Endometriosis
Medical condition
From Wikipedia, the free encyclopedia
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.
| Endometriosis | |
|---|---|
| |
| Specialty | Gynecology |
| Symptoms | Pelvic pain, infertility, painful periods |
| Usual onset | Adolescence or early 20s |
| Duration | Long-term |
| Causes | Unknown |
| Risk factors | Family history, early first period, short cycle length |
| Diagnostic method | Based on symptoms, medical imaging, tissue biopsy |
| Differential diagnosis | Adenomyosis, irritable bowel syndrome, bladder pain syndrome |
| Treatment | NSAIDs, continuous birth control pills, hormonal IUD (coil), surgery |
| Frequency | Roughly 10% of women of reproductive age |
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 menstrual period flow, 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. Endometriosis 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 about 190 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,[1] forming patches called lesions or implants.[2] It is classified into four subtypes:[1]
- Superficial peritoneal endometriosis
- Small lesions that grow on the peritoneum, the membrane lining the abdominal cavity and covering the surface of pelvic organs
- Deep infiltrating endometriosis
- Lesions that grow into the tissue beneath the lining of the pelvis or into the muscle layers of pelvic organs like the bowel or bladder
- Ovarian endometriomas
- Cysts that grow in the ovaries
- Extrapelvic endometriosis
- Lesions outside the pelvic region, such as in the lungs or diaphragm
Subtypes can exist in isolation or in combination with one another.[1] Endometriomas appear dark brown, giving rise to the name "chocolate cysts", and are filled with old menstrual blood among other material.[3] When lesions grow more than 5 mm beneath the peritoneal surface, they are classified as deep infiltrating endometriosis.[4] Deep endometriosis can infiltrate the muscular layer of organs.[1] It often appears as nodules, and can be associated with fibrosis and adhesions.[1]
Endometriosis most commonly affects the ovaries, the fallopian tubes between the ovaries and the uterus, the outer surface of the uterus, and the tissues that hold the uterus in place. Less common pelvic sites are the rectum, bladder, bowel, vulva, vagina, and cervix.[5] Rarely, endometriosis appears outside the pelvis, such as on the lungs or diaphragm (thoracic endometriosis), brain, or skin.[5][6] Scar endometriosis can form on the abdominal wall as a complication of surgery, most often following a caesarean section or other pelvic surgery.[7] It forms at or near the location of the surgical cut.[8]
Signs and symptoms
Endometriosis can cause pain, fatigue, and infertility.[9] Some individuals have no symptoms, while others can 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.[3] Symptoms typically start in adolescence or the early 20s and usually disappear during menopause, as estrogen levels decline. For some, especially women using hormone replacement therapy, symptoms may continue or even appear for the first time during menopause.[1]
Common symptoms include:[9][10]
- 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.[1] The pain has been described as dull and cramping in nature,[11] and can interfere with daily activities, such as school, work, or participating in social events.[9] Some individuals describe the sensation as resembling clawing fingernails or stabbing knives in the lower abdomen. The pain may radiate to the lower back.[11]
About a quarter of women diagnosed with endometriosis experience infertility.[1] In some women, infertility is the only symptom they experience.[12] The World Health Organization estimates that endometriosis is the ultimate cause of female infertility in 4.8% of cases.[13]
Endometriosis can also involve symptoms like constipation, diarrhea, nausea, bloating, and rectal or abdominal pain. This is sometimes caused by endometriosis on the bowels, but often due to concurrent irritable bowel syndrome. People with endometriosis often experience fatigue, which is linked to insomnia, depression, and anxiety.[9] Deep infiltrating endometriosis in the bowel or bladder can cause bowel obstruction and cyclical blood in stool or blood in urine.[1][9]
Thoracic endometriosis—endometriosis on the diaphragm, lungs, or pleura around the lungs—can cause cyclical cough and cyclical shoulder pain. When present in the lungs, it can cause cyclical blood discharge from the lungs during menstruation.[14] When found in the pleura, it can cause cyclical collapsed lung and bleeding into the pleural space. Most often, the endometriosis is found in the right lung.[14] Endometriosis around scars can be painful and swell during periods.[3] Sciatic endometriosis, which involves the sciatic nerve, causes cyclical nerve pain in the leg.[15]
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.[9] The rare complication of spontaneous hemoperitoneum in pregnancy, which is highly dangerous to both mother and fetus, is more common in women with endometriosis too.[16]
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.[9] Depression and anxiety are more common in people with endometriosis compared to healthy people, but occur at the same rate as they do among people with other chronic pain conditions.[17] It is unclear how much this is caused by shared underlying mechanisms, the impact of severe symptoms, stigma, diagnostic delays, or the ineffectiveness of treatment.[9]
