One estimate is that 10.8 million people are affected globally as of 2015[update]. Other sources estimate about 6–10% of women are affected. Endometriosis is most common in those in their thirties and forties; however, it can begin in girls as early as eight years old. It results in few deaths. Endometriosis was first determined to be a separate condition in the 1920s. Before that time, endometriosis and adenomyosis were considered together. It is unclear who first described the disease.
Pain and infertility are common symptoms, although 20-25% of women are asymptomatic.
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 woman feels correlates weakly with the extent or stage (1 through 4) of endometriosis, with some women having little or no pain despite having extensive endometriosis or endometriosis with scarring, while other women may have severe pain even though they have only a few small areas of endometriosis. 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. Symptoms of endometriosis-related pain may include:
dysmenorrhea – painful, sometimes disabling cramps during the menstrual period; pain may get worse over time (progressive pain), also lower back pains linked to the pelvis
bodily movement pain – present during exercise, standing, or walking
Compared with women 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. Individual pain areas and pain intensity appear to be unrelated to the surgical diagnosis, and the area of pain unrelated to area of endometriosis.
There are multiple causes of pain. Endometriosis lesions react to hormonal stimulation and may "bleed" at the time of menstruation. The blood accumulates locally if it is not cleared shortly by the immune, circulatory, and lymphatic system. This may further lead to swelling, which triggers inflammation with the activation of cytokines, which results in pain. Another source of pain is the organ dislocation that arises from adhesion binding internal organs to each other. The ovaries, the uterus, the oviducts, the peritoneum, and the bladder can be bound together. Pain triggered in this way can last throughout the menstrual cycle, not just during menstrual periods.
Also, endometriotic lesions can develop their own nerve supply, thereby creating a direct and two-way interaction between lesions and the central nervous system, potentially producing a variety of individual differences in pain that can, in some women, become independent of the disease itself. Nerve fibres and blood vessels are thought to grow into endometriosis lesions by a process known as neuroangiogenesis.
About a third of women with infertility have endometriosis. Among women with endometriosis about 40% are infertile. The pathogenesis of infertility is dependent on the stage of disease: in early stage disease, it is hypothesised that this is secondary to an inflammatory response that impairs various aspects of conception, whereas in later stage disease distorted pelvic anatomy and adhesions contribute to impaired fertilisation.
Other symptoms include diarrhea or constipation, chronic fatigue, nausea and vomiting, headaches, low-grade fevers, heavy and/or irregular periods, and hypoglycemia.
Endometriosis is a heritable condition that is influenced by both genetic and environmental factors. Daughters or sisters 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. There is an about six-fold increased incidence in women with an affected first-degree relative.
It has been proposed that endometriosis results from a series of multiple hits within target genes, in a mechanism similar to the development of cancer. In this case, the initial mutation may be either somatic or heritable.
Vezatin, an adherens junction transmembrane protein
Tumor suppressor gene
Mucin 16, cell surface associated
Form protective mucous barriers
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.
Some factors associated with endometriosis include:
prolonged exposure to estrogen; for example, in late menopause or early menarche
obstruction of menstrual outflow; for example, in Müllerian anomalies
Several studies have investigated the potential link between exposure to dioxins and endometriosis, but the evidence is equivocal and potential mechanisms are poorly understood. A 2004 review of studies of dioxin and endometriosis concluded that "the human data supporting the dioxin-endometriosis association are scanty and conflicting", and a 2009 follow-up review also found that there was "insufficient evidence" in support of a link between dioxin exposure and women developing endometriosis. A 2008 review concluded that more work was needed, stating that "although preliminary work suggests a potential involvement of exposure to dioxins in the pathogenesis of endometriosis, much work remains to clearly define cause and effect and to understand the potential mechanism of toxicity".
While the exact cause of endometriosis remains unknown, many theories have been presented to better 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.
The main theories for the formation of the ectopic endometrium are retrograde menstruation, Müllerianosis, coelomic metaplasia and transplantation, each further described below.
