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Endometriosis
Endometriosis

According to data for 2020, 176 million women worldwide suffer from endometriosis1. The number of patients with endometriosis can be compared with the number of patients with diabetes. Endometriosis is a global problem. Chronic course of this disease affecting the quality of life of women, permanent infertility caused by endometriosis makes this pathology the most relevant among gynecological diseases b>.

2020

Endometriosis - a global problem

Endometriosis is a complex heterogeneous chronic inflammatory disease that affects about 176 million women worldwide1.

In many countries, national methodological recommendations have been developed, various international medical societies are engaged in the study of this pathology.
In Australia, in 2018, the "national action plan" program was launched.

According to research from the Australian Institute of Health:

 • every 10th girl experiences pelvic pain
 • every 10th woman suffers from endometriosis
 • every 3rd woman with endometriosis is infertile
 • on average, 7-10 years pass before the diagnosis of endometriosis is made

The systematic review published in BJOG in 2018 included two international and five national guidelines2:

American College of Obstetricians and Gynecologists (ACOG);
Australasian Certificate of Reproductive Endocrinology and Infertility Consensus Expert Panel on Trial Evidence (ACCEPT);
College National des Gynecologues et Obstetriciens Francais (CNGOF);
National German Guideline (S2k) Diagnosis and Treatment of Endometriosis (NGG);
Society of Obstetricians and Gynaecologists of Canada (SOGC);

European Society of Human Reproduction and Embryology (ESHRE) Management of women with endometriosis;
World Endometriosis Society (WES) Consensus on current management of endometriosis.

The authors evaluated the methodological quality of endometriosis guidelines, mapped their recommendations, and examined the relationship between the recommendations and the research evidence.

According to a large 2018 study in USA3:

The prevalence of endometriosis was estimated at 6.1% (2,922 of 48,020 women surveyed)

52.7% of women were 18-29 years of age when they were diagnosed with endometriosis.

Most (86.2%) women experienced symptoms before diagnosis.

Women with endometriosis were also more likely to report severe symptoms for menstrual pelvic pain/cramping, for non-menstrual pelvic pain/cramping, and for dyspareunia.

According to a similar study in Canada conducted in 20204:

The prevalence of endometriosis among Canadian women was 7.0% according to the on-line survey in this study, which is higher than reported in a small population-based study of Canadian women aged 15 to 49 years (5.2%) and a similar prevalence estimate of endometriosis among women in the United States (6.1% to 6.6%).

Nearly half (47.5%) of the women were 18 to 29 years old when they were diagnosed with endometriosis, and 84.1% were experiencing symptoms before diagnosis.

Women with endometriosis reported an average 5.4-year delay in diagnosis with a 3.1-year delay from symptom onset to visit a doctor and a 2.3-year delay between doctor consultation and diagnosis.

According to ESHRE5:

The exact prevalence of endometriosis is unknown, but estimates range from 2 to 10% in the general female population, but up to 50% in infertile women.

The delay in diagnosis is:

10 years in Germany and Austria,
8 years in the UK and Spain,
7 years in Norway,
7 to 10 years in Italy,
4-5 years in Ireland and Belgium

The Geneva Foundation for Medical Education and Research (GFMER) collects data from many countries and publishes all official guidelines on endometriosis on its website.
GFMER is a non-profit organization established in 2002. It is supported by the Department of Social Affairs of the City of Geneva and other Swiss and international institutions. The Foundation works in close collaboration with the World Health Organization (WHO). The overall objectives of the Foundation are to promote and develop health education and research programs.

Speaking about the problem of endometriosis today, we can highlight the following goals:

  1. Improving the quality of life of women with endometriosis and chronic pelvic pain.

  2. Reducing the time for diagnosis of endometriosis (establish factors contributing to delayed diagnosis, identify steps to reduce the time for diagnosis)
    3.           ↓
    • Reduce the risk of chronic pain
      •           ↓
    • Reduce the risk of pain-related symptoms

Theories of origin
1927

Implantation theory

The implantation theory6,7,8,9 was first proposed in 1917.

