Endometriosis

Not to be confused with Endometritis.

Endometriosis
SpecialtyGynecology
SymptomsPelvic pain, infertility, painful periods
Usual onsetAdolescence or early 20s
DurationLong-term
CausesUnknown
Risk factorsFamily history, early first period, short cycle length
Diagnostic methodBased on symptoms, medical imaging, tissue biopsy
Differential diagnosisAdenomyosis, irritable bowel syndrome, bladder pain syndrome
TreatmentNSAIDs, continuous birth control pills, hormonal IUD (coil), surgery
FrequencyRoughly 10% of women of reproductive age

Endometriosis is a disease in which tissue similar to the lining of the uterus, the endometrium, 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 physical symptoms, endometriosis can affect a person's mental health and social life. The exact cause is not known. Possible causes include backwards 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, irritable bowel syndrome, and bladder pain syndrome. On average, it takes 5–12 years from the start of symptoms to receive a diagnosis and many patients 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 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 early 20s and tend to improve after menopause. A majority of individuals benefit from drug treatment, even though this approach may lose effectiveness over time. Endometriosis can return after surgical removal.

Subtypes

Subtypes of endometriosis. Clockwise from the top left is superficial peritoneal endometriosis, adhesions seen in deep endometriosis, a ruptured chocolate cyst and a mass of scar endometriosis next to a caesarian section scar.

Endometriosis can be subdivided into four subtypes:[1]

Superficial peritoneal endometriosis
Small spots 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 of 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.[2] When lesions grow more than 5 mm beneath the peritoneal surface, they are classified as deep infiltrating endometriosis.[3] It can infiltrate the muscles around organs.[1] Deep endometriosis 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.[4] Rarely, endometriosis appears outside the pelvis, such as on the lungs or diaphragm (thoracic endometriosis), brain, or skin.[4][5] Scar endometriosis can form on the abdominal wall as a complication of surgery, most often following a caesarean section or other pelvic surgery.[6]

Signs and symptoms

Endometriosis can cause pain, fatigue and infertility.[7] Some individuals have no symptoms, while others can experience severe, life-altering pain. The amount of pain relates poorly to the anatomical extent of endometriosis. Those with 'minimal' endometriosis may have significant pain, while those with 'severe' endometriosis may have few symptoms.[2] Symptoms typically start in adolescence or early 20s and usually disappear during menopause, as estrogen levels go down. For some, especially women using hormone replacement therapy, symptoms may continue or even appear for the first time in menopause.[1]

Common symptoms include:[7][8]

Painful symptoms can occur anytime in the menstrual cycle, but are usually more intense during menstruation.[1] The pain has been described as dull and cramping in nature,[9] and can interfere with daily activities, such as school, work or participating in social events.[7] Some individuals describe the sensation as resembling "clawing fingernails" or "stabbing knives" in the lower abdomen. The pain may radiate to the lower back.[9]

Women with endometriosis are about twice as likely to experience infertility compared to other women. Between 16% and 40% of women with endometriosis experience difficulty conceiving. In those going through assisted reproductive treatment, endometriosis is found in about 30% to 50% of women.[7] The World Health Organization estimates that endometriosis is the ultimate cause of female infertility in 4.8% of cases.[10]

Endometriosis can also involve symptoms like constipation, diarrhea, nausea, bloating, rectal or abdominal pain. This is sometimes caused by endometriosis on the bowels, but often due to co-occurring irritable bowel syndrome. People with endometriosis often experience fatigue, which is linked to insomnia, depression and anxiety.[7] Deep infiltrating endometriosis in the bowel or bladder can cause bowel obstruction, and cyclical blood in stool or blood in urine, that is, symptoms that are worse during menstruation.[1][7]

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. 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.[11] Endometriosis around scars can be painful and swell during periods.[2] Sciatic endometriosis, which involves the sciatic nerve, causes cyclical nerve pain in the leg.[12]

Co-occurring 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.[7] 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.[13]

Beyond its effects in pregnancy, endometriosis is linked to cardiovascular disease, particularly in those who have had the uterus and ovaries removed as treatment. Cohort studies have found associations with strokes, heart attacks (myocardial infarction), high blood pressure and irregular heartbeat.[7] Depression and anxiety are more common in people with endometriosis compared to healthy people, but occur at the same rate as with other chronic pain conditions.[14] It is unclear how much this is caused by shared underlying mechanisms, the impact of severe symptoms, stigma, the related diagnostic delays or the ineffectiveness of treatment.[7]

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 individuals 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, and slightly higher risk of breast cancer.[15]

