Endometriosis is a disease in which tissue similar to the endometrium—the lining of the uterus (womb)—grows elsewhere in the body. The tissue most often grows close to the uterus, such as on the ovaries, fallopian tubes, or the lining of the pelvis. It can also appear on the bowel, bladder, and in some cases on the lungs or skin.
Symptoms vary widely between individuals. Some have no symptoms, while for others it is a debilitating disease. Common symptoms include pelvic pain, heavy and painful periods, pain with bowel movements, painful urination, painful sex, fatigue, and infertility. Beyond bodily symptoms, endometriosis can affect a person's mental health and social life. It is not known exactly what causes the disease. Possible causes include backward (retrograde) flow of menstrual fluid, genetic factors, hormones, and problems with the immune system.
A presumed diagnosis can be made based on symptoms and medical imaging; laparoscopy (keyhole surgery) with a biopsy can provide definite confirmation. Other causes of similar symptoms include adenomyosis, uterine fibroids (both conditions affecting the uterus), irritable bowel syndrome, and bladder pain syndrome. On average, it takes 5–12 years from the start of symptoms to receive a diagnosis. Many women report being incorrectly told their symptoms are trivial or normal.
While there is no cure for endometriosis, several treatments may improve symptoms. These include pain medication, hormonal treatments, or surgery. The recommended pain medication is usually a non-steroidal anti-inflammatory drug (NSAID), such as naproxen. Taking the birth control pill continuously or using a hormonal IUD (coil) are other first-line treatments. Alternative hormonal treatment can be tried if the pill or an IUD are not effective. Lesions may be removed surgically in women whose symptoms are not relieved by other treatments, or where endometriosis is associated with infertility.
Worldwide, endometriosis affects approximately 10% of the female population of reproductive age, representing nearly 200 million women. Symptoms typically start in adolescence or the early 20s, and tend to improve after menopause as estrogen levels go down. Most individuals benefit from drug treatment, even though this approach may lose effectiveness over time. Endometriosis can return after surgical removal.
Subtypes
Endometriosis occurs when endometrium-like tissue grows outside the uterus, It can be classified into three subtypes, or four if extra-pelvic endometriosis is included: Deep endometriosis can infiltrate the muscular layer of organs like the bowel or bladder. Extrapelvic endometriosis—for instance in the lungs or diaphragm (thoracic endometriosis), brain, or skin—is rare. Scar endometriosis can form on the abdominal wall as a complication of surgery, most often following a caesarean section or other pelvic surgery. It forms at or near the location of the surgical cut.
Signs and symptoms
Endometriosis can cause pain, fatigue, and infertility. Some individuals have no symptoms, while others experience severe, life-altering pain. The amount of pain is only weakly related to the anatomical extent of endometriosis. Those with limited endometriosis may have significant pain, while those with severe endometriosis may have few symptoms.
- Painful periods
- Chronic pelvic pain
- Painful sex
- Painful urination or bowel movements
- Fatigue
- Heavy menstrual bleeding
Painful symptoms can occur anytime during the menstrual cycle, but are usually more intense during menstruation; in other words, they follow a cyclical pattern. Symptoms can interfere with daily activities, such as school, work, or participating in social events.
Concurrent conditions
Endometriosis is associated with a higher risk of complications during pregnancy. Women with endometriosis have a three-fold increased risk of a placenta previa, in which the placenta partially or completely covers the cervical opening. Preterm delivery is almost 50% more likely. Other complications are stillbirth, gestational hypertension, pre-eclampsia, and placental abruption.
Beyond its effects in pregnancy, endometriosis is linked to cardiovascular disease, particularly in those who have had the uterus and ovaries removed as treatment for endometriosis. Cohort studies have found associations with strokes, heart attacks (myocardial infarction), high blood pressure, and irregular heartbeat.
