empiric medical therapy and puts an emphasis on the lesion as opposed to the patient and the disease process as a whole. As studies emerge, we gain a deeper understanding of the complex nature of this disease. Laparoscopy has been shown to have variable results, with high recurrence rates and varying improvement in symptoms over time. Additionally, studies have shown a poor correlation between patients’ pain and the stage and location of lesions, with laparoscopy showing greater benefit for later-stage disease and deep infiltrating endometriosis. This article seeks to evaluate the current standards for the management of endometriosis, discuss the place for diagnostic laparoscopy, and review future directions and alternatives.
Lay summary
Endometriosis is an inflammatory disorder that occurs when uterine tissue is found outside the uterus. This condition affects women of reproductive age and can have serious impacts on their lives, causing pain and difficulty getting pregnant. The primary method of diagnosis is surgical, which has associated risks and can delay care to patients. As further studies emerge, our understanding of this condition improves, and it is important to evaluate current practices. This article focuses on the pros and cons of using surgical methods to diagnose endometriosis and alternative options that may be safer and provide more timely care to patients.
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Endometriosis is a chronic neuro-inflammatory disorder the defining feature of which is the growth of tissue (lesions) that resembles the endometrium outside the uterus. Estimates of prevalence quote rates of ~10% of women of reproductive age, equating to at least 190 million women world-wide. Genetic, hormonal and immunological factors have all been proposed as contributing to risk factors associated with the development of lesions. Twin studies report the heritable component of endometriosis as ~50%. Genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) that appear over-represented in patients with endometriosis, particularly those with more extensive disease (stage III/IV). In different sample populations, there has been replication of SNPs near genes involved in oestrogen and other steroid regulated pathways including ESR1 (oestrogen receptor alpha), GREB1, HOXA10, WNT4 and MAPK kinase signalling. Comparisons with GWAS conducted on other patient cohorts have found links with reproductive traits (age at menarche) and disorders (fibroids, endometrial and ovarian cancer) and common co-morbidities (migraine, depression, asthma). In summary, genetic analyses have provided new insights into the hormone-regulated pathways that may contribute to increased risk of developing endometriosis some of which may act in early life. New studies are needed to clarify the relationship between the many SNPs identified, the genes that they regulate and their contribution(s) to development of different forms of endometriosis. We hope that more advanced methods allowing integration between GWAS, epigenetic and tissue expression data will improve risk analysis and reduce diagnositic delay.
Lay summary
Endometriosis is a debilitating reproductive disorder affecting ~10% of reproductive-age women, and those assigned female at birth, which causes a range of symptoms including chronic pain and infertility. The reason why some, but not all these individuals, develop the lesions that characterise the disease are poorly understood, but recently attention has focused on genetic risk factors to explain why the incidence is higher in some families. Studies on large cohorts of patients with comparison of their DNA to women without endometriosis or with other disorders have documented changes in genes associated with steroid hormone production or action. The results provide further evidence that endometriosis shares genetic risk factors with other disorders of the reproductive system and a platform for new ideas related to risk, biomarkers and therapies.
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Endometriosis is a chronic, multisystemic disease often presenting with significant phenotypic variation amongst patients. The impact of race/ethnicity on the prevalence of endometriosis, as well as disease presentation, is a question of interest which has been explored for the last century. This narrative review explores the historical perspective of endometriosis and race/ethnicity as well as the evidence available to date. Furthermore, we discuss the potential implication of the bias perpetuated on this topic, specifically in the areas of medical education, research, and clinical care. In consideration of these intersecting realms, we suggest priorities for future consideration of race/ethnicity as it pertains to the delivery of care for endometriosis patients.
Lay summary
The relationship between race/ethnicity and endometriosis has been explored for over a century. Historical bias and poorly conducted research have led to the idea that this condition is less likely to be diagnosed in certain racial groups, such as Black women. We review the current state of evidence and highlight important limitations within medical education and research on this topic. Finally, we advocate for a shifting viewpoint as we strive to deliver equitable and outstanding care for all endometriosis patients.
Department of Gynecology, Ms.Clinic MayOne, Kashihara, Japan
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Aska Ladies Clinic, Nara, Japan
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Department of Gynecology, Ms.Clinic MayOne, Kashihara, Japan
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Ovarian function suppression is the current pharmacotherapy of endometriosis with limited benefit and adverse effects. New therapeutic strategies other than hormonal therapy are developed based on the molecular mechanisms involved in the hypoxic and oxidative stress environments and metabolism unique to endometriosis. A literature search was performed between January 2000 and March 2021 in the PubMed database using a combination of specific terms. Endometriosis-associated metabolic changes have been organized into four hallmarks: (1) glucose uptake, (2) aerobic glycolysis, (3) lactate production and accumulation, and (4) metabolic conversion from mitochondrial oxidative phosphorylation (OXPHOS) to aerobic glycolysis. Endometriotic cells favor glycolytic metabolism over mitochondrial OXPHOS to produce essential energy for cell survival. Hypoxia, a common feature of the endometriosis environment, is a key player in this metabolic conversion, which may lead to glucose transporter overexpression, pyruvate dehydrogenase kinase 1 (PDK1) and lactate dehydrogenase kinase A (LDHA) activation, and pyruvate dehydrogenase complex inactivation. Evading mitochondrial OXPHOS mitigates excessive generation of reactive oxygen species (ROS) that may trigger cell death. Therefore, the coinactivation of LDHA and PDK1 can induce the accumulation of mitochondrial ROS by converting energy metabolism to mitochondrial OXPHOS, causing endometriotic cell death. Metabolic pattern reconstruction in endometriotic lesions is a critical factor in cell survival and disease progression. One therapeutic strategy that may avoid hormone manipulation is focused on mitigating metabolic changes that have been detected in cells/tissues from women with endometriosis.
Lay summary
The most commonly used medical therapies for endometriosis have contraceptives and other side effects associated with hormone suppression and are therefore unsuitable for women desiring pregnancy. One therapeutic strategy that may avoid hormone manipulation is focused on changing metabolic profiles that have been detected in cells/tissues from women with endometriosis. Endometriotic cells favor glycolytic metabolism over mitochondrial oxidative phosphorylation (OXPHOS) to produce essential energy for cell growth. Furthermore, the metabolic conversion from mitochondrial OXPHOS to aerobic glycolysis suppresses cell death through the reduced generation of reactive oxygen species (ROS). This unique metabolic feature of endometriosis is important for cell survival and disease progression. Thus, changing the specific metabolic switch may increase mitochondrial ROS production, causing severe oxidative stress and cell death. This review describes new treatments by changing the metabolic profiles of endometriosis.