Risk factors

Genetics

Inheritance is significant but not the sole risk factor for endometriosis. Studies attribute 50% of the risk to genetics, the other 50% to environmental factors.[16] Individuals with a first-degree relative who has endometriosis face a three- to nine-fold higher risk of developing it themselves.[17] 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.[18]

There is significant overlap between the genetic basis of endometriosis, other pain conditions and inflammatory conditions. For instance, endometriosis shares a genetic underpinning with migraine and neck, shoulder and back pain. Among inflammatory conditions, it shares genetic variation with asthma and osteoarthritis.[18]

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.[19] 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.[20] 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. Night work and red meat consumption seems to raise risk, as does exposure to some classes of environmental pollutants. The most studied of these are endocrine disruptors—chemicals that interfere with hormones, such as estrogen.[21] They include dioxins, phthalates, bisphenol A and polychlorinated biphenyl. Epidemiological and experimental data suggest that exposure to some of them may increase the risk of endometriosis.[21][22]

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.[23] 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).[24]

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 (called 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 some of them develop endometriosis.[2]

Evidence supporting the theory comes from retrospective epidemiological studies and DNA analysis.[25][26] 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.[25]

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 coelomic metaplasia: the theory that certain cells in the peritoneum may undergo metaplasia (transformation) into endometrium-like tissue. Müllerian remnants, cells that normally disappear during male embryonic development, may explain rare cases of endometriosis in men.[27]

Stem cells may contribute to the formation of endometriosis.[28] 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.[29] Stem cells from bone marrow may drive the further growth of lesions, but also provide an explanation for endometriosis outside of the pelvic region.[2] An alternative explanation for extrapelvic endometriosis is metastasis via the lymphatic or the circulatory system.[1]

Other factors

Because retrograde menstruation is common but endometriosis is not, additional factors must influence whether the disease develops.[2] For endometriosis to develop, as is done by some cancerous tumors, its cells must evade the immune system, attach to a surface, and promote the formation of new blood vessels.[30] Endometriotic lesions differ in their biochemistry, hormonal response, immunology, and inflammatory response compared to the endometrium.[24]

Endometriosis lesions require estrogen to grow. This estrogen is produced both within the lesions themselves and in other parts of the body.[24] 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 of the womb.[31]

Immune dysfunction could be involved in the disease in various ways: it may lead to a decrease in clearance of endometrial cells outside the womb, a local inflammatory environment may make it more likely that the cells attach to a surface, and may reduce programmed cell death (apoptosis).[2]

Angiogenesis, the formation of new blood vessels, plays a key role in the maintenance of endometriotic lesions.[28] Gene expression related to angiogenesis in the endometrium of women with endometriosis differs from that in women without the condition. In addition, cells in the peritoneum of women with endometriosis release more growth factors that stimulate angiogenesis.[2]

Pain

There are multiple possible causes of pain, 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.[2] The inflammation and fibrosis around endometriosis can cause pain by activating pain-sensing nerves.[32] 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.[32] Estrogens can increase communication between immune cells and nerves in lesions, which may contribute to further pain.[2] 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 can also cause poor sleep, memory problems and fatigue.[1]

Infertility

Main article: Endometriosis and 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.[2] 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.[33]

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 an additional nine years to get a diagnosis, reflecting a normalization of symptoms by healthcare providers, limited expertise and tools, and general inefficiencies in healthcare.[34]

Physical examination

Initial assessment includes a 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 are 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 endometrioma and localize deep endometriosis before surgery. Vaginal ultrasound is inexpensive, easily accessible, has no contraindications, and requires no preparation.[36] 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 mobility of organs.[37]

Ultrasounds cannot be used to exclude a diagnosis of endometriosis.[38] If a transvaginal ultrasound is not suitable or declined, an alternative is an ultrasound via the lower abdomen.[39] Abdominal ultrasounds can find endometriomas, but are not suitable for assessing deep endometriosis.[40]

MRI

MRI is another means of detecting lesions without surgery. MRI is not widely used due to its cost and limited availability.[41] 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.[42]

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.[2] In nearly 40% of women undergoing laparoscopic surgery for pelvic pain, no cause is discovered.[2]

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’).[43] Surgery for diagnosis does allow for surgical treatment of uncomplicated endometriosis at the same time.[2]

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 are typically dark brown. Adhesions are made up of fibrous scar tissue. Deep endometriosis looks like multiple distinct nodules.[2] A biopsy may not detect endometriosis even when the disease is present, particularly in younger women. As such, biopsy alone cannot be used to exclude a diagnosis of endometriosis.[2] For confirmation, biopsy samples should show at least two of the following features:[44]

