Endometriosis

Endometriosis is a disease in which tissue similar to the endometrium, the lining of the uterus, grows in other places in the body, outside the uterus.<ref>Template:Cite web</ref><ref>Template:Cite web</ref> It occurs in humans and a limited number of other menstruating mammals. Endometrial tissue most often grows on or around reproductive organs such as the ovaries and fallopian tubes, on the outside surface of the uterus, or the tissues surrounding the uterus and the ovaries (peritoneum).<ref name="WH2014" /> It can also grow on other organs in the pelvic region like the bowels, stomach, bladder, or the cervix.<ref>Template:Cite web</ref> Rarely, it can also occur in other parts of the body.<ref name=WH2014/>

Symptoms can be very different from person to person, varying in range and intensity. About 25% of individuals have no symptoms,<ref name="Bulletti2010" /><ref>Template:Cite journal</ref> while for some it can be a debilitating disease.<ref>Template:Cite web</ref> Common symptoms include pelvic pain, heavy and painful periods, pain with bowel movements, painful urination, pain during sexual intercourse and infertility.<ref name="Bulletti2010">Template:Cite journal</ref><ref>Template:Cite web</ref> Nearly half of those affected have chronic pelvic pain, while 70% feel pain during menstruation.<ref name="Bulletti2010" /> Up to half of affected individuals are infertile.<ref name="Bulletti2010" /> Besides physical symptoms, endometriosis can affect a person's mental health and social life.<ref name="Cul2013">Template:Cite journal</ref>

Diagnosis is usually based on symptoms and medical imaging;<ref name="WH2014" /> however, a definitive diagnosis is made through laparoscopy excision for biopsy.<ref name="WH2014" /> Other causes of similar symptoms include pelvic inflammatory disease, irritable bowel syndrome, interstitial cystitis, and fibromyalgia.<ref name="Bulletti2010" /> Endometriosis is often misdiagnosed and many patients report being incorrectly told their symptoms are trivial or normal.<ref name="Cul2013" /> Patients with endometriosis see an average of seven physicians before receiving a correct diagnosis, with an average delay of 6.7 years between the onset of symptoms and surgically obtained biopsies for diagnosing the condition.<ref>Template:Cite journal</ref>

Worldwide, around 10% of the female population of reproductive age (190 million women) are affected by endometriosis.<ref>Template:Cite web</ref> Ethnic differences have been observed in endometriosis, as Southeast Asian and East Asian women are significantly more likely than White women to be diagnosed with endometriosis.<ref name="zondervan32212520" /><ref name="Velarde" />

The exact cause of endometriosis is not known. Possible causes include problems with menstrual period flow, genetic factors, hormones, and problems with the immune system.<ref name="WH2014" /> Endometriosis is associated with elevated levels of the female sex hormone estrogen, as well as estrogen receptor sensitivity.<ref name="Chantalat Valera Vaysse Noirrit 2020 p. 2815">Template:Cite journal</ref> Estrogen exposure worsens the inflammatory symptoms of endometriosis by stimulating an immune response.<ref name="Lino" /><ref name="Clinical practice. Endometriosis" />

While there is no cure for endometriosis, several treatments may improve symptoms.<ref name="Bulletti2010" /> This may include pain medication, hormonal treatments or surgery.<ref name="WH2014" /> The recommended pain medication is usually a non-steroidal anti-inflammatory drug (NSAID), such as naproxen.<ref name="WH2014" /> Taking the active component of the birth control pill continuously or using an intrauterine device with progestogen may also be useful.<ref name="WH2014" /> Gonadotropin-releasing hormone agonist (GnRH agonist) may improve the ability of those who are infertile to conceive.<ref name="WH2014" /> Surgical removal of endometriosis may be used to treat those whose symptoms are not manageable with other treatments.<ref name="WH2014">Template:Cite web</ref> Surgeons use ablation or excision to remove endometriosis lesions. Excision is the most complete treatment for endometriosis, as it involves cutting out the lesions, as opposed to ablation, which is the burning of the lesions, which leaves no samples for biopsy to confirm endometriosis.

Signs and symptoms

Pain and infertility are common symptoms, although 20–25% of affected women are asymptomatic.<ref name=Bulletti2010/> The presence of pain symptoms is associated with the type of endometrial lesions, as 50% of women with typical lesions, 10% of women with cystic ovarian lesions, and 5% of women with deep endometriosis do not have pain.<ref name="Koninckx Ussia Mashiach Vilos 2021 pp. 1035–1036">Template:Cite journal</ref>

Pelvic pain

A major symptom of endometriosis is recurring pelvic pain. The pain can range from mild to severe cramping or stabbing pain that occurs on both sides of the pelvis, in the lower back and rectal area, and even down the legs. The amount of pain a person feels correlates weakly with the extent or stage (1 through 4) of endometriosis, with some individuals having little or no pain despite having extensive endometriosis or endometriosis with scarring, while others may have severe pain even though they have only a few small areas of endometriosis.<ref name="Stratton2011">Template:Cite journal</ref> The most severe pain is typically associated with menstruation. Pain can also start a week before a menstrual period, during, and even a week after a menstrual period, or it can be constant. The pain can be debilitating and result in emotional stress.<ref>Template:Cite journal</ref> Symptoms of endometriosis-related pain may include:

• Dysmenorrhea (64%)<ref name="ovarianendo">Template:Cite journalFile:CC-BY icon.svg Text was copied from this source, which is available under a Creative Commons Attribution 4.0 International License Template:Webarchive.</ref> – painful, sometimes disabling cramps during the menstrual period; pain may get worse over time (progressive pain), also lower back pains linked to the pelvis
• Chronic pelvic pain – typically accompanied by lower back pain or abdominal pain
• Dyspareunia – painful sexual intercourse
• Dysuria – urinary urgency, frequency, and sometimes painful voiding<ref name="NIH">Template:Cite web</ref>Template:Failed verification
• Mittelschmerz – pain associated with ovulation<ref>Template:Cite journal</ref>
• Bodily movement pain – present during exercise, standing, or walking<ref name="NIH" />

Compared with patients with superficial endometriosis, those with deep disease appear to be more likely to report shooting rectal pain and a sense of their insides being pulled down.<ref name="Ballard">Template:Cite journal</ref> Individual pain areas and intensity appear to be unrelated to the surgical diagnosis, and the area of pain is unrelated to the area of endometriosis.<ref name=Ballard/>

There are multiple causes of pain. Endometriosis lesions react to hormonal stimulation and may "bleed" during menstruation. The blood accumulates locally if not cleared shortly by the immune, circulatory, and lymphatic systems. This accumulation can lead to swelling, which triggers inflammation via cytokines, resulting in pain. Another source of pain is organ dislocation that arises from adhesion binding internal organs together. The ovaries, the uterus, the oviducts, the peritoneum, and the bladder can all be bound together. Pain triggered in this way can last throughout the menstrual cycle, not just during menstrual periods.<ref>Template:Page neededTemplate:Cite book</ref>

Additionally, endometriotic lesions can develop an independent nerve supply, creating a direct and two-way interaction between lesions and the central nervous system. This interaction can produce a variety of individual differences in pain that, in some cases, become independent of the disease itself.<ref name=Stratton2011/> Nerve fibers and blood vessels are thought to grow into endometriosis lesions by a process known as neuroangiogenesis.<ref>Template:Cite journal</ref>

Infertility

Template:Main About a third of women with infertility have endometriosis.<ref name=Bulletti2010/> Among those with endometriosis, about 40% are infertile.<ref name=Bulletti2010/> The pathogenesis of infertility varies by disease stage: in early-stage disease, it is hypothesised to result from an inflammatory response that impairs various aspects of conception, whereas in later stages, distorted pelvic anatomy and adhesions contribute to impaired fertilisation.<ref>Template:Cite web</ref>

Other

Bowel endometriosis may include symptoms like diarrhea, constipation, tenesmus, dyschezia, and, rarely, rectal bleeding. Other symptoms include chronic fatigue, nausea and vomiting, migraines, low-grade fevers, heavy (44%) and/or irregular periods (60%), and hypoglycemia.<ref name="ovarianendo"/><ref>Template:Cite journal</ref><ref name="NIH" /> Endometriosis is associated with certain types of cancers, notably some types of ovarian cancer,<ref name="pmid22361336">Template:Cite journal</ref> non-Hodgkin's lymphoma and brain cancer.<ref>Template:Cite journal</ref> Endometriosis is however unrelated to endometrial cancer.<ref name="pmid21925719">Template:Cite journal</ref>