Endometriosis often co-occurs with other pain disorders, autoimmune disorders (such as lupus or arthritis), certain cancers, stroke, and long COVID. For instance, a quarter of women with endometriosis have at least one other pain condition.[1] Women with endometriosis have an increased risk of developing ovarian and thyroid cancers compared to women without the condition, as well as a slightly higher risk of breast cancer.[18]
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.[19] 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.[20] At least 42 different loci (regions on a chromosome) 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.[21]
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 genetic variation with asthma and osteoarthritis.[21]
Reproductive and environmental factors
People whose menstrual outflow is obstructed are at risk of developing endometriosis. This could for instance be because of an imperforate hymen, a birth defect where the vagina is completely blocked.[22] Another type of obstruction occurs when extra tissue divides the vagina into two sides. This can happen alongside a double uterus. If one side is blocked (an obstructed hemi-vagina), menstrual blood cannot flow out and becomes trapped.[23] 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.[1]
Little is known about environmental risk factors. Exposure to certain classes of environmental pollutants seems to raise risks. The most studied of these are endocrine disruptors—chemicals that interfere with hormones such as estrogen.[24] 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.[24][25] Night work and red meat consumption are associated with an increased risk too.[24]
Mechanism
Endometriosis is an inflammatory disease defined by the presence of tissue similar to the lining of the uterus (the endometrium) elsewhere in the body.[1] The development and growth of these lesions requires estrogen.[27] The lesions promote local inflammation and immune system dysregulation. They also trigger the formation of adhesions (fibrous bands that form between tissues and organs) and fibrosis (excess connective tissue from healing, a form of scarring). It is not well understood how endometriosis causes infertility and pain.[1]
Formation
Origin of endometriosis cells
The main theories for the formation of the endometrium-like tissue outside the womb are backward flow of menstrual blood, metastasis via the lymphatic or the circulatory system, and local transformation of peritoneal cells into endometrial-like cells (coelomic metaplasia).[28]
During menstruation, some menstrual blood, tissue, and fluid can flow backward through the fallopian tubes into the pelvic area (the peritoneal cavity). This backward flow (retrograde menstruation) is thought to be the main reason why endometriosis develops inside the pelvic cavity. However, this explanation alone is not enough, because almost all women have some backward flow of menstrual fluid, but only 10% develop endometriosis.[3]
Evidence supporting the theory comes from retrospective epidemiological studies and DNA analysis.[29][30] 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.[29]
Endometriosis has been documented in men, prepubescent girls, and in female fetuses, demonstrating that menstruation is not required for the condition to develop. One explanation for endometriosis in girls before puberty is the coelomic metaplasia theory, that certain cells in the peritoneum may undergo metaplasia (transformation) into endometrium-like tissue. Endometriosis in men may be explained by the persistence of Müllerian remnants; normally, these cells disintegrate during male embryonic development.[31]
Stem cells may contribute to the formation of endometriosis.[32] 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.[33] Stem cells from bone marrow may drive the further growth of lesions, but also provide an explanation for endometriosis outside the pelvic region.[3] An alternative explanation for extrapelvic endometriosis is metastasis via the lymphatic or the circulatory system.[1]
Other factors
Most women with retrograde menstruation do not develop endometriosis, so other factors must also contribute to its development.[3] For endometriosis to develop, its cells must evade destruction by the immune system, attach to a surface, and promote the formation of new blood vessels, similar to some cancerous tumors.[34] Endometriotic lesions differ from the endometrium in their biochemistry, hormonal response, immunology, and inflammatory response.[28]
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).[3] Angiogenesis, the formation of new blood vessels, is a likely driver in the formation and maintenance of endometriotic lesions.[32][35] Cells in the peritoneum of women with endometriosis release more growth factors that stimulate angiogenesis.[3]
Endometriosis lesions require estrogen to grow.[36][28] This estrogen is produced both within the lesions themselves and in other parts of the body.[28] Sometimes, the cells in endometriosis are progesterone-resistant or develop resistance during treatment with the hormone. This weakened response to progesterone allows endometriosis to continue growing outside the womb.[37]