The implantation theory6,7,8,9 was first proposed in 1917. According to this theory, the high prevalence of endometriosis in women today may be due to a significant increase in the number of menstruations over a woman's lifetime, due to an earlier age of menarche and a progressive decrease in the number of pregnancies.

The pro-endometriotic niche formed as a result of epithelial lesions is an auxiliary microenvironment for the progression of endometriosis. Subsequent retrograde menstruation of stromal endometrial cells into the pro-endometriotic niche contributes to the appearance of endometrioid lesions

1981

The theory of coelomic metaplasia

Metaplasia, or the transition from one normal tissue type to another normal tissue type, is another theory10.

Endometrium and peritoneum are derived from the same epithelium of the coelomic wall. The transformation of the coelomic epithelium into endometrial-type glands in response to as yet unknown stimuli may explain the unusual localization of endometriosis. The coelomic metaplasia is also thought to explain the occurrence of endometriosis in women who have undergone total hysterectomy and do not receive ZGT.

It is assumed that the peritoneal mesothelium retains its embryologic ability to transform into reproductive tissue. This transformation may occur spontaneously or it may be facilitated by exposure to chronic irritation by retrograde menstrual fluid.

2011

The theory of "tissue injury and repair" (TIAR)

Endometriosis appears as a result of a pathological amplification of the physiological mechanism of "tissue injury and repair" (TIAR)11 accompanied by local estrogen production.

Figure 1. Model of ‘tissue injury and repair’ (TIAR) at the level of the endometrial-myometrial interface at the fundo-cornual raphe. The mechanisms of first- and second-step injury are depicted. Persistent uterine peristaltic activity and hyperperistalsis are responsible for perpetuation of injury with permanently increased paracrine estrogen action. (From Leyendecker et al. Arch Gynecol Obstet 2009;280:529–38, with permission w9x.)

Figure 2. Modified original drawing from Werth and Grusdew showing the architecture of the subendometrial myometrium (archimyometrium) in a human fetal uterus. The specific orientation of the circular fibers of the archimyometrium results from the fusion of the two paramesonephric ducts forming a fundo-cornual raphe in the midline (dashed rectangle). The peristaltic pump of the uterus, which is continuously active during the menstrual cycle, is driven by co-ordinated contractions of these muscular fibers. Directed sperm transport into the dominant tube is made possible by differential activation of these fibers. The region of the fundo-cornual raphe is considered the predominant site of mechanical strain. (Modified from Werth and Grusdew. Arch Gynäkol 1898;55:325–409 w12x.)

Indirect evidence suggests that endometriosis and adenomyosis are caused by trauma. In spontaneous disease, chronic uterine peristalsis or hyperperistalsis phases cause microtraumatization at the endometrial-miometrial interface near the fundo-cornial suture with activation of the TIAR mechanism. This leads to local production of estrogen. With continued peristaltic activity, such areas may increase, and increasingly produced estrogens will paracrinely affect ovarian control over uterine peristaltic activity, leading to persistent hyperperistalsis and the formation of a vicious circle. Severe uterine autotraumatization is accompanied by dislocation of basal endometrial fragments into the abdominal cavity with subsequent infiltration of the basal endometrium deep into the myometrial wall.


2014

Review of existing theories

Figure. Summary of the proposed interplay between the different factors reported in the pathogenesis of superficial versus deep endometriosis. The different initiating, propagating, and predisposing factors are indicated through different shapes, respectively. The arrows indicate the interplay between the different factors. As indicated by the bold pink arrows, some of the labelled propagating factors create a microenvironment that impacts the differentiation of stem cells and/or the transdifferentiation of peritoneal cells into endometrial cells.

This review12 examines existing theories on the initiation and propagation of different types of endometriotic lesions, as well as critically appraises the myriad of biologically relevant evidence that support or oppose each of the proposed theories. The current literature suggests that stem cells, dysfunctional immune response, genetic predisposition, and aberrant peritoneal environment may all be involved in the establishment and propagation of endometriotic lesions. An orchestrated scientific and clinical effort is needed to consider all factors involved in the pathogenesis of this multifaceted disease and to propose novel therapeutic targets to reach effective treatments for this distressing condition.