Rarely, endometriosis can cause endometrium-like tissue to be found in other parts of the body. Thoracic endometriosis occurs when endometrium-like tissue implants in the lungs or pleura. Manifestations of this include coughing up blood, a collapsed lung, or bleeding into the pleural space.<ref name=zondervan32212520/><ref>Template:Cite journal</ref> Endometriosis may also affect the nearby colon, which in rare situations may progress to partial obstruction, requiring emergency surgery.<ref>Template:Cite journal</ref>

Stress may be a contributing factor or a consequence of endometriosis.<ref name=stress>Template:Cite journal</ref>

Complications

Physical health

Complications of endometriosis include internal scarring, adhesions, pelvic cysts, ovarian chocolate cysts, ruptured cysts, and bowel and ureter obstruction resulting from pelvic adhesions.<ref>Template:Cite journal</ref> Endometriosis-associated infertility may result from scar formation and anatomical distortions caused by the condition.<ref name="WH2014" />

Ovarian endometriosis may complicate pregnancy through decidualization, abscess formation, and/or rupture.<ref name="Ueda">Template:Cite journal</ref>

Thoracic endometriosis can be associated with recurrent thoracic endometriosis syndrome which manifests during menstrual periods. It includes catamenial pneumothorax in 73% of women, catamenial hemothorax in 14%, catamenial hemoptysis in 7%, and pulmonary nodules in 6%.<ref>Template:Cite journal</ref><ref name=McCann2020p1419/>

A 20-year study involving 12,000 women with endometriosis found that individuals under 40 are three times more likely to develop heart problems compared to their healthy peers.<ref>Template:Cite journal</ref>

A study indicated that 39% of women with surgically confirmed non-graded endometriosis had a 270% higher risk for ectopic pregnancy and a 76% higher risk for miscarriage compared to their peers. For women with deep endometriosis (>5 mm invasion, ASRM Stage II and higher), the risk of miscarriage increased by 298%.<ref name="PMC9588543">Template:Cite journal</ref><ref name="ESHRE2015">Template:Cite web</ref>

Women with endometriosis also face a significantly increased risk of experiencing ante- and postpartum hemorrhage<ref name="ESHRE2015" /> as well as a 170% increased risk of severe pre-eclampsia<ref name="PMID28181672" /> during pregnancy.

Endometriosis slightly increases the risk (about 1% or less) of developing ovarian, breast, and thyroid cancers compared to women without the condition.<ref name="Kvaskoff Mahamat-Saleh Farland Shigesi pp. 393–420">Template:Cite journal</ref>

The mortality rates associated with endometriosis are low, with unadjusted and age-standardized death rates of 0.1 and 0.0 per 100,000, respectively.<ref name="GBD2015Pre">Template:Cite journal</ref>

Sciatic endometriosis, also called catamenial or cyclical sciatica, is a rare form where endometriosis affects the sciatic nerve. Diagnosis is usually confirmed through MRI or CT-myelography.<ref name="Gandhi Wilson Liang Weissbart pp. 3–9">Template:Cite journal</ref>

Endometriosis can also impact a woman's fetus or neonate, increasing the risks for congenital malformations, preterm delivery, and higher neonatal death rates.<ref name="PMID28181672">Template:Cite journal</ref>

Endometriosis can lead to ovarian cysts (endometriomas), adhesions, and damage to the fallopian tubes or ovaries, all of which can interfere with ovulation and fertilization. Treatment for endometriosis often includes hormonal therapies, pain management, and in some cases, surgery to remove the endometrial tissue. For women who struggle with infertility due to endometriosis, assisted reproductive technologies such as in vitro fertilization (IVF) may be recommended, sometimes in combination with surgical treatment to improve fertility outcomes.

Mental health

"Endometriosis is associated with an elevated risk of developing depression and anxiety disorders".<ref>Template:Cite journal</ref> Studies suggest this is partially due to the pelvic pain experienced by endometriosis patients. Template:Blockquote Mental health concerns like depression and anxiety can also result due to poor diagnostic procedures related to cultural norms where women's concerns are devalued or ignored, especially by medical professionals.<ref>Culley L, Law C, Hudson N, Denny E, Mitchell H, Baumgarten M, et al. (1 November 2013). "The social and psychological impact of endometriosis on women's lives: a critical narrative review". Human Reproduction Update. 19 (6): 625–39. doi:10.1093/humupd/dmt027. hdl:2086/8845. PMID 23884896.</ref><ref>Nnoaham KE, Hummelshoj L, Webster P, d'Hooghe T, de Cicco Nardone F, de Cicco Nardone C, et al. (August 2011). "Impact of endometriosis on quality of life and work productivity: a multicenter study across ten countries". Fertility and Sterility. 96 (2): 366–373.e8. doi:10.1016/j.fertnstert.2011.05.090. PMC 3679489. PMID 21718982.</ref>

Risk factors

Genetics

Endometriosis is a heritable condition influenced by both genetic and environmental factors,<ref name=Fauser2011/> a genetic disorder of polygenic/multifactorial inheritance<ref name="GOE-2004">Template:Cite journal</ref> acquired via affected genes from either a person's father or mother. For example, children or siblings of women with endometriosis are at higher risk of developing endometriosis themselves; low progesterone levels may be genetic, and may contribute to a hormone imbalance.<ref name="emed">Kapoor D, Davila W (2005). Endometriosis, Template:Webarchive eMedicine.</ref> Individuals with an affected first-degree relative have an approximate six-fold increase incidence of endometriosis.<ref>Template:Cite journal</ref>

Inheritance is significant but not the sole risk factor for endometriosis. Studies attribute 50% of the risk to genetics, the other 50% to environmental factors.<ref name="Montgomery2020">Template:Cite journal</ref> It has been proposed that endometriosis may result from multiple mutations within target genes, in a mechanism similar to the development of cancer.<ref name=Fauser2011/> In this case, the mutations may be either somatic or heritable.<ref name=Fauser2011/>

A 2019 genome-wide association study (GWAS) review enumerated 36 genes with mutations associated with endometriosis development.<ref name="Vassilopoulou2019">Template:Cite journal</ref> Nine chromosome loci were robustly replicated:<ref>Template:Cite journal</ref><ref name="Gene94025">Template:Cite web</ref><ref name="Gene2335">Template:Cite web</ref><ref name="Sapkota Steinthorsdottir Morris Fassbender p. ">Template:Cite journal</ref>

Chromosome	Gene/cytoband	Gene Product	Function
1	WNT4/1p36.12	Wingless-type MMTV integration site family member 4	Vital for the development of the female reproductive organs
2	GREB1/2p25.1	Growth regulation by estrogen in breast cancer 1/Fibronectin 1	Early response gene in the estrogen regulation pathway/Cell adhesion and migration processes
2	ETAA1/2p14	(ETAA1 Activator Of ATR Kinase) is a protein-coding gene.	Diseases associated with ETAA1 include Adult Lymphoma and Restless Legs Syndrome
2	IL1A/2q13	Interleukin 1 alpha (IL-1α) is encoded by the IL1A gene.	Interleukin 1 alpha (IL-1α) is encoded by the IL1A gene.
4	KDR/4q12	KDR is the human gene encoding kinase insert domain receptor also known as vascular endothelial growth factor receptor 2 (VEGFR-2)	Primary mediator of VEGF-induced endothelial proliferation, survival, migration, tubular morphogenesis and sprouting<ref>Template:Cite web</ref>
6	ID4/6p22.3	Inhibitor of DNA binding 4	Ovarian oncogene, biological function unknown
7	7p15.2	Transcription factors	Influence transcriptional regulation of uterine development
9	CDKN2BAS/9p21.3	Cyclin-dependent kinase inhibitor 2B antisense RNA	Regulation of tumour suppressor genes
12	VEZT/12q22	Vezatin, an adherens junction transmembrane protein	Tumor suppressor gene

There are many findings of altered gene expression and epigenetics, but both of these can also be a secondary result of, for example, environmental factors and altered metabolism. Examples of altered gene expression include that of miRNAs.<ref name=Fauser2011/>

Environmental toxins

Some factors associated with endometriosis include:

• Prolonged exposure to naturally synthesized estrogen; for example, from late menopause<ref name="Clinical practice. Endometriosis">Template:Cite journal</ref> or early menarche<ref>Template:Cite journalTemplate:Dead link</ref><ref>Template:Cite journal</ref>
• Obstruction of menstrual outflow; for example, in Müllerian anomalies<ref name="Clinical practice. Endometriosis"/>

Potential toxins:

• Dioxins - Several studies have investigated the potential link between exposure to dioxins and endometriosis, but evidence is equivocal and potential mechanisms are poorly understood.<ref name="pmid17981650">Template:Cite journal</ref> A 2004 review of studies of dioxin and endometriosis concluded that "the human data supporting the dioxin-endometriosis association are scanty and conflicting",<ref>Template:Cite journal</ref> and a 2009 follow-up review also found that there was "insufficient evidence" in support of a link between dioxin exposure and developing endometriosis.<ref>Template:Cite journal</ref>
• Endocrine-disrupting chemicals (EDCs)- A wider class of hormonally active agents, to which dioxin belongs, consists of both natural and manmade compounds, e.g., bisphenols, phthalates, pesticides (chlorpyrifos, hexachlorobenzene) and polychlorinated biphenyls (PCBs).<ref name="Ahn-2023">Template:Cite journal</ref> Dietary uptake represents a significant source of EDC exposure via consumption of food, water and beverages, but exposure can also occur through ingestion of EDC dust and inhalation of its gases or particles in the air.<ref name="Ahn-2023" /> Most EDCs are lipophilic, allowing them to bioaccumulate in adipose tissue (body fat) and increase in concentration.<ref name="Rumph2020" /> Bisphenol A (BPA), bisphenol S (BPS), phthalates, pesticides and PCBs all have a suspected linkage to endometriosis,<ref name="Ahn-2023" /> though have not been definitively proven as being causative.<ref name="Rumph2020">Template:Cite book</ref>

Pathophysiology

File:Peritoneal endometriosis.jpg

Laparoscopic image of endometriotic lesions at the peritoneum of the pelvic wall

While the exact cause of endometriosis remains unknown, many theories have been presented to understand and explain its development. These concepts do not necessarily exclude each other. The pathophysiology of endometriosis is likely to be multifactorial and to involve an interplay between several factors.<ref name=Fauser2011/>

Formation

The main theories for the formation of the ectopic endometrium-like tissue include retrograde menstruation, Müllerianosis, coelomic metaplasia, vascular dissemination of stem cells, and surgical transplantation, which were postulated as early as 1870. Each is further described below.<ref name=zondervan32212520/><ref name="vanderLinden1996">Template:Cite journal</ref><ref name=hufnagelpmc4986990>Template:Cite journal</ref>

Retrograde menstruation theory

The theory of retrograde menstruation (also called the implantation theory or transplantation theory) is the most commonly accepted theory for the dissemination and transformation of ectopic endometrium into endometriosis. It suggests that during a woman's menstrual flow, some of the endometrial debris flow backward through the fallopian tubes and into the peritoneal cavity, attaching itself to the peritoneal surface (the lining of the abdominal cavity) where it can proceed to invade the tissue as or transform into endometriosis. It is unclear at what stage the transformation of endometrium, or any cell of origin such as stem cells or coelomic cells (see those theories below), to endometriosis begins.<ref name="Fauser2011">Template:Cite journal</ref><ref name="vanderLinden1996"/><ref name="koninckx1999">Template:Cite journal</ref>

Proofs in support of the theory are based on retrospective epidemiological studies that an association with endometrial implants attached to the peritoneal cavity, which would develop into endometrial lesions and retrograde menstruation; and the fact that animals like rodents and non-human primates whose endometrium is not shed during the estrous cycle don't develop naturally endometriosis contrary to animals that have a natural menstrual cycle like rhesus monkeys and baboons.<ref name="Malvezzi Marengo Podgaec Piccinato p. ">Template:Cite journal</ref>

Retrograde menstruation alone is not able to explain all instances of endometriosis, and additional factors such as genetics, immunology, stem cell migration, and coelomic metaplasia (see "Other theories" on this page) are needed to account for disseminated disease and why many individuals with retrograde menstruation are not diagnosed with endometriosis. In addition, endometriosis has shown up in people who have never experienced menstruation including cisgender men,<ref name="pmid445352">Template:Cite journal</ref> fetuses,<ref name="signorile2009"/> and prepubescent girls.<ref>Template:Cite journal</ref><ref name="Marsh EE 2004">Template:Cite journal</ref> Further theoretical additions are needed to complement the retrograde menstruation theory to explain why cases of endometriosis show up in the brain<ref>Template:Cite journal</ref> and lungs.<ref>Template:Cite journal</ref>

Researchers are investigating the possibility that the immune system may be unable to cope with the cyclic onslaught of retrograde menstrual fluid. In this context there is interest in studying the relationship of endometriosis to autoimmune disease, allergic reactions, and the impact of toxic materials.<ref name="Lino">Template:Cite journal</ref><ref>Template:Cite journal</ref> It is still unclear what, if any, causal relationship exists between toxic materials or autoimmune disease and endometriosis. There are immune system changes in people with endometriosis, such as an increase in macrophage-derived secretion products, but it is unknown if these contribute to the disorder or are reactions to it.<ref name="Young2013">Template:Cite journal</ref>

Endometriotic lesions differ in their biochemistry, hormonal response, immunology, and inflammatory response compared to the endometrium.<ref name=zondervan32212520/><ref name="pmid12372441">Template:Cite journal</ref> This is likely because the cells that give rise to endometriosis are a side population of cells.<ref name=Fauser2011/> Similarly, there are changes in, for example, the mesothelium of the peritoneum in people with endometriosis, such as loss of tight junctions. It is unknown if these are causes or effects of the disorder.<ref name=Young2013/>

In rare cases where imperforate hymen does not resolve itself before the first menstrual cycle and goes undetected, blood and endometrium are trapped within the uterus until the problem is resolved by surgical incision. Many health care practitioners never encounter this defect, and due to the flu-like symptoms, it is often misdiagnosed or overlooked until multiple menstrual cycles have passed. By the time a correct diagnosis has been made, endometrium and other fluids have filled the uterus and Fallopian tubes with results similar to retrograde menstruation, resulting in endometriosis. The initial stage of endometriosis may vary based on the time elapsed between onset and surgical procedure.Template:Citation needed

The theory of retrograde menstruation as a cause of endometriosis was first proposed by John A. Sampson.<ref name="vanderLinden1996"/><ref name=sampson27ajppmcid>Template:Cite journal</ref>