Risk factors
Genetics
Inheritance is a significant but not the sole risk factor for endometriosis. Studies attribute 50% of the risk to genetics; the other 50% is attributed to environmental factors. Individuals who have a first-degree relative with endometriosis—such as a parent, sibling, or child—have a three- to nine-fold higher risk of developing the condition. Eighty genetic regions (loci) have been associated with endometriosis risk. The genes linked to endometriosis risk help control cancer-related processes, sex-hormone signals, womb development, molecules related to inflammation and adhesions, and the growth of new blood vessels.
There is significant overlap between the genetic basis of endometriosis, other pain conditions, and inflammatory conditions. For instance, endometriosis shares some genetic risk factors with migraine, headaches, neck, and back pain. Among inflammatory conditions, it shares associated genetic variants with asthma and osteoarthritis. Other risk factors are having a first period before age 12, a menstrual cycle of fewer than 28 days, a low BMI, and not having had children. They include dioxins, phthalates, bisphenol A, and polychlorinated biphenyl. Epidemiological and experimental data suggest that exposure to some of them can increase the risk of endometriosis. Night work and red meat consumption are associated with an increased risk too.) and epithelial cells, and associated blood vessels and nerves.|alt=schematic showing uterus with endometriosis on the outside, and a close-up of a lesion. The closeup shows regions with epithelial cells surrounded by stromal cells, and associated blood supply and nerves.]]
Endometriosis is an inflammatory disease defined by the presence of tissue similar to the lining of the uterus (the endometrium) elsewhere in the body.
This trapped tissue, together with the lesions themselves, causes inflammation and can trigger the formation of adhesions,fibrous bands that form between tissues and organs and cause organs to be bound together. Evidence supporting the theory comes from retrospective epidemiological studies and DNA analysis. Furthermore, only animals with a menstrual cycle, such as rhesus monkeys and baboons, develop endometriosis. In contrast, animals like rodents and non-human primates with an estrous cycle, in which the endometrium is reabsorbed rather than shed, do not develop the disease naturally. However, this theory is insufficient on its own to explain the formation of the condition, because almost all women have some backward flow of menstrual fluid, but only 10% develop endometriosis.
Stems cells in the basal layer of the endometrium play a role in renewing the tissue after menstruation. In women with endometriosis, more tissue is shed from this layer during menstruation, allowing more stem cells to flow back into the peritoneum with retrograde menstruation, and form lesions. Stem cells from bone marrow may provide an explanation for endometriosis outside the pelvic region. Immune dysfunction could be involved in the disease in various ways. It may lead to a decrease in destruction of endometrial cells outside the womb. Additionally, a local inflammatory environment may make it more likely that the cells attach to a surface, and may reduce programmed cell death (apoptosis). Cells in the peritoneum of women with endometriosis release more growth factors that stimulate angiogenesis.
Pain
There are multiple possible causes of pain associated with endometriosis and the main drivers of pain may differ from person to person. The growth of new blood vessels and nerves in lesions is thought to play an important role. Neuropathic pain can arise from nerve damage; In rare cases, endometriosis infiltrates or compresses nerves,
Diagnosis
Endometriosis may be suspected in women with chronic pelvic pain, painful periods affecting daily life, pain during sex, bowel or urinary symptoms linked to the menstrual cycle, or infertility. The diagnostic process starts with a health history and a physical examination. A presumed diagnosis can be made based on symptoms together with ultrasound or MRI imaging. The gold standard for definite diagnosis is via surgery and a biopsy, but there has been a shift away from requiring surgical confirmation to prevent treatment delays. There are no validated blood tests for endometriosis. In the United Kingdom, a survey by the charity Endometriosis UK suggested that average diagnosis time was 9 years and 4 months, or 11 years in the case of ethnic minority communities. Even if nothing is found on examination, endometriosis may still be present; a physical exam cannot detect superficial peritoneal endometriosis.|alt=see caption]]
Transvaginal ultrasound can be used to diagnose endometriomas and deep infiltrating endometriosis. To detect deep endometriosis more reliably, the ultrasound is extended to look at locations deep endometriosis is often found at the back of the pelvis. In addition, pressure is applied with hands or the probe (the transducer) to assess organ mobility. Not all lesions are visible on ultrasound scans, so a scan cannot be used to rule out a diagnosis of endometriosis. Transvaginal ultrasound is inexpensive, easily accessible, has no contraindications, and requires no preparation.