Retrograde menstruation theory
The theory of retrograde menstruation (also called the implantation theory or transplantation theory) is the oldest theory for the formation of ectopic endometrium in endometriosis. It suggests that during a woman's menstrual flow, some of the endometrial debris flow backwards 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 endometriosis.
Retrograde menstruation alone is not able to explain all instances of endometriosis, and additional factors such as genetic or immune differences need to be invoked to account for the fact that many women with retrograde menstruation do not have endometriosis. In addition, endometriosis has shown up in people who have never experienced menstruation including men, fetuses, and prepubescent girls. Further detracting from the retrograde menstruation theory are cases of endometriosis showing up in the brain and lungs. This theory has numerous other associated issues.
Researchers are investigating the possibility that the immune system may not be able 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. It is still unclear what, if any, causal relationship exists between toxic materials, autoimmune disease, and endometriosis. There are immune system changes in women with endometriosis, such as an increase of macrophage-derived secretion products, but it is unknown if these are contributing to the disorder or are reactions from it.
In addition, at least one study found that endometriotic lesions differ in their biochemistry from artificially transplanted ectopic tissue. This is likely because the cells that give rise to endometriosis are a side population of cells. Similarly, there are changes in for example the mesothelium of the peritoneum in women with endometriosis, such as loss of tight junctions, but it is unknown if these are causes or effects of the disorder.
In rare cases where imperforate hymen does not resolve itself prior to the first menstrual cycle and goes undetected, blood and endometrium are trapped within the uterus of the woman until such time as 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.
The theory of retrograde menstruation as a cause of endometriosis was first proposed by John A. Sampson.
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.
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.
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.
Neural growth: An increased expression of new nerve fibres is found in endometriosis but does not fully explain the formation of ectopic endometrial tissue and is not definitely correlated with the amount of perceived pain.[clarification needed]
Autoimmune: Graves disease is an autoimmune disease characterized by hyperthyroidism, goiter, ophthalmopathy, and dermopathy. Women with endometriosis had higher rates of Graves disease. One of these potential links between Graves disease and endometriosis is autoimmunity.
Rarely, endometriosis appears in other parts of the body, such as the lungs, brain, and skin.
Rectovaginal or bowel endometriosis affects approximately 5-12% of women with endometriosis, and can cause severe pain with bowel movements.
Endometriosis may spread to the cervix and vagina or to sites of a surgical abdominal incision, known as "scar endometriosis." 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.
Less commonly lesions can be found on the diaphragm. Diaphragmatic endometriosis is rare, almost always on the right hemidiaphragm, and may inflict the cyclic pain of the right shoulder just before and during a menstrual period. Rarely, endometriosis can be extraperitoneal and is found in the lungs and CNS.
A health history and a physical examination can lead the health care practitioner to suspect endometriosis. Although doctors can often feel the endometrial growths during a pelvic exam, and these symptoms may be signs of endometriosis, diagnosis cannot be confirmed by exam only.
In the UK, there is an average of 7.5 years between a woman first seeing a doctor about their symptoms and receiving a firm diagnosis.
Laparoscopy, a surgical procedure where a camera is used to look inside the abdominal cavity, is the only way to officially diagnose the extent and severity of endometriosis. Laparoscopy permits lesion visualization unless the lesion is visible externally (e.g., an endometriotic nodule in the vagina). If the growths (lesions) are not visible, a biopsy may be taken to determine the diagnosis. 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. Some within the pelvis walls may not be visible, as normal-appearing peritoneum of infertile women reveals endometriosis on biopsy in 6–13% of cases. Early endometriosis typically occurs on the surfaces of organs in the pelvic and intra-abdominal areas. 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.
Use of pelvic ultrasound may identify large endometriotic cysts (called endometriomas). However, smaller endometriosis implants cannot be visualized with ultrasound technique.
Vaginal ultrasound has a clinical value in the diagnosis of endometrioma and before operating for deep endometriosis. This applies to the identification of the spread of disease in women with well-established clinical suspicion of endometriosis. Vaginal ultrasound is inexpensive, easily accessible, has no contraindications and requires no preparation. Healthcare professionals conducting ultrasound examinations need to be experienced. By extending the ultrasound assessment into the posterior and anterior pelvic compartments the sonographer is able to evaluate structural mobility and look for deep infiltrating endometriotic nodules noting the size, location and distance from the anus if applicable. An improvement in sonographic detection of deep infiltrating endometriosis will not only reduce the number of diagnostic laparoscopies, it will guide management and enhance quality of life.