Other theories

• Stem cells: Endometriosis may arise from stem cells from bone marrow and potentially other sources. In particular, this theory explains endometriosis found in areas remote from the pelvis, such as the brain or lungs.<ref name=hufnagelpmc4986990/> Stem cells may be from local cells such as the peritoneum (see coelomic metaplasia below) or cells disseminated in the bloodstream (see vascular dissemination below) such as those from the bone marrow.<ref name="vanderLinden1996"/><ref name=hufnagelpmc4986990/><ref name=sampson27ajogdoi>Template:Cite journal</ref>
• Vascular dissemination: Vascular dissemination is a 1927 theory that has been revived with new studies of bone marrow stem cells involved in pathogenesis.<ref name=hufnagelpmc4986990/><ref name=sampson27ajogdoi/>
• Environment: Environmental toxins (e.g., dioxin, nickel) may cause endometriosis.<ref name="Bruner-Tran_2008">Template:Cite journal</ref><ref>Template:Cite journal</ref> Toxins such as dioxins and dioxin-like compounds tend to bioaccumulate within the human body. Further research is needed but "it is plausible that inflammatory-like processes, caused by dioxin-like environmental chemicals, can alter normal endometrial and immune cell physiology allowing persistence and development of endometrial tissue within the peritoneal cavity, normally cleared by immune system cells".<ref>Template:Cite journal</ref>
• Müllerianosis: A theory supported by foetal autopsy is that cells with the potential to become endometrial, which are laid down in tracts during embryonic development called the female reproductive (Müllerian) tract as it migrates downward at 8–10 weeks of embryonic life, could become dislocated from the migrating uterus and act like seeds or stem cells.<ref name="vanderLinden1996"/><ref name="signorile2009">Template:Cite journal</ref>
• Coelomic metaplasia: Coelomic cells which are the common ancestor of endometrial and peritoneal cells may undergo metaplasia (transformation) from one type of cell to the other, perhaps triggered by inflammation.<ref name="vanderLinden1996"/><ref name="aafp1999">Template:Cite journal</ref>
• Vasculogenesis: Up to 37% of the microvascular endothelium of ectopic endometrial tissue originates from endothelial progenitor cells, which result in de novo formation of microvessels by the process of vasculogenesis rather than the conventional process of angiogenesis.<ref>Template:Cite journal</ref>Template:Clarify
• Neural growth: An increased expression of new nerve fibres is found in endometriosis, but does not fully explain the formation of ectopic endometriotic tissue and is not definitely correlated with the amount of perceived pain.<ref name="MorottiVincent2014">Template:Cite journal</ref>Template:Clarify
• Autoimmune: Graves disease is an autoimmune disease characterized by hyperthyroidism, goiter, ophthalmopathy, and dermopathy. People with endometriosis had higher rates of Graves' disease. One of these potential links between Graves disease and endometriosis is autoimmunity.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>
• Oxidative stress: Influx of iron is associated with the local destruction of the peritoneal mesothelium, leading to the adhesion of ectopic endometriotic cells.<ref name=":3" /> Peritoneal iron overload has been suggested to be caused by the destruction of erythrocytes, which contain the iron-binding protein hemoglobin, or a deficiency in the peritoneal iron metabolism system.<ref name=":3">Template:Cite journal</ref> Oxidative stress activity and reactive oxygen species (ROS) (such as superoxide anions and peroxide levels) are reported to be higher than normal in people with endometriosis.<ref name=":3" /> Oxidative stress and the presence of excess ROS can damage tissue and induce rapid cellular division.<ref name=":3" /> Mechanistically, there are several cellular pathways by which oxidative stress may lead to or may induce proliferation of endometriotic lesions, including the mitogen activated protein (MAP) kinase pathway and the extracellular signal-related kinase (ERK) pathway.<ref name=":3" /> Activation of both of the MAP and ERK pathways lead to increased levels of c-Fos and c-Jun, which are proto-oncogenes that are associated with high-grade lesions.<ref name=":3" />
• Microbiome: Some studies have reported differences in gut microbial composition in individuals with endometriosis compared to healthy controls. These findings have led to suggestions that alterations in the gut microbiome may contribute to the pathophysiology of endometriosis, though further research is needed to clarify this relationship.<ref>Template:Cite journal</ref>

Localization

Most often, endometriosis is found on the:

• Ovaries
• Fallopian tubes
• Tissues that hold the uterus in place (ligaments)
• Outer surface of the uterus<ref name="WH2014" />

Less common pelvic sites are:

• Vagina
• Cervix
• Vulva
• Bowel
• Bladder
• Rectum<ref name="WH2014" />

Rectovaginal or bowel endometriosis affects approximately 5-12% of those with endometriosis, and can cause severe pain with bowel movements.<ref>Template:Cite journal</ref>Template:Citation needed

Deep infiltrating endometriosis (DIE) has been defined as the presence of endometrial glands and stroma infiltrating more than 5 mm in the subperitoneal tissue. The prevalence of DIE is estimated to be 1 to 2% in women of reproductive age. Deep endometriosis typically presents as a single nodule in the vesicouterine fold or the lower 20 cm of the bowel. Deep endometriosis can be associated with severe pain. However, it can be present without severe levels of pain.<ref name="Van den Bosch Van Schoubroeck 2018 pp. 16–24">Template:Cite journal</ref>

Male endometriosis

Endometriosis has been reported in people who were assigned male at birth. Prostate endometriosis has been reported following estrogen therapy for prostate cancer<ref>Template:Cite journal</ref> and feminizing hormone therapy.<ref>Template:Cite journal</ref>

Abdominal endometriosis also happens in men following cirrhosis.<ref>Template:Cite journal</ref>

Extrapelvic endometriosis

Rarely, endometriosis appears in extrapelvic parts of the body, such as the lungs, brain, and skin.<ref name="WH2014" /><ref name=McCann2020p1419>Template:Cite journal</ref> Risk factors for scar endometriosis include previous abdominal surgeries, such as a hysterotomy or cesarean section, or ectopic pregnancies, salpingostomy puerperal sterilization, laparoscopy, amniocentesis, appendectomy, episiotomy, vaginal hysterectomies, and hernia repair.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Less commonly, lesions can be found on the diaphragm or lungs. Diaphragmatic endometriosis is rare, almost always on the right hemidiaphragm, and may cause the cyclic pain of the right scapula (shoulder) or cervical area (neck) during a menstrual period.<ref name=Andres2020p373>Template:Cite journal</ref> Pulmonary endometriosis can be associated with a thoracic endometriosis syndrome that can include catamenial (occurs during menstruation) pneumothorax seen in 73% of women with the syndrome, catamenial hemothorax in 14%, catamenial hemoptysis in 7%, and pulmonary nodules in 6%.<ref name=McCann2020p1419/>

Diagnosis

A health history and a physical examination can lead the health care practitioner to suspect endometriosis. There is a clear benefit for performing a transvaginal ultrasound (TVUS) as a first step of testing for endometriosis.<ref name="Van den Bosch Van Schoubroeck 2018 pp. 16–24"/>

Definitive diagnosis is based on the morphology (form and structure) of the pelvic region, determined by observation (surgical or non-invasive imaging), and classified into four different stages of endometriosis. The American Society of Reproductive Medicine's scale, revised in 1996, gives higher scores to deep, thick lesions or intrusions on the ovaries and dense, enveloping adhesions on the ovaries or fallopian tubes.<ref name="pmid9130884"/> Additionally, histological studies, when performed, should show specific findings.

For many patients, there are significant delays in diagnosis. Studies show an average delay of 11.7 years in the United States. Patients in the UK have an average delay of 8 years and in Norway of 6.7 years.<ref name="ReferenceA">Template:Cite journal</ref> A third of women had consulted their GP six or more times before being diagnosed.<ref name="ReferenceA"/>

The most common sites of endometriosis are the ovaries, followed by the Douglas pouch, the posterior leaves of the broad ligaments, and the sacrouterine ligaments.<ref name="ovarianendo"/>

As for deep infiltrating endometriosis, TVUS, TRUS and MRI are the techniques of choice for non-invasive diagnosis with a high sensitivity and specificity.<ref name="Zhang He Shen 2020 p.">Template:Cite journal</ref>

Laparoscopy

File:Endometrioma.jpg

Transvaginal ultrasonography showing a 67 x 40 mm endometrioma as distinguished from other types of ovarian cysts by a somewhat grainy and not completely anechoic content

Laparoscopy, a surgical procedure where a camera is used to look inside the abdominal cavity, is the only way to accurately diagnose the extent and severity of pelvic/abdominal endometriosis.<ref name="Imaging">Template:Cite journal</ref> Laparoscopy is not an applicable test for extrapelvic sites such as umbilicus, hernia sacs, abdominal wall, lung, or kidneys.<ref name="Imaging"/>

Reviews in 2019 and 2020 concluded that 1) with advances in imaging, endometriosis diagnosis should no longer be considered synonymous with immediate laparoscopy for diagnosis, and 2) endometriosis should be classified as a syndrome that requires confirmation of visible lesions seen at laparoscopy in addition to characteristic symptoms.<ref>Template:Cite journal</ref><ref>Template:Cite web</ref>

Laparoscopy permits lesion visualization unless the lesion is visible externally (e.g., an endometriotic nodule in the vagina) or is extra-abdominal.<ref name="Imaging" /> If the growths (lesions) are not visible, a biopsy must be taken to determine the diagnosis.<ref name="John2013"/> Surgery for diagnoses also allows for surgical treatment of endometriosis at the same time.