If a transvaginal ultrasound is not suitable or declined, an alternative is an ultrasound via the lower abdomen. Abdominal ultrasounds can find endometriomas, but are not suitable for assessing deep endometriosis.thumb|upright=1.2|Trichromatic color MRI of ovarian cysts. The bottom right cyst is endometriosis.|alt=Four MRI images of ovarian cysts. The MRI image distinguishes fat, water, blood, and blood products and therefore shows the endometrioma in a unique colour.
Although MRI is not widely used due to cost and limited availability, it can reliably detect endometriomas and deep infiltrating endometriosis. MRI is sometimes used for planning surgery, for instance if an ultrasound is unclear, or for diagnosis if a transvaginal ultrasound is not appropriate or is declined. The field of view is larger in an MRI compared to an ultrasound, which allows a larger part of the bowel to be assessed, as well as extrapelvic endometriosis.
Keyhole surgery
Laparoscopy (keyhole surgery) is a surgical procedure where a camera is used to look inside the abdominal cavity. Laparoscopy with a biopsy is the most accurate way to diagnose endometriosis.
- Endometrial type stroma
- Endometrial epithelium with glands
- Evidence of chronic bleeding, such as hemosiderin (iron) deposits
<gallery mode="packed" heights="175">
File:Endometriosis, abdominal wall.jpg|Endometriosis, abdominal wall. The yellow adipose (fat) tissue contains dark blood-filled cysts, white fibrous bands, and areas of bleeding.|alt=yellow-white abdominal wall with dark spots
File:Endometriosis of the ovary.jpg|Microscope image showing endometriosis (right) and ovarian stroma (left)|alt=Purple microscope image showing two types of tissue
File:Endometrioma1.jpg|Microscope image of the wall of an endometrioma. All features of endometriosis are present (endometrial glands, endometrial stroma and iron in macrophages)
</gallery>
Staging
There are various staging or classification systems commonly used. Endometriosis is most often staged with the revised American Society of Reproductive Medicine (rASRM) staging system. rASRM classifies endometriosis as stage I–IV, ranging from minimal (stage I) to severe (stage IV). The scale uses a point system that assesses lesions and adhesions during surgery. The ENZIAN system does not predict well which symptoms women have. There are associations between some modifiable risk factors and endometriosis: women with endometriosis tend to consume more red meat, trans fats, alcohol, and caffeine. Physical activity does not seem to prevent endometriosis, but can lessen pain. It is unclear whether these factors cause the disease. Whether hormonal contraception can prevent endometriosis is controversial.
Management
While there is no cure for endometriosis, there are treatments for pain and endometriosis-associated infertility. Pain can be treated with hormones, painkillers, or, in severe cases, surgery. The goal of management is to provide pain relief, to restrict the progression of the process, and to restore or preserve fertility where needed.
Combined estrogen-progestin birth control pills are another first-line treatment. They usually cause few side effects and the recommendation is to use the pills continuously to stop periods. A formulation with the lowest level of estrogen that can still stop periods is advised. The combined pill may not be suitable for those with liver disease, migraine with aura, or those at high risk of blood clots.
Gonadotropin-releasing hormone (GnRH) modulators are second-line treatments. These drugs include GnRH agonists such as leuprorelin and GnRH antagonists such as elagolix, which decrease estrogen levels. They come with side effects of hot flashes and decreased bone density. GnRHs can be prescribed with hormonal 'add-back' therapy or with calcium-regulating agents to reduce the amount of bone loss. In premenopausal women, these should be taken with other hormones (such as the combined pill) to prevent ovarian stimulation and menopause symptoms. They can be an option for post-menopausal women who still have endometriosis symptoms, as their action is not limited to suppressing estrogen from the ovaries. Evidence is limited. They are first-line treatments and can work well for mild pain.|alt=a small instrument is inserted around the belly button and shines a light on the womb and fallopian tubes]]
Clinical guidelines recommend surgery when medical treatment does not work sufficiently, has unacceptable side effects, or should be avoided due to health risks (a contraindication). Large endometriomas can only effectively be treated with surgery. Surgery is also recommended when deep endometriosis causes problems in the bowels or urinary tract, such as obstruction. It is unclear what the effect of surgery is for pain relief in cases of superficial peritoneal endometriosis.
