We searched PubMed for articles published in English between Jan 1, 1927, and June 14, 2020, using the terms “endometriosis”, “pain”, “systemic inflammation”, “infertility”, “biomarkers”, and “treatment”. Articles resulting from these searches and relevant references cited in those articles were reviewed.
ReviewEndometriosis is a chronic systemic disease: clinical challenges and novel innovations
Introduction
Endometriosis is a chronic, debilitating disease associated with pelvic pain and infertility.1, 2 The most common types of pelvic endometriosis are superficial peritoneal lesions, deep-infiltrating endometriosis, and ovarian endometriotic cysts (endometriomas).3 Deep infiltrating lesions are defined as lesions with more than 5 mm depth of invasion beneath the peritoneum, or infiltration into the muscularis propria of hollow viscera.4 Histologically, endometriosis is defined as the presence of ectopic endometrial glands and stroma, often with haemosiderin.5 Although a definitive diagnosis of endometriosis is often made on the basis of histological criteria, visual diagnosis is commonly used in practice; visualisation can be challenging as a result of the heterogeneity in lesion location and highly variable appearance.6, 7, 8 The disease is traditionally characterised by pelvic manifestations; however, in this Review, we describe endometriosis as more than a pelvic disease. Increasing evidence suggests that this disease has multifactorial effects throughout the body. Therefore, a shift in our perspective towards acknowledging endometriosis as a systemic disease is required.
Section snippets
Endometriosis prevalence and misdiagnosis
Endometriosis affects 5–10% of women of reproductive age. The economic burden exceeds US$22 billion in the USA alone.9 Clinical symptoms include pelvic pain, dysmenorrhoea, non-menstrual pelvic pain, and infertility.10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 Endometriosis is observed in 50–80% of women with pelvic pain and up to 50% of women with infertility; more than 176 million women have endometriosis worldwide.1, 21 Despite this high prevalence, disease recognition is inadequate and
Staging and classification systems
At present, the American Society for Reproductive Medicine (ASRM) system, which was originally developed in 1985 and revised in 1997, is the global standard used for endometriosis staging.3, 32 Despite widespread implementation, the ASRM system is insufficient because it poorly correlates with pain symptoms, infertility, and excludes extra-pelvic lesions.33, 34, 35 To improve classification of deep-infiltrating endometriosis, the Enzian system was developed.36, 37, 38 However, the World
Endometriosis pathogenesis
Although several theories exist to explain the cause of endometriosis, the most widely accepted is Sampson's retrograde menstruation theory.40 Sampson's theory is supported by data showing that women commonly have retrograde menstrual flow; increased retrograde flow caused by outflow tract obstructive defects substantially increase the prevalence of endometriosis. 41, 42
Endometrial stem cells have been extensively studied and have been shown to contribute to the development of endometriosis
Redefining endometriosis as a systemic inflammatory disease
Endometriosis has erroneously been considered as a predominantly pelvic disease, although in the past 15 years research has documented its systemic effects.118, 119, 120, 121 The presence of proinflammatory cytokines and shifts in circulating immune cell populations creates a widespread inflammatory environment extending outside the pelvis.99, 102, 104 Additionally, a myriad of circulating microRNAs (miRNAs), which modulate gene expression throughout the body, are known to be present in varying
Clinical presentation
Considering the diffuse effects of endometriosis on multiple organ systems, the fact that endometriosis has been difficult to diagnose and is so often initially misdiagnosed is not surprising. A comprehensive, clinically based approach is needed to facilitate accurate and timely diagnosis, underscoring the importance of patient history.4, 31 Pelvic pain is the most common symptom, but it is not a specific indicator of endometriosis since the pain is associated with several gynaecological and
The need for improved clinical diagnostics
Efforts have been made to find laboratory tests and radiological methods to reliably diagnose endometriosis. Transvaginal ultrasound is the most commonly used imaging tool. Despite being an effective method for diagnosing endometriomas (93% sensitivity and 95% specificity), the technique has limited capability when attempting to visualise peritoneal lesions.142, 143, 144 Transvaginal ultrasound for deep-infiltrating endometriosis can offer improved sensitivity and specificity.145, 146, 147 An
Development of new diagnostics and predictors of therapeutic response
In the past 5–10 years, research has focused on identifying alternative markers, which take into account the systemic nature of endometriosis. Circulating miRNAs have been considered promising biomarker candidates because they are stable in circulation and have highly specific expression profiles. The combination of miRNAs—let-7b, let-7d, let-7f, miR-3613, miR-451, and miR-125b-5p—reliably distinguished endometriosis patients from controls.123, 124 A prospective, blinded study showed that the
NSAIDs
Treatment of endometriosis is aimed at suppressing lesion growth, treating pain, and ideally treating the systemic effects of the disease.162 According to the National Institute for Health and Care Excellence guideline, first-line treatment consists of NSAIDs, typically in combination with progestin-based therapy.162 NSAIDs inhibit the function of cyclooxygenase enzymes, thus reducing prostaglandin concentrations and inflammation.
Progestin-based therapies
Low-dose combined oral contraceptives are effective in the
Oral GnRH antagonists
Elagolix is the first oral non-peptide GnRH antagonist available for the treatment of moderate to severe endometriosis-associated pain. Elagolix prevents the release of follicle-stimulating hormone and luteinising hormone in a dose-dependent manner. Gonadotropin concentrations are reduced within 6 h and estradiol concentrations are reduced within 24 h of administration, with avoidance of the flare effect.185 The available doses of elagolix are 150 mg/day and 200 mg twice daily (table). Both
Conclusion
Endometriosis is a systemic, heterogeneous disorder. The current gold standard for diagnosis does little to facilitate early diagnosis or avoid long-term sequelae. We propose a shift in the current diagnostic framework and in our understanding of endometriosis pathogenesis. Pelvic pain is the most distinct and problematic symptom that coincides with the observed location of the lesions. The complete effect of the disease is still not fully recognised and is not restricted to the pelvis. Modern
Search strategy and selection criteria
References (229)
- et al.
Endometriosis and infertility: a review of the pathogenesis and treatment of endometriosis-associated infertility
Obstet Gynecol Clin North Am
(2012) - et al.
Histologic study of peritoneal endometriosis in infertile women
Fertil Steril
(1990) - et al.
Endometriosis and pelvic pain: epidemiological evidence of the relationship and implications
Gynécol Obstét Fertil
(2009) - et al.
Self-reported prevalence of endometriosis and its symptoms among Puerto Rican women
Int J Gynaecol Obstet
(2008) - et al.
Validation study of nonsurgical diagnosis of endometriosis
Fertil Steril
(2001) - et al.
Diagnostic experience among 4,334 women reporting surgically diagnosed endometriosis
Fertil Steril
(2009) - et al.
Diagnosis of stage I endometriosis: comparing visual inspection to histologic biopsy specimen
J Minim Invasive Gynecol
(2008) - et al.
Laparoscopic excision of lesions suggestive of endometriosis or otherwise atypical in appearance: relationship between visual findings and final histologic diagnosis
J Minim Invasive Gynecol
(2008) - et al.
Using location, color, size, and depth to characterize and identify endometriosis lesions in a cohort of 133 women
Fertil Steril
(2008) - et al.
Clinical diagnosis of endometriosis: a call to action
Am J Obstet Gynecol
(2019)