During a laparoscopic procedure, lesions can appear dark blue, powder-burn black, red, white, yellow, brown, or non-pigmented. Lesions vary in size.<ref name="pmid20436318"/> Some within the pelvic walls may not be visible, as the normal-appearing peritoneum of infertile women reveals endometriosis on biopsy in 6–13% of cases.<ref>Template:Cite journal</ref> Early endometriosis typically occurs on the surfaces of organs in the pelvic and intra-abdominal areas.<ref name="pmid20436318">Template:Cite journal</ref> Health care providers may call areas of endometriosis by different names, such as implants, lesions, or nodules. Larger lesions may be seen within the ovaries as endometriomas or "chocolate cysts"; "chocolate" because they contain a thick brownish fluid, mostly old blood.<ref name="pmid20436318"/>

Frequently, during diagnostic laparoscopy, no lesions are found in individuals with chronic pelvic pain, a symptom common to other disorders including adenomyosis, pelvic adhesions, pelvic inflammatory disease, congenital anomalies of the reproductive tract, and ovarian or tubal masses.<ref name="committee">Template:Cite journal</ref>

Ultrasound

Vaginal ultrasound can be used to diagnosis endometriosis, or for localizing endometrioma before surgery.<ref name=":0">Template:Cite web</ref> This can be used to identify the spread of disease in individuals with well-established clinical suspicion of endometriosis.<ref name=":0" /> Vaginal ultrasound is inexpensive, easily accessible, has no contraindications and requires no preparation.<ref name=":0" /> By extending the ultrasound assessment into the posterior and anterior pelvic compartments a sonographer can evaluate structural mobility and look for deep infiltrating endometriotic nodules.<ref name=":2">Template:Cite journal</ref> Better sonographic detection of deep infiltrating endometriosis could reduce the number of diagnostic laparoscopies, as well as guide disease management and enhance patient quality of life.<ref name=":2" />

Magnetic resonance imaging

MRI is another means of detecting lesions in a non-invasive manner.<ref name="Imaging"/> MRI is not widely used due to its cost and limited availability, although it can be used to detect the most common form of endometriosis (endometrioma) with sufficient accuracy.<ref name="Imaging"/> A 2020 article recommended administering an anti-spasmodic agent (i.e., hyoscine butylbromide) and a big glass of water (if the bladder is empty) and scanning in the supine position with an abdominal strap for better image quality.<ref name=deependomri>Template:Cite journal</ref> It also recommended using pelvic-phased array coils and T1 (spin-lattice) weighted scanning, with and without suppression of fat for endometriomas, and sagittal, axial and oblique 2D T2 (spin-spin) weighting for deep infiltrating endometriosis.<ref name=deependomri/> Template:See also

Stages of disease

By surgical observation, endometriosis can be classified as stage I–IV by the 1996 scale of the American Society of Reproductive Medicine (ASRM).<ref name="pmid9130884">Template:Cite journal</ref> The scale uses a point system that assesses lesions and adhesions in the pelvic organs. It is important to note that staging assesses physical disease only, not the level of pain or infertility.<ref>Template:Cite journal</ref> A person with Stage I endometriosis may have a little disease and severe pain, while a person with Stage IV endometriosis may have severe disease and no pain or vice versa. The various stages are summarized by:

Stage I (Minimal)

Findings restricted to only superficial lesions and possibly a few filmy adhesions.

Stage II (Mild)

In addition, some deep lesions are present in the cul-de-sac.

Stage III (Moderate)

As above, plus the presence of endometriomas on the ovary and more adhesions.

Stage IV (Severe)

As above, plus large endometriomas and extensive adhesions. Implants and adhesions may be found beyond the uterus. Large ovarian cysts are common.

Markers

An area of research is the search for endometriosis markers.<ref name=May2010/>

In 2010, essentially all proposed biomarkers for endometriosis were of unclear medical use, although some appear to be promising.<ref name="May2010">Template:Cite journal</ref> The one biomarker that has been in use over the last 20 years is CA-125.<ref name=May2010/> A 2016 review found that this biomarker was present in those with symptoms of endometriosis; and, once ovarian cancer has been ruled out, a positive CA-125 may confirm the diagnosis.<ref name="Hir2016">Template:Cite journal</ref> Its performance in ruling out endometriosis is low.<ref name=Hir2016/> CA-125 levels appear to fall during endometriosis treatment, but it has not shown a correlation with disease response.<ref name=May2010/>

Another review in 2011 identified several putative biomarkers upon biopsy, including findings of small sensory nerve fibers or defectively expressed β3 integrin subunit.<ref>Template:Cite journal</ref> It has been postulated a future diagnostic tool for endometriosis will consist of a panel of several specific and sensitive biomarkers, including both substance concentrations and genetic predisposition.<ref name=May2010/>

A 2016 review of endometrial biomarkers for diagnosing endometriosis was unable to draw conclusions due to the low quality of the evidence.<ref>Template:Cite journal</ref>

MicroRNAs have the potential to be used in diagnostic and therapeutic decisions.<ref name=rna>Template:Cite journal</ref>

Histopathology

For a histopathological diagnosis, at least two of the following three criteria should be present:<ref>Template:Cite web</ref>

• Endometrial type stroma
• Endometrial epithelium with glands
• Evidence of chronic hemorrhage, mainly hemosiderin deposits

Immunohistochemistry is useful in diagnosing endometriosis as stromal cells have a peculiar surface antigen, CD10, thus allowing the pathologist go straight to a staining area and confirm the presence of stromal cells and sometimes glandular tissue is identified that was missed on routine H&E staining.<ref>Template:Cite conference</ref>

• Endometriosis, abdominal wall
  Endometriosis, abdominal wall
• Micrograph showing endometriosis (right) and ovarian stroma (left)
  Micrograph showing endometriosis (right) and ovarian stroma (left)
• Micrograph of the wall of an endometrioma. All features of endometriosis are present (endometrial glands, endometrial stroma and hemosiderin-laden macrophages).
  Micrograph of the wall of an endometrioma. All features of endometriosis are present (endometrial glands, endometrial stroma and hemosiderin-laden macrophages).

Pain quantification

The most common pain scale for quantification of endometriosis-related pain is the visual analogue scale (VAS); VAS and numerical rating scale (NRS) were the best adapted pain scales for pain measurement in endometriosis. For research purposes, and more detailed pain measurement in clinical practice, VAS or NRS for each type of typical pain related to endometriosis (dysmenorrhea, deep dyspareunia and non-menstrual chronic pelvic pain), combined with the clinical global impression (CGI) and a quality of life scale, are used.<ref name="BourdelAlves2014">Template:Cite journal</ref>

Prevention

Limited evidence indicates that the use of combined oral contraceptives is associated with a reduced risk of endometriosis, as is regular exercise and the avoidance of alcohol and caffeine.<ref name=WH2014/> There is little known information on preventing endometriosis.<ref>Template:Cite web</ref>

Management

While there is no cure for endometriosis, there are treatments for pain and endometriosis-associated infertility.<ref name="TreatmentEKSNI">Template:Cite web</ref> Pain can be treated with hormones, painkillers, or, in severe cases, surgery.<ref>Template:Cite web</ref>

In most cases, the symptoms disappear or improve with menopause (natural or surgical).<ref name="pmid20627430">Template:Cite journal</ref> In the reproductive years, endometriosis is merely managed: the goal is to provide pain relief, to restrict the progression of the process, and to restore or preserve fertility where needed. In younger individuals, some surgical treatments attempt to remove endometriotic tissue and preserve the ovaries without damaging normal tissue.<ref name="zondervan32212520" /><ref name="AFFDiagnosisandTreat">Template:Cite journal</ref>

Pharmacotherapy for pain management can be initiated based on the presence of symptoms, examination, and ultrasound findings that rule out other potential causes.<ref name="Women's Healthcare 2020">Template:Cite web</ref>

In general, the diagnosis of endometriosis is confirmed during surgery, at which time removal can be performed. Further steps depend on circumstances: someone without infertility can manage symptoms with pain medication and hormonal medication that suppresses the natural cycle, while an infertile individual may be treated expectantly after surgery, with fertility medication, or with in vitro fertilisation (IVF).