Entry of endometrial or hematopoietic stem cells into the abdominal cavity or abnormal differentiation into endometrioid tissue of peritoneal stem cells can be the first step in the formation of endometriosis foci.
Impaired immune response and genetic predisposition, which allow these ectopic lesions to grow in an altered microenvironment, can also contribute to the development of the disease.
Existing treatment regimens for endometriosis are usually based on the influence on sex hormones, which mainly affect differentiated ectopic endometrioid cells, which normally die off through apoptosis, while the stem cells that spread the disease may be unaffected.

2017

Pathogenesis of deep endometriosis

DIE requires genetic/epigenetic endometrioid cell changes in the lesions.
Typical, cystic and deep endometriosis must be considered as 3 different diseases.

This article13 explored the causes and development of DIE.The pathophysiology of (deep) endometriosis is still unclear. As originally suggested by Cullen, change the definition "deeper than 5 mm" to "adenomyosis externa." With the discovery of the old European literature on uterine bleeding in 5%-10% of the neonates and histologic evidence that the bleeding represents decidual shedding, it is postulated/hypothesized that endometrial stem/progenitor cells, implanted in the pelvic cavity after birth, may be at the origin of adolescent and even the occasionally premenarcheal pelvic endometriosis. Endometriosis in the adolescent is characterized by angiogenic and hemorrhagic peritoneal and ovarian lesions.

The development of deep endometriosis at a later age suggests that deep infiltrating endometriosis is a delayed stage of endometriosis. Another hypothesis is that the endometriotic cell has undergone genetic or epigenetic changes and those specific changes determine the development into deep endometriosis. This is compatible with the hereditary aspects, and with the clonality of deep and cystic ovarian endometriosis. It explains the predisposition and an eventual causal effect by dioxin or radiation. Specific genetic/epigenetic changes could explain the various expressions and thus typical, cystic, and deep endometriosis become three different diseases. Subtle lesions are not a disease until epi(genetic) changes occur. A classification should reflect that deep endometriosis is a specific disease. In conclusion the pathophysiology of deep endometriosis remains debated and the mechanisms of disease progression, as well as the role of genetics and epigenetics in the process, still needs to be unraveled.

2018

Bacterial contamination hypothesis: a new concept in endometriosis

This theory14 relates the development of endometriosis to the presence of E. Coli

According to this theory lipopolysaccharide regulates the pro-inflammatory response in the pelvis and growth of endometriosis via the LPS/TLR4 cascade. The menstrual blood was highly contaminated with Escherichea coli and the endometrial samples were colonized with other microbes. A cross-talk between inflammation and ovarian steroids or the stress reaction also was observed in the pelvis.

Treatment with GnRHa further worsens intrauterine microbial colonization, with the consequent occurrence of endometritis in women with endometriosis.

2020

Endometriosis-Associated Macrophages: Origin, Phenotype, and Function

Endometriosis is defined by the growth of endometrium-like tissue outside the uterus, usually on the pelvic cavity peritoneum and ovaries (known as "lesions"). Macrophages are the complex cells at the center of this mysterious condition; they are crucial to the growth, development, vascularization, and innervation of lesions, as well as to the formation of pain symptoms. From a health perspective, tissue-dwelling macrophages, which appear early in embryonic development, are vital to tissue development and homeostasis. In adults during inflammatory processes, monocytes are recruited from the blood and differentiate into macrophages in tissues, where they perform functions such as infection control and wound repair. The interaction between resident and recruited macrophages is currently at the forefront of macrophage research because of their different roles in inflammatory diseases. In some cancers, tumor-associated macrophages (TAMs) consist of resident macrophages and recruited inflammatory monocytes that differentiate into macrophages within the tumor. These macrophages of different origin play different roles in the progression of the disease.

According to this theory15, in disease, macrophages, which normally maintain homeostasis, are altered so that they contribute to the disease. Evidence supporting the existence of multiple phenotypic populations and origins of macrophages in endometriosis and how this can be used for therapy is being studied.

Figure 1. Endometriosis is a chronic inflammatory condition. Endometriosis is characterized by the presence of endometrial-like tissue found outside the uterus, most commonly in the peritoneal cavity. Endometriosis lesions are heterogenous but usually contain endometrial stromal cells and epithelial glands, immune cell infiltrates and are vascularized and innervated by nerves.

