Endometriosis affects approximately 190 million women and people assigned female at birth worldwide. It is a chronic, inflammatory, gynecologic disease marked by the presence of endometrial-like ...tissue outside the uterus, which in many patients is associated with debilitating painful symptoms. Patients with endometriosis are also at greater risk of infertility, emergence of fatigue, multisite pain, and other comorbidities. Thus, endometriosis is best understood as a condition with variable presentation and effects at multiple life stages. A long diagnostic delay after symptom onset is common, and persistence and recurrence of symptoms despite treatment is common. This review discusses the potential genetic, hormonal, and immunologic factors that lead to endometriosis, with a focus on current diagnostic and management strategies for gynecologists, general practitioners, and clinicians specializing in conditions for which patients with endometriosis are at higher risk. It examines evidence supporting the different surgical, pharmacologic, and non-pharmacologic approaches to treating patients with endometriosis and presents an easy to adopt step-by-step management strategy. As endometriosis is a multisystem disease, patients with the condition should ideally be offered a personalized, multimodal, interdisciplinary treatment approach. A priority for future discovery is determining clinically informative sub-classifications of endometriosis that predict prognosis and enhance treatment prioritization.
Endometriosis is a common condition associated with infertility that causes chronic pain in many, but not all, women. It is defined by the presence of endometrial-like tissue outside the uterus. ...Although the cause and natural history of the disorder remain uncertain, hormonal, neurological, and immunological factors are all implicated in the mechanisms contributing to development of symptoms. Because definitive diagnosis requires surgery, there is often a long diagnostic delay after onset of symptoms. Current interventions for endometriosis have limited efficacy and unacceptable side effects/risks and are associated with high rates of symptom recurrence. Here, we review recent advances in our understanding of the etiology of endometriosis, discuss current diagnostic and treatment strategies, highlight current clinical trials, and consider how recent results offer new avenues for the identification of endometriosis biomarkers and the development of effective non-surgical therapies that are fertility-sparing.
Endometriosis is a critical unsolved women’s health problem causing debilitating pelvic pain in up to 10% of women of reproductive age. Recent advances in understanding endometriosis as an inflammatory, pain, and metabolic disorder suggest new avenues for therapeutics.
Although pain is one of the main symptoms women with endometriosis present with, there is poor correlation between symptom severity and disease burden and the underlying biological mechanisms by ...which pain arises are still only poorly understood. We briefly review the neurobiology of pain before considering mechanisms that may be specifically relevant in the context of endometriosis. The role of pelvic factors such as new nerve fibre growth, peritoneal fluid and inflammation is explored with a particular focus on studies where these factors have been associated with pain symptoms rather than just being compared between women with endometriosis and disease-free controls. We then consider the role of the central nervous system and associated systems, including the stress axis and psychological factors, in the modulation of pain. The potential for changes in these systems to be a cause and/or a consequence of the pain and how they might explain some of the known associations between endometriosis and other somatic symptoms is discussed. The chapter concludes by considering the implications of these mechanisms on treatment strategies for these women.
•There are changes in the periphery, which are associated with endometriosis-associated pain.•Central changes also occur in endometriosis-associated pain.•The use of the characteristics of the pain experienced has led to useful discoveries.
Endometriosis is a complex, heterogeneous, chronic inflammatory condition impacting ~176 million women worldwide. It is associated with chronic pelvic pain, infertility, and fatigue, and has a ...substantial impact on health-related quality of life. Endometriosis is defined by the growth of endometrial-like tissue outside the uterus, typically on the lining of the pelvic cavity and ovaries (known as "lesions"). Macrophages are complex cells at the center of this enigmatic condition; they are critical for the growth, development, vascularization, and innervation of lesions as well as generation of pain symptoms. In health, tissue-resident macrophages are seeded during early embryonic life are vital for development and homeostasis of tissues. In the adult, under inflammatory challenge, monocytes are recruited from the blood and differentiate into macrophages in tissues where they fulfill functions, such as fighting infection and repairing wounds. The interplay between tissue-resident and recruited macrophages is now at the forefront of macrophage research due to their differential roles in inflammatory disorders. In some cancers, tumor-associated macrophages (TAMs) are comprised of tissue-resident macrophages and recruited inflammatory monocytes that differentiate into macrophages within the tumor. These macrophages of different origins play differential roles in disease progression. Herein, we review the complexities of macrophage dynamics in health and disease and explore the paradigm that under disease-modified conditions, macrophages that normally maintain homeostasis become modified such that they promote disease. We also interrogate the evidence to support the existence of multiple phenotypic populations and origins of macrophages in endometriosis and how this could be exploited for therapy.