A 2020 Cochrane systematic review found that for all types of endometriosis, "it is uncertain whether laparoscopic surgery improves overall pain compared to diagnostic laparoscopy".<ref name="Bafort Beebeejaun Tomassetti Bosteels p.">Template:Cite journal</ref>

Surgery

Based on strong evidence, experts recommend that surgery be performed laparoscopically (through keyhole surgery) rather than open.<ref name="John2013">Template:Cite journal</ref> Treatment consists of the ablation or excision of the endometriosis, electrocoagulation,<ref name="Vercellini Viganò Somigliana Fedele 2014 pp. 261–275"/> lysis of adhesions, resection of endometriomas, and restoration of normal pelvic anatomy as much as is possible.<ref name="John2013"/><ref name=speroff>Template:Cite book</ref> When laparoscopic surgery is used, small instruments are inserted through the incisions to remove the endometriosis tissue and adhesions. Because the incisions are tiny, there will only be small scars on the skin after the procedure, and most individuals recover from surgery quickly and have a reduced risk of adhesions.<ref>Template:Cite web</ref> Many endometriosis specialists believe that excision is the ideal surgical method to treat endometriosis.<ref>Template:Cite web</ref> A 2017 literature review found that excision improved some outcomes over ablation.<ref>Template:Cite journal</ref> In the United States, some specialists trained in excision for endometriosis do not accept health insurance because insurance companies do not reimburse the higher costs of this procedure over ablation.<ref>Template:Cite news</ref>

As for deep endometriosis, a segmental resection or shaving of nodules is effective but is associated with an increased rate of complications, of which about 4.6% are major.<ref name="Dunselman Vermeulen Becker Calhaz-Jorge 2014 pp. 400–412">Template:Cite journal</ref>

Historically, a hysterectomy (removal of the uterus) was thought to be a cure for endometriosis in individuals who do not wish to conceive. Removal of the uterus may be beneficial as part of the treatment if the uterus itself is affected by adenomyosis. However, this should only be done in combination with the removal of the endometriosis by excision. If endometriosis is not also removed at the time of hysterectomy, pain may persist.<ref name="John2013"/> A study of hysterectomy patients found that those with endometriosis did not use less pain medication three years after the procedure.<ref>Brunes, M, Altman, D, Pålsson, M, Söderberg, MW, Ek, M. Impact of hysterectomy on analgesic, psychoactive and neuroactive drug use in women with endometriosis: nationwide cohort study. BJOG 2021; 128: 846– 855. [1] Template:Webarchive</ref>

Presacral neurectomy may be performed where the nerves to the uterus are cut. However, this technique is not usually used due to the high incidence of associated complications, including presacral hematoma and irreversible problems with urination and constipation.<ref name="John2013"/>

Recurrence

The underlying process that causes endometriosis may not cease after a surgical or medical intervention. Even though surgery can improve symptoms, the resurgence of pain is common.<ref name=":9">Template:Cite journal</ref> A study has shown that dysmenorrhea recurs at a rate of 30 percent within a year following laparoscopic surgery. Resurgence of lesions tends to appear in the same location if the lesions were not completely removed during surgery. It has been shown that laser ablation resulted in higher and earlier recurrence rates when compared with endometrioma cystectomy, and recurrence after repetitive laparoscopy was similar to that after the first surgery. Endometriosis has a 10% recurrence rate after hysterectomy and bilateral salpingo-oophorectomy.<ref name=updateonrecur>Template:Cite journal</ref>

Endometriosis recurrence following conservative surgery is estimated as 21.5% at 2 years and 40–50% at 5 years.<ref>Template:Cite journal</ref>

The recurrence rate for DIE after surgery is less than 1%.<ref name="Koninckx Ussia Keckstein Adamyan 2018 pp. 360–365">Template:Cite journal</ref>

Risks and safety of pelvic surgery

The risk of developing complications following surgery depends on the type of lesion that has undergone surgery.<ref name="Vercellini Viganò Somigliana Fedele 2014 pp. 261–275">Template:Cite journal</ref> 55% to 100% of individuals develop adhesions following pelvic surgery,<ref name="LiakokosPAE">Template:Cite journal</ref> which can result in infertility, chronic abdominal and pelvic pain, and difficult reoperative surgery. Trehan's temporary ovarian suspension, a technique in which the ovaries are suspended for a week after surgery, may be used to reduce the incidence of adhesions after endometriosis surgery.<ref>Template:Cite journal</ref><ref name="pmid11821616">Template:Cite journal</ref> Removal of cysts on the ovary without removing the ovary is a safe procedure.<ref name="Vercellini Viganò Somigliana Fedele 2014 pp. 261–275"/>

Hormonal medications

• Hormonal birth control therapy: Birth control pills reduce the menstrual pain and recurrence rate for endometrioma following conservative surgery for endometriosis.<ref>Template:Cite journal</ref> A 2018 Cochrane systematic review found that there is insufficient evidence to make a judgement on the effectiveness of the combined oral contraceptive pill compared with placebo or other medical treatment for managing pain associated with endometriosis partly because of lack of included studies for data analysis (only two for COCP vs placebo).<ref name="Brown Crawford Datta Prentice p. ">Template:Cite journal</ref>
• Progestogens: Progesterone counteracts estrogen and inhibits the growth of the endometrium.<ref name="PatelElguero2014">Template:Cite journal</ref> Danazol and gestrinone are suppressive steroids with some androgenic activity.<ref name="AFFDiagnosisandTreat"/> Both agents inhibit the growth of endometriosis but their use has declined, due in part to virilizing side effects such as excessive hair growth and voice changes.<ref>Template:Cite web</ref> There is tentative evidence based on cohort studies that dienogest and norethisterone acetate (NETA) may help patients with DIE in terms of pain.<ref name="DAlterio DAncona Raslan Tinelli 2021 pp. 88–94">Template:Cite journal</ref> There is tentative evidence based on a prospective study that vaginal danazol reduces pain in those affected by DIE.<ref name="DAlterio DAncona Raslan Tinelli 2021 pp. 88–94"/>
• Gonadotropin-releasing hormone (GnRH) modulators: These drugs include GnRH agonists such as leuprorelin, and GnRH antagonists such as elagolix and are thought to work by decreasing estrogen levels.<ref name="brown2010" /> A 2010 Cochrane review found that GnRH modulators were more effective for pain relief in endometriosis than no treatment or placebo, but were not more effective than danazol or intrauterine progestogen, and had more side effects than danazol.<ref name="brown2010">Template:Cite journal</ref> A 2018 Swedish systematic review found that GnRH modulators had similar pain-relieving effects to gestagen but also decreased bone density.<ref name=":0" />
• Aromatase inhibitors are medications that block the formation of estrogen and have become of interest for researchers who are treating endometriosis.<ref>Template:Cite journal</ref> Examples of aromatase inhibitors include anastrozole and letrozole. Evidence for aromatase inhibitors is confirmed by numerous controlled studies that show benefit in terms of pain control and quality of life when used in combination with gestagens or oral contraceptives, with fewer side effects when used in combination with oral contraceptives like norethisterone acetate.<ref name="Słopień Męczekalski 2016 pp. 43–47">Template:Cite journal</ref> Despite multiple benefits, there are a lot of things to consider before using aromatase inhibitors for endometriosis, as it is common for them to induce functional cysts as an adverse effect. Moreover, dosages, treatment length, appropriate add-back therapies and mode of administration is still being investigated.<ref name="Garzon Laganà Barra Casarin 2020 pp. 1377–1388">Template:Cite journal</ref>
• Progesterone receptor modulators like mifepristone and gestrinone have the potential (based on only one randomized controlled trial each) to be used as a treatment to manage pain caused by endometriosis.<ref name="Fu Song Zhou Zhu p. ">Template:Cite journal</ref>

Other medicines

• Opioids: Morphine sulphate tablets and other opioid painkillers work by mimicking the action of naturally occurring pain-reducing chemicals called "endorphins". Different long-acting and short-acting medications can be used alone or in combination to provide appropriate pain control.Template:Med cn
• Chinese herbal medicine was reported to have comparable benefits to gestrinone and danazol in patients who had had laparoscopic surgery, though the review notes that the two trials were small and of "poor methodological quality" and results should be "interpreted cautiously" as better quality research is needed.<ref>Template:Cite journal</ref>
• Serrapeptase, a digestive enzyme found in the intestines of silkworms. Serrapeptase is widely used in Japan and Europe as an anti-inflammatory treatment.<ref>Template:Cite journal</ref> More research is needed but serrapeptase may be used by endometriosis patients to reduce inflammation.<ref>Template:Cite journal</ref>
• Angiogenesis inhibitors lack clinical evidence of efficacy in endometriosis therapy.<ref name="Laschke2012">Template:Cite journal</ref> Under experimental in vitro and in vivo conditions, compounds that have been shown to exert inhibitory effects on endometriotic lesions include growth factor inhibitors, endogenous angiogenesis inhibitors, fumagillin analogues, statins, cyclo-oxygenase-2 inhibitors, phytochemical compounds, immunomodulators, dopamine agonists, peroxisome proliferator-activated receptor agonists, progestins, danazol and gonadotropin-releasing hormone agonists.<ref name=Laschke2012/> However, many of these agents are associated with undesirable side effects, and more research is necessary. An ideal therapy would diminish inflammation and underlying symptoms without being contraceptive.<ref name="pmid23485944">Template:Cite journal</ref><ref name="pmid23356536">Template:Cite journal</ref>
• Pentoxifylline, an immunomodulating agent, has been theorized to improve pain as well as improve pregnancy rates in individuals with endometriosis. There is not enough evidence to support the effectiveness or safety of either of these uses.<ref>Template:Cite journal</ref> Current American Congress of Obstetricians and Gynecologists (ACOG) guidelines do not include immunomodulators, such as pentoxifylline, in standard treatment protocols.<ref>Template:Cite journal</ref>
• NSAIDs are anti-inflammatory medications commonly used for endometriosis patients despite unproven efficacy and unintended adverse effects.<ref>Template:Cite journal</ref>
• Neuromodulators like gabapentin did not prove to be superior to placebo in managing pain caused by endometriosis.<ref name="Saunders Horne 2021 pp. 2807–2824">Template:Cite journal</ref>