Two literature reviews have compared excision to ablation. A 2017 literature review found that excision improved some outcomes compared to ablation for endometriosis in general. A 2021 literature review on minimal to mild endometriosis found no difference. For deep endometriosis, excision is the standard therapy, as ablation does not allow the surgeon to see if all lesions are removed. 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.
Endometriomas are usually excised (cut out completely). For endometriomas larger than , the cyst is unlikely to disappear with just hormonal treament. Compared to drainage and coagulation of the cyst, excision makes it less likely the cysts and pain symptoms come back.
For women who still have significant pain after hormonal treatment and other surgery, and do not want to become pregnant, a hysterectomy (removal of the uterus) can be offered. This is done in combination with removal of endometriosis lesions. Removal of the uterus may be beneficial if the uterus itself is affected by adenomyosis. When the ovaries are removed too, women will experience early menopause and may need hormone replacement therapy. Removal of the ovaries comes with cardiovascular, metabolic, and mental health risks. endometriosis recurred in 26% of women without postoperative hormonal suppression, compared with 10% of women who received it.
Infertility
thumb|Assistive reproductive technology like IVF can help with fertility in endometriosis.
Infertility can be treated with assistive reproductive technology (ART), such as in vitro fertilization (IVF), or with surgery. IVF procedures are effective in improving fertility in many women with endometriosis. IVF is increasingly recommended over surgery for older women or for those who may have multiple reasons why they struggle to conceive. It does not increase recurrence of endometriosis. The Endometriosis Fertility Index can help guide decisions on treatment of infertility. Surgery is typically not recommended before starting ART.
Surgery to remove endometriomas can help with fertility. Draining and destroying them (ablation) may better preserve the number of remaining viable eggs (the ovarian reserve), compared to cutting out the endometrioma. Surgery likely also helps with infertility in the case of superficial peritoneal endometriosis. but evidence for pregnancy outcomes is mixed. Both the UK National Institute for Health and Care Excellence (NICE) and the European Society of Human Reproduction and Embryology recommend against hormonal suppression to improve fertility.
Prognosis
Endometriosis is often a long-term condition, with symptoms typically emerging during adolescence and easing after menopause. For some women, pain persists after menopause. Treatments, whether medical or surgical, can alleviate symptoms but do not provide a definitive cure. In studies that tracked people over time, lesions became worse in 29%, improved in 42%, and stayed the same in 29% of cases. The likelihood of symptoms returning after surgery is highly variable; studies have reported recurrence rates anywhere between 6% and 67%.
Epidemiology
Endometriosis is commonly reported to affect approximately 10% of women of reproductive age. Around 22 million had a surgically confirmed diagnosis as of 2021. It is difficult to determine an exact prevalence, given the large delays in diagnosis and the need for a surgical confirmation for a definite diagnosis.
The disease is typically diagnosed when women are in their 30s, but symptoms typically start in the early 20s or in adolescence. The prevalence in trans men is comparable to that in women, at around 9%.