Fibroids are the most common benign tumours of the female genital tract and are associated with numerous clinical problems including a possible negative impact on fertility. In women requesting ...preservation of fertility, fibroids can be surgically removed (myomectomy) by laparotomy, laparoscopically or hysteroscopically depending on the size, site and type of fibroid. Myomectomy is however a procedure that is not without risk and can result in serious complications. It is therefore essential to determine whether such a procedure can result in an improvement in fertility and, if so, to then determine the ideal surgical approach.
To examine the effect of myomectomy on fertility outcomes and to compare different surgical approaches.
We searched the Cochrane Gynaecology and Fertility Group (CGFG) Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, Epistemonikos database, World Health Organization (WHO) International Clinical Trials Registry Platform search portal, Database of Abstracts of Reviews of Effects (DARE), LILACS, conference abstracts on the ISI Web of Knowledge, OpenSigle for grey literature from Europe, and reference list of relevant papers. The final search was in February 2019.
Randomised controlled trials (RCTs) examining the effect of myomectomy compared to no intervention or where different surgical approaches are compared regarding the effect on fertility outcomes in a group of infertile women suffering from uterine fibroids.
Data collection and analysis were conducted in accordance with the procedure suggested in the Cochrane Handbook for Systematic Reviews of Interventions.
This review included four RCTs with 442 participants. The evidence was very low-quality with the main limitations being due to serious imprecision, inconsistency and indirectness. Myomectomy versus no intervention One study examined the effect of myomectomy compared to no intervention on reproductive outcomes. We are uncertain whether myomectomy improves clinical pregnancy rate for intramural (odds ratio (OR) 1.88, 95% confidence interval (CI) 0.57 to 6.14; 45 participants; one study; very low-quality evidence), submucous (OR 2.04, 95% CI 0.62 to 6.66; 52 participants; one study; very low-quality evidence), intramural/subserous (OR 2.00, 95% CI 0.40 to 10.09; 31 participants; one study; very low-quality evidence) or intramural/submucous fibroids (OR 3.24, 95% CI 0.72 to 14.57; 42 participants; one study; very low-quality evidence). Similarly, we are uncertain whether myomectomy reduces miscarriage rate for intramural fibroids (OR 1.33, 95% CI 0.26 to 6.78; 45 participants; one study; very low-quality evidence), submucous fibroids (OR 1.27, 95% CI 0.27 to 5.97; 52 participants; one study; very low-quality evidence), intramural/subserous fibroids (OR 0.80, 95% CI 0.10 to 6.54; 31 participants; one study; very low-quality evidence) or intramural/submucous fibroids (OR 2.00, 95% CI 0.32 to 12.33; 42 participants; one study; very low-quality evidence). This study did not report on live birth, preterm delivery, ongoing pregnancy or caesarean section rate. Laparoscopic myomectomy versus myomectomy by laparotomy or mini-laparotomy Two studies compared laparoscopic myomectomy to myomectomy at laparotomy or mini-laparotomy. We are uncertain whether laparoscopic myomectomy compared to laparotomy or mini-laparotomy improves live birth rate (OR 0.80, 95% CI 0.42 to 1.50; 177 participants; two studies; I
= 0%; very low-quality evidence), preterm delivery rate (OR 0.70, 95% CI 0.11 to 4.29; participants = 177; two studies; I
= 0%, very low-quality evidence), clinical pregnancy rate (OR 0.96, 95% CI 0.52 to 1.78; 177 participants; two studies; I
= 0%, very low-quality evidence), ongoing pregnancy rate (OR 1.61, 95% CI 0.26 to 10.04; 115 participants; one study; very low-quality evidence), miscarriage rate (OR 1.25, 95% CI 0.40 to 3.89; participants = 177; two studies; I