Manual physical therapy's effectiveness in treating endometriosis is unclear.<ref name="pmid21589790">Template:Cite journal</ref>

Comparison of interventions

A 2021 meta-analysis found that GnRH analogs and combined hormonal contraceptives were the best treatment for reducing dyspareunia and menstrual and non-menstrual pelvic pain.<ref name="Samy Taher Sileem Abdelhakim 2021 p=101798">Template:Cite journal</ref> A 2018 Swedish systematic review found several studies but a general lack of scientific evidence for most treatments.<ref name=":0" /> There was only one study of sufficient quality and relevance comparing the effect of surgery and non-surgery.<ref name=":1">Template:Cite web</ref> Cohort studies indicate that surgery is effective in decreasing pain.<ref name=":1" /> Most complications occurred in cases of low intestinal anastomosis, while risk of fistula occurred in cases of combined abdominal or vaginal surgery, and urinary tract problems were common in intestinal surgery.<ref name=":1" /> The evidence was found to be insufficient regarding surgical intervention.<ref name=":1" />

The advantages of physical therapy techniques are decreased cost, absence of major side-effects, it does not interfere with fertility, and near-universal increase of sexual function.<ref name="JOEPPD">Template:Primary source inline Template:Cite journal</ref> Disadvantages are that there are no large or long-term studies of its use for treating pain or infertility related to endometriosis.<ref name="JOEPPD"/>

Treatment of infertility

Surgery is more effective than medicinal intervention for addressing infertility associated with endometriosis.<ref name="AFFDiagnosisandTreat"/> Surgery attempts to remove endometrium-like tissue<ref name=zondervan32212520 /> and preserve the ovaries without damaging normal tissue.<ref name="AFFDiagnosisandTreat"/> Receiving hormonal suppression therapy after surgery might be positive regarding endometriosis recurrence and pregnancy.<ref>Template:Cite journal</ref> In vitro fertilization (IVF) procedures are effective in improving fertility in many individuals with endometriosis.<ref name="Bulletti2010"/>

During fertility treatment, the ultralong pretreatment with GnRH-agonist has a higher chance of resulting in pregnancy for individuals with endometriosis compared to the short pretreatment.<ref name=":0" />

Epidemiology

Determining how many people have endometriosis is challenging because a definitive diagnosis requires surgical visualization through laparoscopic surgery.<ref name="Risk">Template:Cite journal</ref> Criteria that are commonly used to establish a diagnosis include pelvic pain, infertility, surgical assessment, and in some cases, magnetic resonance imaging. An ultrasound can identify large clumps of tissue as potential endometriosis lesions and ovarian cysts, but it is not effective for all patients, especially in cases with smaller, superficial lesions.<ref>Template:Cite web</ref>

Ethnic differences in endometriosis have been observed. The condition is more common in women of East Asian and Southeast Asian descent than in White women.<ref name=zondervan32212520/> Risk factors include having a family history of the condition.<ref name="Velarde">Template:Cite journal "Compared with Caucasian women, Asian women are more likely to be diagnosed with endometriosis (odds ratio (OR) 1.63, 95% CI 1.03–2.58) (14). Filipinos, Indians, Japanese, and Koreans are among the top Asian ethnicities who are more likely to have endometriosis than Caucasian women (17)."</ref>

One estimate is that 10.8 million people are affected globally Template:As of.<ref name="GBD2015Pre" /> Other sources estimate 6 to 10% of the general female population<ref name="Bulletti2010" /> and 2 to 11% of asymptomatic women<ref name=zondervan32212520/> are affected. In addition, 11% of women in a general population have undiagnosed endometriosis that can be seen on magnetic resonance imaging (MRI).<ref name="bucklewis21719000">Template:Cite journal</ref><ref name="Risk" /> Endometriosis is most common in those in their thirties and forties; however, it can begin in girls as early as eight years old.<ref name="WH2014" /><ref name="Mc2013" /> It results in few deaths with unadjusted and age-standardized death rates of 0.1 and 0.0 per 100,000.<ref name="GBD2015Pre" /> Endometriosis was first determined to be a separate condition in the 1920s.<ref name="Bro2012">Template:Cite book</ref> Before that time, endometriosis and adenomyosis were considered together.<ref name="Bro2012" /> It is unclear who first described the disease.

It chiefly affects adults from premenarche to postmenopause, regardless of race or ethnicity or whether or not they have had children, and is estimated to affect over 190 million women in their reproductive years.<ref name="Nothnick">Template:Cite journal</ref> Incidences of endometriosis have occurred in postmenopausal individuals,<ref name="Medscape">Template:Cite journal</ref> and in less common cases, individuals may have had endometriosis symptoms before they even reach menarche.<ref>Template:Cite journal</ref><ref name="Marsh EE 2004"/>

The rate of recurrence of endometriosis is estimated to be 40-50% for adults over five years.<ref name=":4">Template:Cite journal</ref> The rate of recurrence has been shown to increase with time from surgery and is not associated with the stage of the disease, initial site, surgical method used, or post-surgical treatment.<ref name=":4" />

History

Endometriosis was first discovered microscopically by Karl von Rokitansky in 1860,<ref name="batt">Template:Cite book</ref> although the earliest antecedents may have stemmed from concepts published almost 4,000 years ago.<ref name="nezhat">Template:Cite journal</ref> The Hippocratic Corpus outlines symptoms similar to endometriosis, including uterine ulcers, adhesions, and infertility.<ref name=nezhat/> Historically, women with these symptoms were treated with leeches, straitjackets, bloodletting, chemical douches, genital mutilation, pregnancy (as a form of treatment), hanging upside down, surgical intervention, and even killing due to suspicion of demonic possession.<ref name=nezhat/> Hippocratic doctors recognized and treated chronic pelvic pain as a true organic disorder 2,500 years ago, but during the Middle Ages, there was a shift into believing that women with pelvic pain were mad, immoral, imagining the pain, or simply misbehaving.<ref name=nezhat/> The symptoms of inexplicable chronic pelvic pain were often attributed to imagined madness, female weakness, promiscuity, or hysteria.<ref name=nezhat/> The historical diagnosis of hysteria, which was thought to be a psychological disease, may have indeed been endometriosis.<ref name=nezhat/> The idea that chronic pelvic pain was related to mental illness influenced modern attitudes regarding individuals with endometriosis, leading to delays in correct diagnosis and indifference to the patients' true pain throughout the 20th and into the 21st century.<ref name=nezhat/>

Hippocratic doctors believed that delaying childbearing could trigger diseases of the uterus, which caused endometriosis-like symptoms. Women with dysmenorrhea were encouraged to marry and have children at a young age.<ref name=nezhat/> The fact that Hippocratics were recommending changes in marriage practices due to an endometriosis-like illness implies that this disease was likely common, with rates higher than the 5-15% prevalence that is often cited today.<ref name=nezhat/> If indeed this disorder was so common historically, this may point away from modern theories that suggest links between endometriosis and dioxins, PCBs, and chemicals.<ref name=nezhat/>