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.[3] The inflammation and fibrosis around endometriosis can cause pain by activating pain-sensing nerves.[38] Neuropathic pain can arise from damage to nerves. In rare cases, endometriosis can infiltrate or compress nerves,[1] and damage to nerves might also occur due to surgery.[38] Estrogens can increase communication between immune cells and nerves in lesions, which may contribute to further pain.[3] Finally, there may be systemic (body-wide) inflammation, involving white blood cells. This can lead to nociplastic pain, which amplifies pain signals and reduces pain inhibition. This type of pain is associated with poor sleep, memory problems, and fatigue.[1]
Infertility
The infertility associated with endometriosis likely has multiple causes. Inflammation and hormonal dysfunction explain some instances: they can disrupt the ovarian environment and reduce egg quality. The ovarian reserve, the number of viable egg cells in the ovaries, is typically lower in those with endometriosis. In particular, endometriomas may reduce ovarian reserve in affected ovaries.[3] There is contradictory evidence on whether endometriosis causes reduced ovulation. Anatomical distortions, for instance from adhesions, can explain further instances of infertility, and in severe cases, sperm or egg cells may be fully blocked. Pain during sex may lead couples to avoid it, leading to fewer opportunities for natural conception.[39]
Diagnosis
A health history and a physical examination may lead a health care practitioner to suspect endometriosis. 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 is a shift away from requiring surgical confirmation to prevent treatment delays.[1]
Diagnosis takes an average of five to twelve years from the onset of symptoms.[1] This delay has remained persistent. On average, individuals wait one to four years before seeking medical help, which might be explained by the normalization of symptoms, the lack of awareness, and lack of access to healthcare. After seeking help, it can take up to nine years to get a diagnosis, reflecting a normalization of symptoms by healthcare providers, limited expertise and tools, and general inefficiencies in healthcare.[40]
Physical examination
Initial assessment includes screening of risk factors and an evaluation of symptoms. Both general symptoms and those linked to deep endometriosis or endometriosis outside the pelvis are assessed. A trauma-informed approach validates pain, fosters trust, and screens for trauma before a physical exam.[1]
The physical examination can include an abdominal exam, a single digit exam of the vagina and pelvic floor, a bimanual exam and examination with a speculum. Findings that suggest endometriosis include nodularity or tenderness at the back of the uterus, decreased mobility of the uterus, and the finding of tender blue-gray nodules in the vagina. Even if nothing is found on examination, endometriosis may still be present.[1]
Ultrasound
Vaginal ultrasound can be used to diagnose endometriomas and deep infiltrating endometriosis. It cannot rule out a diagnosis of endometriosis; a normal scan may require further investigations.[42] Vaginal ultrasound is inexpensive, easily accessible, has no contraindications, and requires no preparation.[43] The ultrasound can be extended to look at the front and back of the pelvis. This allows the examiner to assess deep infiltrating endometriosis and organ mobility.[44]
If a transvaginal ultrasound is not suitable or declined, an alternative is an ultrasound via the lower abdomen.[45] Abdominal ultrasounds can find endometriomas, but are not suitable for assessing deep endometriosis.[46]
MRI
MRI is another means of detecting lesions without surgery. MRI is not widely used due to its cost and limited availability.[47] It can reliably detect endometriomas and deep infiltrating endometriosis. It 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 extra-pelvic endometriosis.[48]
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.[1] It can be used when endometriosis is suspected, and imaging does not show any clear causes for symptoms.[3] In nearly 40% of women undergoing laparoscopic surgery for pelvic pain, no cause is discovered.[3]
Surgery is not always needed: if imaging does not show clear signs of endometriosis, clinicians may first try treatment and give a presumed diagnosis if symptoms improve ('empirical treatment').[49] Surgery for diagnosis allows for surgical treatment of uncomplicated endometriosis at the same time.[3]
The lesions of superficial endometriosis often appear dark blue or black. In the earlier stages of disease, they may be white, red, or yellow-brown. Ovarian cysts (also called chocolate cysts) are typically dark brown. Adhesions are made up of fibrous scar tissue. Deep endometriosis looks like multiple distinct nodules.[3] A biopsy may not detect endometriosis even when the disease is present, particularly in younger women. As such, a biopsy alone cannot be used to rule out a diagnosis of endometriosis.[3] For confirmation, biopsy samples should show at least two of the following features:[50]
- Endometrial type stroma
- Endometrial epithelium with glands
- Evidence of chronic bleeding, such as hemosiderin (iron) deposits
Endometriosis, abdominal wall. The yellow adipose (fat) tissue contains dark blood-filled cysts, white fibrous bands, and areas of bleeding.