Magnetic resonance imaging
Use of MRIs is another method to detect lesions in a non-invasive manner. MRI is not widely used due to its cost and limited availability, however, it has the ability to detect deep and small endometriotic lesions.
Surgically, endometriosis can be staged I–IV by the revised classification of the American Society of Reproductive Medicine from 1997. The process is a complex point system that assesses lesions and adhesions in the pelvic organs, but it is important to note staging assesses physical disease only, not the level of pain or infertility. 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. In principle the various stages show these findings:
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, extensive adhesions.
An area of research is the search for endometriosis markers.
In 2010, essentially all proposed biomarkers for endometriosis were of unclear medical use, although some appear to be promising. The one biomarker that has been in use over the last 20 years is CA-125. A 2016 review found that in those with symptoms of endometriosis; and, once ovarian cancer has been ruled out, a positive CA-125 may confirm the diagnosis. Its performance in ruling out endometriosis is low. CA-125 levels appear to fall during endometriosis treatment, but has not shown a correlation with disease response.
Another review in 2011 identified several putative biomarkers upon biopsy, including findings of small sensory nerve fibers or defectively expressed β3 integrin subunit. 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.
Immunohistochemistry has been found to be useful in diagnosing endometriosis as stromal cells have a peculiar surface antigen, CD10, thus allowing the pathologist go straight to a staining area and hence confirm the presence of stromal cells and sometimes glandular tissue is thus identified that was missed on routine H&E staining.[better source needed]
While there is no cure for endometriosis, there are two types of interventions; treatment of pain and treatment of endometriosis-associated infertility. In many women, menopause (natural or surgical) will abate the process. In women in the reproductive years, endometriosis is merely managed: the goal is to provide pain relief, to restrict progression of the process, and to restore or preserve fertility where needed. In younger women, surgical treatment attempts to remove endometrial tissue and preserve the ovaries without damaging normal tissue.
In general, the diagnosis of endometriosis is confirmed during surgery, at which time ablative steps can be taken. Further steps depend on circumstances: a woman without infertility can be managed with hormonal medication that suppresses the natural cycle and pain medication, while an infertile woman may be treated expectantly after surgery, with fertility medication, or with IVF. As to the surgical procedure, ablation (or fulguration) of endometriosis (burning and vaporizing the lesions with an electric device) has shown a high rate of short-term recurrence after the procedure. The best surgical procedure with much lower rate of short-term recurrence is to excise (cut and remove) the lesions completely.
Surgery, if done should generally be laparoscopically (through keyhole surgery) rather than open. Treatment consists of the excision of the endometrium, adhesions, resection of endometriomas, and restoration of normal pelvic anatomy as much as is possible. Endometrioma on the ovary of any significant size (Approx. 2 cm +) —sometimes misdiagnosed as ovarian cysts— must be removed surgically because hormonal treatment alone will not remove the full endometrioma cyst, which can progress to acute pain from the rupturing of the cyst and internal bleeding.Laparoscopy, besides being used for diagnosis, can also be used to perform surgery. It's considered a "minimally invasive" surgery because the surgeon makes very small openings (incisions) at (or around) the belly button and lower portion of the belly. A thin telescope-like instrument (the laparoscope) is placed through one incision, which allows the doctor to look for endometriosis using a small camera attached to the laparoscope. Small instruments are inserted through the incisions to remove the endometriosis tissue and adhesions. Because the incisions are very small, there will only be small scars on the skin after the procedure, and all endometriosis can be removed, and women recover from surgery quicker and have a lower risk of adhesions.
55% to 100% of women develop adhesions following pelvic surgery, 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.
Conservative treatment involves excision of endometriosis while preserving the ovaries and uterus, very important for women wishing to conceive, but may increase the risk of recurrence.