The early treatment of endometriosis was surgical and included oophorectomy (removal of the ovaries) and hysterectomy (removal of the uterus).<ref name="pmid17857917">Template:Cite journal</ref> In the 1940s, the only available hormonal therapies for endometriosis were high-dose testosterone and high-dose estrogen therapy.<ref name=barbieri1992>Template:Cite journal</ref> High-dose estrogen therapy with diethylstilbestrol for endometriosis was first reported by Karnaky in 1948 and was the main pharmacological treatment for the condition in the early 1950s.<ref name="Aiman2012">Template:Cite book</ref><ref name="Josimovich2013">Template:Cite book</ref><ref name="Kistner1995">Template:Cite book</ref> Pseudopregnancy (high-dose estrogen–progestogen therapy) for endometriosis was first described by Kistner in the late 1950s.<ref name="Aiman2012" /><ref name="Josimovich2013" /> Pseudopregnancy, as well as progestogen monotherapy, dominated the treatment of endometriosis in the 1960s and 1970s.<ref name="Kistner1995" /> These agents, although efficacious, were associated with intolerable side effects. Danazol was first described for endometriosis in 1971 and became the main therapy in the 1970s and 1980s.<ref name="Aiman2012" /><ref name="Josimovich2013" /><ref name="Kistner1995" /> In the 1980s, GnRH agonists gained prominence for the treatment of endometriosis and by the 1990s had become the most widely used therapy.<ref name="Josimovich2013" /><ref name="Kistner1995" /> Oral GnRH antagonists such as elagolix were introduced for the treatment of endometriosis in 2018.<ref name="pmid30763525">Template:Cite journal</ref>

Society and culture

Public figures

Several public figures have spoken about their experience with endometriosis, including: Template:Div col

• RuthAnne<ref>Template:Cite web</ref>
• Emma Barnett<ref>Template:Cite web</ref>
• Emma Bunton<ref>Template:Cite web</ref>
• Alexa Chung<ref>Template:Cite web</ref>
• Danielle Collins<ref>Template:Cite news</ref>
• Olivia Culpo<ref>Template:Cite magazine</ref>
• Lena Dunham<ref>Template:Cite web</ref>
• Abby Finkenauer<ref>Template:Cite web</ref>
• Bethenny Frankel<ref>Template:Cite web</ref>
• Whoopi Goldberg<ref>Template:Cite web</ref>
• Mel Greig<ref>Template:Cite news</ref>
• Halsey<ref>Template:Cite magazine</ref>
• Emma Hayes<ref>Template:Cite web</ref>
• Julianne Hough<ref>Template:Cite web</ref><ref>Template:Cite web</ref><ref>Template:Cite web</ref>
• Bridget Hustwaite<ref>Template:Cite web</ref>
• Bindi Irwin<ref>Template:Cite news</ref>
• Jaime King<ref>Template:Cite web</ref>
• Padma Lakshmi<ref>Template:Cite web</ref>
• Cyndi Lauper<ref>Template:Cite news</ref>
• Jillian Michaels<ref>Template:Cite web</ref>
• Monica<ref>Template:Cite web</ref>
• Marilyn Monroe<ref>Template:Cite web</ref>
• Tia Mowry<ref>Template:Cite web</ref>
• Sinéad O'Connor<ref>Template:Cite web</ref>
• Dolly Parton<ref>Template:Cite web</ref>
• Florence Pugh<ref>Template:Cite web</ref>
• Daisy Ridley<ref>Template:Cite web</ref>
• Emma Roberts<ref>Template:Cite web</ref>
• Susan Sarandon<ref>Template:Cite web</ref>
• Amy Schumer<ref>Template:Cite web</ref>
• Kirsten Storms<ref>Template:Cite web</ref>
• Gabrielle Union<ref>Template:Cite web</ref>
• Lacey Schwimmer<ref>Template:Cite web</ref><ref>Template:Cite web</ref><ref>Template:Cite web</ref>
• Chrissy Teigen<ref>Template:Cite web</ref>
• Emma Watkins<ref>Template:Cite web</ref>
• Mae Whitman<ref>Template:Cite web</ref>
• Jessica Williams<ref>Template:Cite web</ref>
• Leah Williamson<ref>Template:Cite web</ref>

Economic burden

The economic burden of endometriosis is widespread and multifaceted.<ref name=":5">Template:Cite journal</ref> Endometriosis is a chronic disease that has direct and indirect costs, which include loss of work days, direct costs of treatment, symptom management, and treatment of other associated conditions such as depression or chronic pain.<ref name=":5" /> One factor that seems to be associated with especially high costs is the delay between the onset of symptoms and diagnosis.

Costs vary greatly between countries.<ref>Template:Cite journal</ref> Two factors that contribute to the economic burden include healthcare costs and losses in productivity. A Swedish study of 400 endometriosis patients found "Absence from work was reported by 32% of the women, while 36% reported reduced time at work because of endometriosis".<ref>Template:Cite journal</ref> An additional cross sectional study with Puerto Rican women, "found that endometriosis-related and coexisting symptoms disrupted all aspects of women's daily lives, including physical limitations that affected doing household chores and paid employment. The majority of women (85%) experienced a decrease in the quality of their work; 20% reported being unable to work because of pain, and over two-thirds of the sample continued to work despite their pain."<ref>Template:Cite journal</ref> A study published in the UK in 2025 found that after women received a diagnosis of endometriosis in an English NHS hospital their earnings were on average £56 per month less in the four to five years after diagnosis than they were in the two years before. There was also a reduction in the proportion of women in employment.<ref>Template:Cite news</ref>

Medical culture

There are many barriers that those affected face in receiving diagnosis and treatment for endometriosis. Some of these include outdated standards for laparoscopic evaluation, stigma about discussing menstruation and sex, lack of understanding of the disease, primary-care physicians' lack of knowledge, and assumptions about typical menstrual pain.<ref>Template:Cite journal</ref> On average, those later diagnosed with endometriosis waited 2.3 years after the onset of symptoms before seeking treatment, and nearly three-quarters of women receive a misdiagnosis before endometriosis.<ref>Template:Cite journal</ref> Self-help groups say practitioners delay making the diagnosis, often because they do not consider it a possibility. There is a typical delay of 7–12 years from symptom onset in affected individuals to professional diagnosis.<ref>Template:Cite journal</ref> There is a general lack of knowledge about endometriosis among primary care physicians. Half of the general health care providers surveyed in a 2013 study could not name three symptoms of endometriosis.<ref>Template:Cite journal</ref> Healthcare providers are also likely to dismiss described symptoms as normal menstruation.<ref name="Time elapsed from onset of symptoms">Template:Cite journal</ref> Younger patients may also feel uncomfortable discussing symptoms with a physician.<ref name="Time elapsed from onset of symptoms"/>

Race and ethnicity

Race and ethnicity may impact how endometriosis affects one's life. Endometriosis is less thoroughly studied among Black people, and the research that has been done is outdated.<ref>Template:Cite journal</ref> <ref name=":6">Template:Cite journal</ref> Cultural differences among ethnic groups also contribute to attitudes toward and treatment of endometriosis, especially in Hispanic or Latino communities. A study done in Puerto Rico in 2020 found that health care and interactions with friends and family related to discussing endometriosis were affected by stigma.<ref name=":8">Template:Cite journal</ref> The most common finding was a referral to those expressing pain related to endometriosis as "changuería" or "changas", terms used in Puerto Rico to describe pointless whining and complaining, often directed at children.<ref name=":8" />

Stigma

The existing stigma surrounding women's health, specifically endometriosis, can lead to patients not seeking diagnoses, lower quality of healthcare, increased barriers to care and treatment, and negative reception from members of society.<ref>Template:Cite journal</ref> Additionally, menstrual stigma significantly contributes to the broader issue of endometriosis stigma, creating an interconnected challenge that extends beyond reproductive health.<ref>Template:Cite journal</ref><ref>Template:Cite web</ref> Widespread awareness campaigns, developments, and implementations aimed to multilevel anti-stigma organizational and structural changes, as well as more qualitative studies of the endometriosis stigma, help to overcome the harm of the phenomenon.<ref>Template:Cite journal</ref>

Research

Preliminary research on mouse models showed that monoclonal antibodies, as well as inhibitors of MyD88 downstream signaling pathway, can reduce lesion volume. Thanks to that, clinical trials are being done on using a monoclonal antibody directed against IL-33 and using anakinra, an IL-1 receptor antagonist.<ref name="Saunders Horne 2021 pp. 2807–2824" />

Taking contraceptive pills or getting long-acting progestogen injections seems to be equally effective for preventing recurring pain after endometriosis surgery. Compared to taking the pill, progestogen might result in a reduced risk of needing further treatments or surgery.<ref name=":9" /><ref>Template:Cite journal</ref>

Clinical trials are exploring the potential benefits of cannabinoid extracts, dichloroacetic acid, and curcuma capsules.<ref name="Saunders Horne 2021 pp. 2807–2824" />

External links

• Endometriosis fact sheet from the World Health Organization