Figure 2. Macrophages are mononuclear phagocytes. Tissue macrophages are seeded during fetal life from the fetal liver and yolk sack and undergo self-renewal. In adults, monocyte precursors extravasate from the bone marrow into the circulation, where they can then infiltrate into tissues and differentiate into macrophages. In tissues, macrophages modulate their phenotype dependent on local cytokines and growth factors to specific tissue or disease-associated phenotypes.

Figure 3. Endometriosis lesions are infiltrated by blood vessels, nerves, and macrophages. Lesion resident macrophages are derived from macrophages originating from the endometrium and recruited macrophages. Macrophages interact with blood vessels and nerves to stimulate their growth. Signaling also occurs between macrophages and stromal cells, which increases their clonal expansion and invasive properties.



Pathogenesis of endometriomas formation

Special attention should be paid to the issue of ovarian endometriosis. Today there is no consensus in the world when we can remove endometriomas and when we can observe them.
A lot of recommendations are based on the size of the endometrioma, whether the ovarian surgery is repeated. It's no secret that ovarian surgery reduces the ovarian reserve. In order to preserve the ovarian reserve, the cyst removal technique, the method of removal is important. However, the very presence of endometriomas and their growth also have a negative impact on the ovary, affecting its tissue. More information on the removal of endometriomas and cyst removal techniques will be described in more detail in the "surgical treatment" section. Here we will focus on the theories of cyst formation. There are 3 theories of endometrioma formation (see diagram).

endometrioma Invagination of endometriosis lesions Celomic metaplasia of invaginated epithelial inclusions Colonization of functional ovarian cysts endometrioma Invagination of endometriosis lesions Celomic metaplasia of invaginated epithelial inclusions Colonization of functional ovarian cysts

Understanding the mechanism for the formation of endometriomas, we can find the best way to remove them.

Classification

In 2017, Human Reproduction published an article entitled "World Endometriosis Society consensus on the classification of endometriosis16". In this article, the authors reviewed the existing classifications and attempted to develop the concept of a unified classification. The article recommends that until better classification systems are developed, surgeons should use a toolkit for surgical classification of endometriosis (including the r-ASRM system and, if necessary, Enzian and EFI staging systems) to maximize the information available to women after surgery.

Proposed Toolbox for Surgical Classification for Endometriosis:

a. Revised American Society for Reproductive Medicine scoring system for all women with endometriosis. 1996

b: Enzian scoring system for women with deep endometriosis. 2016

c: Endometriosis Fertility Index for women with endometriosis for whom future fertility is a consideration. Fertil Steril 2010

In 2021, a new methodology for assessing endometriosis lesions was proposed and published in the JIMG: "AAGL 2021 Endometriosis Classification: An Anatomy-based Surgical Complexity Score17".
The AAGL 2021 Endometriosis Classification allows for identifying objective intraoperative findings that reliably discriminate surgical complexity levels better than the ASRM staging system. The AAGL severity stage correlates comparably with pain and infertility symptoms with the ASRM stage.
a. The size corresponds to the sum of the major diameter of the cysts in the affected ovary.
b. Refers to retrocervical, uterosacral ligaments (part of retrocervical region), paracervical, or torus uterinus lesions.
c. Refers to the lesions of the rectovaginal space below the line passing along the lower border of the posterior lip of the cervix (under the peritoneum) [27]. If the patient has an anterior low rectal lesion compromising the rectovaginal septum, score here and also under rectum/sigmoid endometriosis.
d. If more than 1 bowel lesion, add up the total sum of the major longitudinal diameters of each of the lesions.

Clinical manifestations

Endometriosis has a significant impact on women's quality of life. Women with endometriosis have a higher risk/frequency of the following symptoms18:

Quality of life Dysmenorrhea OR = 8,1 Dyspareunia and/or postcoital bleeding OR = 6,8 Abdominal and pelvic pain OR = 5,2 More frequent doctor visits 88% have anxiety 87% have symptoms of depression Menorrhagia OR = 4,0 Twice as often take a vacation

Main manifestations:
endometriosis asymptomatic pain dysmenorrhea abdominal pain dyspareunia dyschezia infertility
2017

NICE. Endometriosis: diagnosis und management.

