Elsevier

The Lancet

Volume 397, Issue 10276, 27 February–5 March 2021, Pages 839-852
The Lancet

Review
Endometriosis is a chronic systemic disease: clinical challenges and novel innovations

https://doi.org/10.1016/S0140-6736(21)00389-5Get rights and content

Summary

Endometriosis is a common disease affecting 5–10% of women of reproductive age globally. However, despite its prevalence, diagnosis is typically delayed by years, misdiagnosis is common, and delivery of effective therapy is prolonged. Identification and prompt treatment of endometriosis are essential and facilitated by accurate clinical diagnosis. Endometriosis is classically defined as a chronic, gynaecological disease characterised by endometrial-like tissue present outside of the uterus and is thought to arise by retrograde menstruation. However, this description is outdated and no longer reflects the true scope and manifestations of the disease. The clinical presentation is varied, the presence of pelvic lesions is heterogeneous, and the manifestations of the disease outside of the female reproductive tract remain poorly understood. Endometriosis is now considered a systemic disease rather than a disease predominantly affecting the pelvis. Endometriosis affects metabolism in liver and adipose tissue, leads to systemic inflammation, and alters gene expression in the brain that causes pain sensitisation and mood disorders. The full effect of the disease is not fully recognised and goes far beyond the pelvis. Recognition of the full scope of the disease will facilitate clinical diagnosis and allow for more comprehensive treatment than currently available. Progestins and low-dose oral contraceptives are unsuccessful in a third of symptomatic women globally, probably as a result of progesterone resistance. Oral gonadotropin-releasing hormone (GnRH) antagonists constitute an effective and tolerable therapeutic alternative when first-line medications do not work. The development of GnRH antagonists has resulted in oral drugs that have fewer side-effects than other therapies and has allowed for rapid movement between treatments to optimise and personalise endometriosis care. In this Review, we discuss the latest understanding of endometriosis as a systemic disease with multiple manifestations outside the parameters of classic gynaecological disease.

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

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.

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