Microscope image showing endometriosis (right) and ovarian stroma (left)
Microscope image of the wall of an endometrioma. All features of endometriosis are present (endometrial glands, endometrial stroma and iron in macrophages)
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.[51] rASRM classifies endometriosis as stage I–IV, ranging from minimal (stage I) to severe (stage IV).[52] These stages correlate poorly with how much pain women have.[3] The scale uses a point system that assesses lesions and adhesions during surgery. The ENZIAN system is more detailed and provides a structured description of endometriosis by anatomical compartments, particularly for deep endometriosis, including the extent of lesions within each compartment.[53] The ENZIAN system does not predict well which symptoms women have.[3]
The American Association of Gynecologic Laparoscopists (AAGL) endometriosis staging system, introduced in 2021, was designed to correlate well with the complexity of surgery. Like rASRM, it divides endometriosis into four stages.[31] Fertility is assessed separately with the Endometriosis Fertility Index (EFI).[3] The EFI is scored from 0 to 10, with higher scores indicating a greater likelihood of natural pregnancy.[31]
Differential diagnosis
Various conditions exhibit similar symptoms to endometriosis. Adenomyosis, the growth of endometrium-like tissue in the muscles of the uterus, is one example. It sometimes shows characteristics on an MRI that distinguish it from endometriosis. Bladder pain syndrome (interstitial cystitis) is mainly characterized by painful urination, but also causes more diffuse pain. It can be distinguished from endometriosis with a cystoscopy (bladder examination), which shows pinpoint bleeding spots in the bladder in bladder pain syndrome. Irritable bowel syndrome can sometimes be distinguished from endometriosis via the presence of diarrhea or constipation, and can be diagnosed in the absence of endometriosis via imaging or surgery.[54] Other conditions with overlapping symptoms are uterine fibroids, cervical stenosis, and pelvic floor myofascial pain.[1]
Prevention
According to the World Health Organization, there is no known way to prevent endometriosis.[55] 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.[56]
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.[57] The goal of management is to provide pain relief, to restrict the progression of the process, and to restore or preserve fertility where needed.[28] The UK National Institute for Health and Care Excellence recommends starting initial medication for those with suspected endometriosis at the same time as referral for investigations such as an ultrasound.[58] Alternatively, initial treatment is started after an ultrasound.[1] Surgery is an option when medical treatment is insufficiently effective, for advanced disease or infertility.[59]
Hormonal medications
The various hormonal options to treat endometriosis have comparable efficacy. Individuals respond differently to the medications, finding the best option often involves trial and error to balance pain relief with minimal side effects. Hormonal treatment is not suitable for women who are trying to become pregnant.[1]
Progestin-only hormonal suppression (progestogen) is a first-line therapy. It comes in different forms and includes the hormonal coil (an intrauterine device), the oral drug dienogest, an injection of medroxyprogesterone acetate every three months or an implant under the skin.[1] Dienogest, which may be more effective than injections,[60] is not available on its own in the US.[1] Oral progestins likely reduce overall pain and period pain compared to placebo, and may also help with pelvic pain. It is unclear how well they work compared to other hormonal therapies.[60]
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.[1]
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.[1] GnRH agonists mimic the effects of menopause, and seem more effective than placebo or oral progestin at reducing pain.[61] 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.[1][61]
Aromatase inhibitors, such as anastrozole and letrozole, are third-line treatments and block estrogen production throughout the body. Common side effects are hot flashes, night sweats, and functional cysts.[1][62] 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.[1]
Pain medication
NSAIDs like naproxen or ibuprofen are anti-inflammatory medications commonly used for endometriosis pain.[63] They are first-line treatments and can work well for mild pain.[1][57] NSAIDs can be used separately (for instance, if fertility is a priority), or in combination with hormonal treatment.[1] Evidence for their effectiveness is limited, with only one small randomized trial conducted. NSAIDs can have side effects, predominantly gastrointestinal, but they are generally safe to try.[64] NSAIDs pose some risks for people with heart disease, kidney disease, or uncontrolled hypertension.[1]
Surgery
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.[1]