In the presence of 1 of the symptoms:
• Chronic pelvic pain
• dysmenorrhea
• dyspareunia
• Recurrent or cyclical abdominal pain
• Recurrent or cyclical dysuria
• Infertility in combination with 1 of the following symptoms




• Paracetamol or NSAIDs alone or in combination with
• Hormone therapy (gestagens, OCs)


Pregnancy planning




If:
• Paracetamol or NSAIDs do not provide adequate pain relief • Hormone therapy is ineffective, intolerable, or contraindicated.





Diagnostic

2019

Clinical diagnosis of endometriosis: a call to action

In 2019, an algorithm for a clinical diagnosis of endometriosis20 was published in the American Journal of Obstetrics & Gynecology.

In an effort to provide a unified practical approach to the clinical diagnosis of endometriosis, an algorithm based on literature data and clinical experience has been developed. The proposed algorithm uses methods readily available to most practitioners and allows clinicians to initiate treatment without delay or invasive procedures. At each stage, symptoms that are consistent with endometriosis and those that indicate a possible alternative diagnosis are identified. In general, persistent and/or worsening cyclic or persistent pelvic pain, especially in the presence of other symptoms associated with endometriosis, medical history and physical examination findings suggest endometriosis. If these findings are unclear, imaging by transvaginal ultrasound is a widely available and inexpensive option.

Diagnostic
Diagnostic Complaints Anamnesis Examination Transvaginal ultrasound MRI Diagnostic Complaints Anamnesis Examination Transvaginal ultrasound MRI
Do not rule out endometriosis if abdominal, pelvic, ultrasound, and MRI examinations show no abnormalities. If clinical suspicion or symptoms persist: Diagnostic laparoscopy * Do not rule out endometriosis if abdominal, pelvic, ultrasound, and MRI examinations show no abnormalities. If clinical suspicion or symptoms persist: Diagnostic laparoscopy *

* - National Guideline Alliance (UK). Endometriosis: diagnosis and management.19

CA-125 ? Most global recommendations do not recommend the use of CA-125 in the diagnostic of endometriosis CA-125 Most global recommendations do not recommend the use of CA-125 in the diagnostic of endometriosis CA-125 Most global recommendations do not recommend the use of CA-125in the diagnostic of endometriosis

Endometriosis is considered a risk factor that can lead to the development of ovarian cancer within 5 years [1].

According to one study, the overall risk is approximately 2.5% [2].

  1. Aris A. Endometriosis-associated ovarian cancer: a ten-year cohort study of women living in the Estrie Region of Quebec, Canada. J Ovarian Res 2010; 3: 2
  2. Van Gorp T, Amant F, Neven P et al. Endometriosis and the development of malignant tumors of the pelvis. A review of literature. Best Pract Res Clin Obstet Gynaecol 2004; 18: 349-371
    3.