Historically, the disease was considered more prevalent among white women than in black women and in the United States, the condition is still more commonly diagnosed in white women. This may reflect health inequities rather than true differences in prevalence, as disadvantaged groups have poorer access to healthcare, in particular to diagnostic surgery. Around 1896, Thomas Cullen and others described endometriosis and adenomyosis under the single name "adenomyoma". Between 1903 and 1920, Cullen showed that the tissue in adenomyomas was endometrial. John A. Sampson defined endometriosis in 1932. He studied its pathogenesis and was the first to propose retrograde menstruation as a cause. He also suggested that endometrial tissue could be inadvertently transplanted during surgery, such as a Caesarean section. During operations, he observed that endometriotic lesions would bleed in sync with a woman's menstrual cycle. In the 1940s, the only available hormonal therapies for endometriosis were high-dose testosterone and high-dose estrogen therapy. Success of high-dose estrogen therapy with diethylstilbestrol for endometriosis was first reported by Karnaky in 1948, but was associated with severe risks upon withdrawal. It was used for some 40 years, but had masculinizing side effects, including weight gain, excessive body hair growth, and shrinking of breasts. From the 1990s, GnRH agonists gained prominence for the treatment of endometriosis, but had disadvantages. They needed to be administered either nasally or via injections and were slow to act. Oral fast-acting GnRH antagonists, such as elagolix, were introduced for endometriosis in 2018.
Society and culture
Stigma and medical culture
Multiple forms of stigma related to fertility, pain, and menstruation, contribute to dismissal of symptoms, delayed diagnosis, and adverse mental health outcomes in individuals with endometriosis. There can also be stigma around painful sex. In other countries, women who have unperforated hymens or are not sexually active may also be denied transvaginal ultrasounds.
Race and ethnicity can impact how endometriosis affects one's life. For instance, the stereotype in the United States that non-white women have a higher pain threshold than white women may reduce quality of care. Cultural attitudes also play a role; in a 2020 Puerto Rican study, stigma led to endometriosis pain being dismissed by friends and family as or , local terms for whining or complaining that are often directed at children.
Further barriers to treatment come from outdated standards for laparoscopic evaluation and lack of understanding of the disease. Healthcare providers sometimes dismiss described symptoms as normal menstruation, or psychologize the issue (ascribing the pain to a psychological cause).
Economic burden
The economic burden of endometriosis is substantial. Endometriosis 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. Surgery is the main component of medical costs. Cost estimates vary greatly between countries. Annual productivity losses ranged from $293 per affected person in Nigeria to $33,428 in Italy (in 2022 currency values), while annual direct medical costs ranged from $1459 to $20,239 per woman. whereas a survey of Swedish women with endometriosis found that 32% did not work. In the United Kingdom, one researcher has estimated that one in six women with the condition end up leaving the workforce permanently, with the economic impact stated, , to be £12.5 billion for healthcare costs and workforce implications.
Research funding
Like many conditions mainly affecting women, endometriosis is underfunded in relation to its disease burden. For example, in the US, the NIH spent 5 to 10 times less on endometriosis research between 2015 and 2019 than on the average condition, relative to the number of healthy life years lost to each disease. In the EU, endometriosis got significantly less funding than 9 comparator conditions, including psoriasis and male infertility.
Research directions
A priority area of research is the search for endometriosis biomarkers (for example, something detectable via a blood test), which can help with earlier diagnosis. Studies have examined potential biomarkers such as microRNAs, glycoproteins, and immune markers in blood, menstrual, and urine samples, but none have shown the high accuracy needed for clinical use yet. CA-125, a tumor marker, has been studied extensively. It is elevated in endometriosis, but also in many other conditions, and so cannot be used on its own. MicroRNAs might be most promising, but levels are not consistent among studies, making them a challenging target.
Medical management of endometriosis is typically based on hormonal therapy, but these treatments can produce undesirable side effects, driving the search for alternatives. Emerging strategies target endometriosis as an inflammatory, metabolic, or pain disorder. Anti-inflammatory research targets include anakinra, a drug used in rheumatoid arthritis. The cancer drug dichloroacetic acid is being explored for its potential metabolic effects in endometriosis. Pain-focused treatments under investigation include cannabinoid extracts, migraine medications, and therapies directed at affected nerves.
Little research has been done on the differences between lesions (the molecular phenotypes). Classifying lesions might make it possible to design more targeted therapies, an approach that has worked well for cancer.), but the tissue can differ substantially from human endometriosis.
References
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