Laparoscopy (keyhole surgery) is the standard surgical approach. Treatment consists of the removal of endometriosis and the restoration of pelvic anatomy via the division of adhesions.[66] The removal takes place via excision (cutting out) or electrosurgery (coagulation or ablation/vaporization).[67][68] With laparoscopic surgery, small instruments are inserted through incisions to remove the endometriosis tissue and adhesions. After surgery, people can usually return home the same day.[69]
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 endometriosis is removed.[70] 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.[71]
Endometriomas are usually excised (removed completely). Compared to drainage and coagulation of the cyst, excision makes it less likely the cysts and pain symptoms come back. However, excision may damage fertility, as it can affect the ovarian reserve, the amount of egg cells that can be fertilized.[3][1]
For deep endometriosis, surgery improves quality of life and pain symptoms.[72] However, the procedure can be complicated, especially if the lesions are in or near the bowel, ureter (which transports urine from the kidneys to the bladder), or the chest, and requires an interdisciplinary surgical team in those cases. For instance, for rectovaginal endometriosis, a study reported 7% of surgeries had complications.[1] When endometriosis involves the bowel or bladder, part of the affected organ may be removed.[73][74]
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.[75][1]
Recurrence and postoperative hormonal suppression
In an analysis with a median follow-up of 24 months, pain after surgery recurred in about 16% of women.[1] Endometriosis recurrence following surgery is estimated as 21.5% at 2 years and 40–50% at 5 years. Hormonal therapy before surgery has little effect on recurrence, but treatment afterwards reduces the risk.[3] At a median follow-up of 18 months (studies varied between 12 and 36 months),[76] endometriosis recurred in 26% of women without postoperative hormonal suppression, compared with 10% of women who received it.[1] The risk of recurrence is higher in younger women and in those with a less aggressive surgery.[68]
Additional therapies
There is limited knowledge about the effectiveness of additional or adjunct therapies for endometriosis. Additional therapies sometimes used are pelvic floor physical therapy, exercise, acupuncture, pain education, or psychotherapy targeting pain.[1] Diets high in antioxidants might help reduce period pain, based on a small number of studies.[1][77]
Infertility
Infertility can be treated with assistive reproductive technology (ART), such as in vitro fertilization (IVF), or with surgery.[78] IVF procedures are effective in improving fertility in many women with endometriosis. IVF is increasingly recommended over surgery for older women or for those where there might be multiple reasons why they struggle to conceive.[79] It does not increase recurrence of endometriosis.[80] The Endometriosis Fertility Index can help guide decisions on treatment of infertility.[81] Surgery is typically not recommended before starting ART.[82]
Surgery to remove endometriomas can help with fertility. They can be cut out (in a cystectomy) or drained and destroyed (ablation). The ablation technique may better preserve the number of remaining viable eggs (the ovarian reserve), compared to cutting out the endometrioma.[83] On the other hand, cutting out the endometrioma may help more with pain.[79] Surgery likely also helps with infertility in the case of superficial peritoneal endometriosis.[1] Receiving hormonal suppression therapy after surgery might help with endometriosis recurrence and pregnancy,[84] but evidence for pregnancy outcomes is mixed.[85] 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.[85][86]
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.[87] The disease does not always worsen; in studies that tracked people over time, endometriosis became worse in 29%, improved in 42%, and stayed the same in 29% of cases.[3]
Around 70% of people see initial improvements with medical therapy, but the drugs can lose their effectiveness over time.[88] The likelihood of symptoms returning after surgery is highly variable; studies have reported recurrence rates anywhere between 6% and 67%. For some, endometriosis becomes associated with persistent, complex pain, possibly linked to changes in the nervous system, as part of a constellation of chronic pain disorders.[87]
Epidemiology
Endometriosis is commonly reported to affect approximately 10% of women of reproductive age.[1] Worldwide, this corresponds to an estimated 190 million girls and women.[89] Around 22 million had a surgically confirmed diagnosis as of 2021.[90] 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.[89] The prevalence depends on the population studied and the way endometriosis is diagnosed (imaging, surgery). Of women with pelvic pain undergoing laparoscopy, 28% are diagnosed with endometriosis. Of those with infertility undergoing laparoscopy, 25% are diagnosed.[1]
The disease is most diagnosed when women are in their 30s, but symptoms typically start in their early 20s or in adolescence.[1] Individuals can develop endometriosis symptoms before their first period and in menopause too.[89] Up to 4% of women still have endometriosis after reaching menopause, mostly in the form of ovarian endometriosis.[91] In the United States, the condition is more commonly diagnosed in white women than in black women.[92] This may reflect health inequities rather than true differences in prevalence.[88]