Endometriosis recurrence following conservative surgery is estimated as 21.5% at 2 years and 40-50% at 5 years.
Historically, a hysterectomy (removal of the uterus) was thought to be a cure for endometriosis in women who do not wish to conceive. Removal of the uterus may, in some people, be beneficial as part of the treatment when the uterus itself is affected by adenomyosis. However, this should only be done when combined with removal of the endometriosis by excision, as if endometriosis is not also removed at the time of hysterectomy, pain may persist.
For women with extreme pain, a presacral neurectomy may be very rarely performed where the nerves to the uterus are cut. However, this technique is almost never used due to the high incidence of associated complications including presacral hematoma and irreversible problems with urination and constipation.
Hormonal birth control therapy: Birth control pills reduce the menstrual pain associated with endometriosis. They may function by reducing or eliminating menstrual flow and providing estrogen support. Combined estrogen–progestogen birth control is the first-line treatment for most women with endometriosis due to its ability to be used over long periods of time, relative inexpensiveness and ease of use, and additional benefit of reducing ovarian/endometrial cancer risk.
Progestogens: Progesterone counteracts estrogen and inhibits the growth of the endometrium. Such therapy can reduce or eliminate menstruation in a controlled and reversible fashion. Progestins are chemical variants of natural progesterone. An example of a progestin is dienogest (Visanne). Whilst progestogens are often given as part of a combined hormonal therapy with the addition of estrogen, progestogen-only therapy may be an acceptable alternative.
Gonadotropin-releasing hormone (GnRH) modulators: These drugs include GnRH agonists such as leuprorelin (Lupron) and GnRH antagonists such as elagolix (Orilissa) and are thought to work by decreasing estrogen levels. A 2010 Cochrane review found that GnRH modulators were more effective for pain relief in endometriosis than no treatment or placebo, but were no more effective than danazol or intrauterine progestogen, and had more side effects than danazol. A 2018 Swedish systematic review found that GnRH modulators had similar pain-relieving effects to gestagen, but also decreased bone density.
Aromatase inhibitors are medications that block the formation of estrogen and have become of interest for researchers who are treating endometriosis. Examples of aromatase inhibitors include anastrozole and letrozole. Evidence for aromatase inhibitors is limited due to the limited number and quality of studies available, though show promising benefit in terms of pain control.
NSAIDs: Anti-inflammatory. They are commonly used in conjunction with other therapy. For more severe cases narcotic prescription drugs may be used. NSAID injections can be helpful for severe pain or if stomach pain prevents oral NSAID use. Examples of NSAIDs include ibuprofen and naproxen.
Opioids: Morphine sulphate tablets and other opioid painkillers work by mimicking the action of naturally occurring pain-reducing chemicals called "endorphins". There are different long acting and short acting medications that can be used alone or in combination to provide appropriate pain control.
Following laparoscopic surgery women who were given Chinese herbs were reported to have comparable benefits to women with conventional drug treatments, though the journal article that reviewed this study also noted that "the two trials included in this review are of poor methodological quality so these findings must be interpreted cautiously. Better quality randomised controlled trials are needed to investigate a possible role for CHM [Chinese Herbal Medicine] in the treatment of endometriosis."
Pentoxifylline, an immunomodulating agent, has been theorized to improve pain as well as improve pregnancy rates in women with endometriosis. A 2012 Cochrane review found that there was not enough evidence to support the effectiveness or safety of either of these uses. Current American Congress of Obstetricians and Gynecologists (ACOG) guidelines do not include immune-modulators, such as pentoxifylline, in standard treatment protocols.
The overall effectiveness of manual physical therapy to treat endometriosis has not yet been identified. There is no evidence to support nutritional therapy as effective.
Comparison of interventions
Medicinal and surgical interventions produce roughly equivalent pain-relief benefits. Recurrence of pain was found to be 44 and 53 percent with medicinal and surgical interventions, respectively. Each approach has advantages and disadvantages. Manual therapy showed a decrease in pain for 84 percent of study participants, and a 93 percent improvement in sexual function.[unreliable medical source?]