= 0%, very low-quality evidence), or caesarean section rate (OR 0.69, 95% CI 0.34 to 1.39; participants = 177; two studies; I
= 21%, very low-quality evidence). Monopolar resectoscope versus bipolar resectoscope One study evaluated the use of two electrosurgical systems during hysteroscopic myomectomy. We are uncertain whether bipolar resectoscope use compared to monopolar resectoscope use improves live birth/ongoing pregnancy rate (OR 0.86, 95% CI 0.30 to 2.50; 68 participants; one study, very low-quality evidence), clinical pregnancy rate (OR 0.88, 95% CI 0.33 to 2.36; 68 participants; one study; very low-quality evidence), or miscarriage rate (OR 1.00, 95% CI 0.19 to 5.34; participants = 68; one study; very low-quality evidence). This study did not report on preterm delivery or caesarean section rate.
There is limited evidence to determine the role of myomectomy for infertility in women with fibroids as only one trial compared myomectomy with no myomectomy. If the decision is made to have a myomectomy, the current evidence does not indicate a superior method (laparoscopy, laparotomy or different electrosurgical systems) to improve rates of live birth, preterm delivery, clinical pregnancy, ongoing pregnancy, miscarriage, or caesarean section. Furthermore, the existing evidence needs to be viewed with caution due to the small number of events, minimal number of studies and very low-quality evidence.
Endometriosis is an incurable, under-diagnosed, systemic inflammatory disease affecting millions world-wide. Common symptoms include life-impacting pain, gastrointestinal/urinary symptoms, excessive ...fatigue, and infertility. Global public health policies are urgently needed to promote awareness, implement multidisciplinary care, and fund research for aetiology, biomarker discovery, and effective therapies for symptoms associated with endometriosis.
To investigate the relationship between endometriosis and adverse pregnancy outcomes.
Women between ages 25 and 42 years in 1989 (n=116,429) reported detailed information on pregnancies and ...reproductive health at baseline and every 2 years thereafter in the Nurses' Health Study II, a cohort study. In 2009, they completed a detailed, pregnancy-focused questionnaire. A total of 196,722 pregnancies were reported. Adverse pregnancy outcomes included spontaneous abortion, ectopic pregnancy, stillbirth, gestational diabetes mellitus (GDM), hypertensive disorders of pregnancy (preeclampsia or gestational hypertension), preterm birth, and low birth weight. We estimated the relative risks (RRs) and 95% CIs of adverse pregnancy outcomes comparing pregnancies in women with and without a history of laparoscopically confirmed endometriosis using multivariable log-binomial regression, with generalized estimating equations to account for multiple pregnancies per woman.
Endometriosis was associated with a greater risk of pregnancy loss (spontaneous abortion: RR 1.40, 95% CI 1.31-1.49; ectopic pregnancy: RR 1.46, 95% CI 1.19-1.80). Endometriosis was also associated with a greater risk of GDM (RR 1.35, 95% CI 1.11-1.63) and hypertensive disorders of pregnancy (RR 1.30, 95% CI 1.16-1.45).
We observed an association between laparoscopically confirmed endometriosis and several adverse pregnancy outcomes. Future research should focus on the potential biological pathways underlying these relationships to inform screening or preventive interventions.
Endometriosis is chronic disorder with high socioeconomic impact defined by the presence of endometrial-like tissue (“lesions”) outside the uterus. Genetic, hormonal, and immunological factors as ...well as endometrial progenitor cells are implicated in development of lesions. A hallmark of the disorder is chronic pain associated with neuroinflammation and changes in the CNS. Women with endometriosis are at increased risk of infertility. Current therapies are inadequate. To view this SnapShot, open or download the PDF.