History
.jpg)
The earliest references to what may have been endometriosis are from Ancient Egypt, nearly 4,000 years ago.[94] In Ancient Greece, the Hippocratic Corpus—written between the 5th and 4th centuries BCE—outlines symptoms similar to endometriosis, including adhesions and infertility.[95] Over the centuries, numerous explanations for pelvic pain in women were proposed, often attributing the condition to supposed flaws in women themselves, such as madness, promiscuity, or inherent weakness. Many women who received the now-discredited diagnosis of hysteria may have instead suffered from endometriosis.[96]
Endometriosis proper was first defined between the end of the 19th century and the start of the 20th. Some attribute the first description to Carl von Rokitansky in 1860, who found endometrial glands in tissues using microscopy.[97] Other authors consider it more likely he was describing malignant tissue, given his use of the term sarcoma, which already then referred to cancer.[98] 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.[99] 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.[98]
One early recommendation to prevent and treat endometriosis was pregnancy. For older women, another approach was surgery, involving oophorectomy (removal of the ovaries) and hysterectomy (removal of the uterus).[100] In the 1940s, the only available hormonal therapies for endometriosis were high-dose testosterone and high-dose estrogen therapy.[101] 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.[100]
Pseudopregnancy (high-dose estrogen–progestogen therapy simulating pregnancy) for endometriosis was first described by Kistner and Andrews in the late 1950s and became widely employed.[100] Danazol was first described for endometriosis in 1971.[102] It was used for some 40 years, but had masculinizing side effects, including weight gain, excessive body hair growth, and shrinking of breasts.[103] 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.[104] Oral fast-acting GnRH antagonists, such as elagolix, were introduced for endometriosis in 2018.[104][105]
Society and culture
Stigma and medical culture
Endometriosis is affected by multiple forms of stigma related to fertility, pain, and menstruation, contributing to dismissal, delayed diagnosis, and adverse mental health outcomes.[106] Menstrual stigma contributes by discouraging discussion among peers and by casting doubt on accounts of period pain.[106][107] There can also be stigma around painful sex.[108] Cultural norms can reinforce these barriers. In India, unmarried women are often not offered a transvaginal ultrasound, because of taboos about sex before marriage. This causes delays in diagnosis.[109] In other countries, women who have unperforated hymens or are not sexually active may also be denied transvaginal ultrasounds.[110][111]
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.[112][113] Cultural attitudes also play a role; in a 2020 Puerto Rican study, stigma led to endometriosis pain being dismissed as changaría or changas by friends and family, local terms for whining or complaining, often directed at children.[114]
Further barriers come from outdated standards for laparoscopic evaluation and lack of understanding of the disease.[108] Healthcare providers sometimes dismiss described symptoms as normal menstruation, or psychologize the issue (ascribing the pain to a psychological cause).[106] Menstrual disorders are generally not covered extensively in medical education, leading to gaps in knowledge of healthcare professionals.[115]
Economic burden
The economic burden of endometriosis is substantial.[116] 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.[117] Surgery is the main component of medical costs. Costs vary greatly between countries. Annual productivity losses ranged from $293 per 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.[116] Some women are unable to work due to endometriosis: a survey of Puerto Rican women showed a 20% absence from work,[118] whereas a survey of Swedish women with endometriosis found that 32% did not work.[119]
Research funding
Like many conditions mainly affecting women, endometriosis is underfunded in relation to its disease burden.[120] 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.[121] In the EU, endometriosis got significantly less funding than 9 comparator conditions, including psoriasis and male infertility.[122]
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.[123] 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.[124]
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.[125]
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.[126] Endometriosis has been studied in a large variety of animal models (e.g. mice developed to have endometriosis[127]), but the tissue can differ substantially from human endometriosis.[126] One alternative is the use of organoids with cells derived from women with endometriosis. These miniature organs can then be studied in vitro to investigate the disease mechanism more precisely.[126]