As of 2013[update] evidence on how effective medication is for relieving pain associated with endometriosis was limited . A 2018 Swedish systematic review found a large number of studies but a general lack of scientific evidence for most treatments. There was only one study of sufficient quality and relevance comparing the effect of surgery and non-surgery. Cohort studies indicate that surgery is effective in decreasing pain. 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. The evidence was found to be insufficient regarding surgical intervention.
The advantages of surgery are demonstrated efficacy for pain control, it is more effective for infertility than medicinal intervention, it provides a definitive diagnosis, and surgery can often be performed as a minimally invasive (laparoscopic) procedure to reduce morbidity and minimize the risk of post-operative adhesions. Efforts to develop effective strategies to reduce or prevent adhesions have been undertaken, but their formation remain a frequent side effect of abdominal surgery.
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. Disadvantages are that there are no large or long-term studies of its use for treating pain or infertility related to endometriosis.
Surgery is more effective than medicinal intervention for addressing infertility associated with endometriosis. Surgery attempts to remove endometrial tissue and preserve the ovaries without damaging normal tissue.In-vitro fertilization (IVF) procedures are effective in improving fertility in many women with endometriosis.
During fertility treatment, the ultralong pretreatment with GnRH-agonist has a higher chance of resulting in pregnancy for women with endometriosis, compared to the short pretreatment.
Proper counseling of women with endometriosis requires attention to several aspects of the disorder. Of primary importance is the initial operative staging of the disease to obtain adequate information on which to base future decisions about therapy. The woman's symptoms and desire for childbearing dictate appropriate therapy. Not all therapy works for all women. Some women have recurrences after surgery or pseudo-menopause. In most cases, treatment will give women significant relief from pelvic pain and assist them in achieving pregnancy.
The underlying process that causes endometriosis may not cease after a surgical or medical intervention. Studies have shown that endometriosis recurs at a rate of 20 to 40 percent within five years following conservative surgery.[unreliable medical source?] Monitoring of women consists of periodic clinical examinations and sonography.
Determining how many people have endometriosis is challenging because definitive diagnosis requires surgical visualization. Criteria that are commonly used to establish a diagnosis include pelvic pain, infertility, surgical assessment, and in some cases, magnetic resonance imaging. These studies suggest that endometriosis affects approximately 11% of women in the general population. It may affect more than 11% of American women between 15 and 44. Endometriosis is most common in those in their thirties and forties; however, it can begin in girls as early as 8 years old.
It can affect any female, from premenarche to postmenopause, regardless of race or ethnicity or whether or not they have had children. It is primarily a disease of the reproductive years. Incidences of endometriosis have occurred in postmenopausal women, and in less common cases, girls may have endometriosis symptoms before they even reach menarche.
The rate of recurrence of endometriosis is estimated to be 40-50% for adults over a 5-year period. 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.
Endometriosis was first discovered microscopically by Karl von Rokitansky in 1860, although it was documented in medical texts more than 4,000 years ago. The Hippocratic Corpus outlines symptoms similar to endometriosis, including uterine ulcers, adhesions, and infertility. 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. 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. The symptoms of inexplicable chronic pelvic pain were often attributed to imagined madness, female weakness, promiscuity, or hysteria. The historical diagnosis of hysteria, which was thought to be a psychological disease, may have indeed been endometriosis. The idea that chronic pelvic pain was related to mental illness influenced modern attitudes regarding women with endometriosis, leading to delays in correct diagnosis and indifference to the patients' true pain during the 20th century.
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. 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. 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.
Society and culture
There are public figures who speak out about their experience with endometriosis including Whoopi Goldberg, Mel Greigs, and Julianne Hough.
The economic burden of endometriosis is widespread and multifaceted. 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. One factor which seems to be associated with especially high costs is the delay between onset of symptoms and diagnosis. Costs vary greatly between countries.
As recently as 1995, reports found that over 50% of women with chronic pelvic pain had no organic cause, with women still often being considered mentally unstable. Self-help groups say practitioners delay making the diagnosis, often because they do not consider it a possibility. In the US, as of 2007, about 27% of women with endometriosis had had the symptoms for at least six years before it is diagnosed.[needs update]
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