Endometriosis is estimated to affect 6-10% of women of reproductive age and it is associated with chronic pelvic pain, dysmenorrhoea and subfertility. It is currently managed surgically or medically ...but symptoms recur in up to 75% of cases and available medical treatments have undesirable side effects. Endometriosis is defined as the presence of endometrial tissue outside the uterus with lesions typically found on the peritoneum. The aetiology of endometriosis is uncertain but there is increasing evidence that transforming growth factor (TGF)-β plays a major role.
A descriptive review was undertaken of the published literature on the expression pattern of TGF-β ligands and signalling molecules in women with and without endometriosis, and on the potential roles of TGF-β signalling in the development and progression of peritoneal endometriosis. The current understanding of the TGF-β signalling pathway is summarized.
We searched the Pubmed database using the terms 'transforming growth factor beta' and 'endometriosis' for studies published between 1995 and 2016. The initial search identified 99 studies and these were used as the basic material for this review. We also extended our remit for important older publications. In addition, we searched the reference lists of studies used in this review for additional studies we judged as relevant. Studies which were included in the review focused on peritoneal endometriosis only as increasing evidence suggests that ovarian and deep endometriosis may have a differing pathophysiology. Thus, a final 95 studies were included in the review.
TGF-β1 is reported to be increased in the peritoneal fluid, serum, ectopic endometrium and peritoneum of women with endometriosis compared to women without endometriosis, and TGF-β1-null mice have reduced endometriosis lesion growth when compared to their wild-type controls. Studies in mice and women have indicated that increasing levels of TGF-β ligands are associated with decreased immune cell activity within the peritoneum, together with an increase in ectopic endometrial cell survival, attachment, invasion and proliferation, during endometriosis lesion development. TGF-β1 has been associated with changes in ectopic endometrial and peritoneal cell metabolism and the initiation of neoangiogenesis, further fuelling endometriosis lesion development.
Together these studies suggest that TGF-β1 plays a major role in the development of peritoneal endometriosis lesions and that targeting this pathway may be of therapeutic potential.
BACKGROUND Endometriosis affects 6-10% of women of reproductive age and is associated with chronic pelvic pain, dysmenorrhoea, dyspareunia and infertility. Endometriosis is defined by the presence of ...endometrial tissue outside the uterus, most commonly attached to the pelvic peritoneum. The endometrium in women with endometriosis is reported to be altered and there is increasing evidence that the phenotype of the pelvic peritoneum may also play a role in the establishment and maintenance of the disease. The aim of this review is to discuss the putative role of the pelvic peritoneum in the pathophysiology of peritoneal endometriosis. METHODS A review was undertaken of the published literature on (i) the anatomy and physiology of the peritoneum and (ii) the potential roles played by peritoneal cells in the establishment and maintenance of peritoneal endometriosis. The current understanding of the biology of peritoneal endometriosis is summarized and the potential interaction of the peritoneum with ectopic endometrial cells in endometriosis is highlighted. RESULTS Several studies indicate that differential expression of peritoneal mesothelial adhesion factors occurs in women with endometriosis, providing potential ectopic endometrial cell attachment sites for the establishment of endometriosis lesions. Changes in the peritoneal mesothelial cell phenotype, including loss of tight junctions, may allow ectopic cells to bind to, or early lesions to invade into, the extracellular matrix. Epithelial-to-mesenchymal transition of peritoneal mesothelial cells may also lead to an increase in lesion invasion and formation of fibrotic tissue in and around the lesion. There is evidence that the peritoneal mesothelium may also play a role in the invasion potential of ectopic cells by production of MMPs increasing local tissue remodelling. Peritoneal immune scavenging function may be lowered in women with endometriosis; for example there is a notable increase in macrophage-derived secretion products in women with endometriosis associated with increases in cell proliferation, cell adhesion and neovascularization. CONCLUSIONS The pelvic peritoneum appears to play a key role in the development and maintenance of endometriosis.
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