  1. Hogg C, Horne AW and Greaves E (2020) Endometriosis-Associated Macrophages: Origin, Phenotype, and Function. Front. Endocrinol. 11:7. doi: 10.3389/fendo.2020.00007);
  2. Hirsch M, Begum MR, Paniz É, Barker C, Davis CJ, Duffy J. Diagnosis and management of endometriosis: a systematic review of international and national guidelines. BJOG. 2018;125(5):556‐564. doi:10.1111/1471-0528.14838
  3. Fuldeore MJ, Soliman AM. Prevalence and Symptomatic Burden of Diagnosed Endometriosis in the United States: National Estimates from a Cross-Sectional Survey of 59,411 Women. Gynecol Obstet Invest. 2017;82(5):453‐461. doi:10.1159/000452660
  4. Singh S, Soliman AM, Rahal Y, et al. Prevalence, Symptomatic Burden, and Diagnosis of Endometriosis in Canada: Cross-Sectional Survey of 30 000 Women [published online ahead of print, 2020 Jan 27]. J Obstet Gynaecol Can. 2020;S1701-2163(19)30980-6. doi:10.1016/j.jogc.2019.10.038
  5. Dunselman GA, Vermeulen N, Becker C, et al. ESHRE guideline: management of women with endometriosis. Hum Reprod. 2014;29(3):400‐412. doi:10.1093/humrep/det457
  6. Sampson J A. Peritoneal endometriosis due to menstrual dissemination of the endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol. 1927;14:422.
  7. Sampson J A. Metastatic or embolic endometriosis due to the menstrual dissemination of endometrial tissue into the venous circulation. Am J Pathol. 1927;3:93–109.
  8. Tahir A. Mahmood, Allan Templeton Prevalence and genesis of endometriosis Human Reproduction, Volume 6, Issue 4, April 1991, Pages 544–549
  9. Liang Y, Wu J, Wang W, Xie H, Yao S. Pro-endometriotic niche in endometriosis. Reprod Biomed Online. 2019;38(4):549‐559. doi:10.1016/j.rbmo.2018.12.025
  10. Meyer R. Über den Stand der Frage der Adenomyositis, Adenomyome im allgemeinen und insbesondere über Adenomyositis seroepithelialis und Adenomyometritis sarcomatosa. Zentralbl Gynäkol. 1919;36:745–750
  11. Ridley JH. Coelomic metaplasia. Am J Obstet Gynecol. 1981;140(2):233‐234. doi:10.1016/0002-9378(81)90113-7
  12. Leyendecker G, Wildt L. A new concept of endometriosis and adenomyosis: tissue injury and repair (TIAR). Horm Mol Biol Clin Investig. 2011;5(2):125‐142. doi:10.1515/HMBCI.2011.002
  13. Sourial S, Tempest N, Hapangama DK. Theories on the pathogenesis of endometriosis. Int J Reprod Med. 2014;2014:179515. doi:10.1155/2014/179515
  14. Gordts S, Koninckx P, Brosens I. Pathogenesis of deep endometriosis. Fertil Steril. 2017;108(6):872‐885.e1. doi:10.1016/j.fertnstert.2017.08.036
  15. Khan KN, Fujishita A, Hiraki K, et al. Bacterial contamination hypothesis: a new concept in endometriosis. Reprod Med Biol. 2018;17(2):125‐133. Published 2018 Jan 18. doi:10.1002/rmb2.12083
  16. Hogg C, Horne AW and Greaves E (2020) Endometriosis-Associated Macrophages: Origin, Phenotype, and Function. Front. Endocrinol. 11:7. doi: 10.3389/fendo.2020.00007
  17. Johnson NP, Hummelshoj L, Adamson GD, et al. World Endometriosis Society consensus on the classification of endometriosis. Hum Reprod. 2017;32(2):315‐324. doi:10.1093/humrep/dew293
  18. Abrao MS, Andres MP, Miller CE, Gingold JA, Rius M, Neto JS, Carmona F. AAGL 2021 Endometriosis Classification: An Anatomy-based Surgical Complexity Score. J Minim Invasive Gynecol. 2021 Nov;28(11):1941-1950.e1. doi: 10.1016/j.jmig.2021.09.709. Epub 2021 Sep 25. PMID: 34583009.
  19. Ballard KD, Seaman HE, de Vries CS, Wright JT. Can symptomatology help in the diagnosis of endometriosis? Findings from a national case-control study--Part 1. BJOG. 2008 Oct;115(11):1382-91. doi: 10.1111/j.1471-0528.2008.01878.x. Epub 2008 Aug 19. PMID: 18715240.
  20. National Guideline Alliance (UK). Endometriosis: diagnosis and management. London: National Institute for Health and Care Excellence (NICE); 2017 Sep. PMID: 29787038.
  21. Clinical diagnosis of endometriosis: a call to action Sanjay K. Agarwal, MD; Charles Chapron, MD; Linda C. Giudice, MD, PhD; Marc R. Laufer, MD; Nicholas Leyland, MD; Stacey A. Missmer, ScD; Sukhbir S. Singh, MD; Hugh S. Taylor, MD American Journal of Obstetrics & Gynecology APRIL 2019