  • Endometriosis, abdominal wall. The adipose (fat) tissue contained blood-filled cysts, 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.[45] rASRM classifies endometriosis as stage I–IV, ranging from minimal (stage I) to severe (stage IV).[46] These stages correlate poorly with how much pain women have.[2] 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 extent of lesions within each compartment.[47] The ENZIAN system does not predict well which symptoms women have.[2]

The American Association of Gynecologic Laparoscopists (AAGL) endometriosis staging system, introduced in 2021, was designed to correlate well with complexity of surgery. Like rASRM, it divides endometriosis into four stages.[27] Fertility is assessed separately with the Endometriosis Fertility Index (EFI).[2] The EFI is scored from 0 to 10, with higher scores indicating a greater likelihood of natural pregnancy.[27]

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 can 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, which shows pinpoint hemorrhages 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.[48] 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.[49] There are associations between some 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.[50]

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.[51] The goal of management is to provide pain relief, to restrict the progression of the process, and to restore or preserve fertility where needed.[24] 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 ultrasound.[52] Alternatively, initial treatment is started after an ultrasound.[1] Surgery is an option when medical treatment is insufficiently effective, for advanced disease or infertility.[53]

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.[1]

Progestin-only hormonal suppression (progestogen) is a first-line therapy. It comes in different forms and includes the hormonal coil (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,[54] 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.[54]

Combined estrogren-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.[1] However, evidence from randomized controlled trials is limited. A 2018 Cochrane review found insufficient evidence to assess their effectiveness compared with placebo or other medical treatments, largely due to the small number of eligible studies.[55]

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.[56] 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][56]

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][57] 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 ovaries. Evidence is limited.[1]

Pain medication

NSAIDs like naproxen are anti-inflammatory medications commonly used for endometriosis pain.[58] They are first-line treatments and can work well for mild pain.[1][51] 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.[59]

Surgery

See also: Endometrioma § Surgery

Clinical guidelines recommend surgery when medical treatment does not work sufficiently, has unacceptable side effects or is contraindicated. 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.[60] The removal takes place via excision (cutting out) or electrosurgery (coagulation or ablation/vaporization).[61][62] 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.[63]

Two literature reviews have compared excision to ablation. A 2017 literature review found that excision improved some outcomes over 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.[64] 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.[65]

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.[2][1]

For deep endometriosis, surgery improves quality of life and pain symptoms.[66] However, the procedure can be complicated, especially if the lesions are in or near the bowel, ureter of the urinary system or the chest, and requires an interdisciplinary surgical team in those cases. For instance, for rectovaginal endometriosis, 7% of surgeries had complications.[1] When endometriosis involves the bowel or bladder, part of the affected organ may be removed.[67][68]

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.[69][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.[2] At a median follow-up of 18 months, 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.[62]

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][70]

Treatment of infertility

Main article: Endometriosis and infertility

Infertility can be treated with assistive reproductive technology (ART) such as in vitro fertilization (IVF) or surgery.[71] IVF procedures are effective in improving fertility in many individuals 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.[72] It does not increase recurrence of endometriosis.[73] The Endometriosis Fertility Index can help guide decisions on treatment of infertility.[74] Surgery is typically not recommended before starting ART.[75]

In terms of surgery, endometriomas can be cut out (a cystectomy), or drained and destroyed (ablation). The ablation technique may be better able to preserve the number of remaining viable eggs (the ovarian reserve), compared to cutting out the endometrioma.[76] On the other hand, cutting out the endometrioma may help more with pain.[72] Surgery likely also helps with infertility in the case of superficial peritoneal endometriosis.[1] Receiving hormonal suppression therapy after surgery might be help with endometriosis recurrence and pregnancy,[77] but evidence for pregnancy outcomes is mixed[78] and the both NICE and the European Society of Human Reproduction and Embryology recommend against hormonal suppression to improve fertility.[78][79]

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.[80] The disease does not always worsen over time; in repeat surgeries, endometriosis became worse in 29%, improved in 42% and stayed the same in 29%.[2]

Around 70% of people see initial improvements with medical therapy, but the drugs can lose their effectiveness over time.[81] The likelihood of symptoms returning after surgery is highly variable, with studies reporting 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.[80]

Epidemiology

Endometriosis is commonly reported to affect approximately 10% of women of reproductive age.[1] Worldwide, an estimated 176–190 million girls and women are affected,[82][83] with around 22 million having a diagnosis confirmed surgically as of 2021.[82] 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.[83] 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]

It is most diagnosed when women are in their 30s, but symptoms typically start in early 20s or in adolescence.[1] People can develop endometriosis symptoms before their first period and in menopause too.[83] The condition is more commonly diagnosed in women of East Asian and Southeast Asian descent than in White women,[24] and less often in Black women. It is possible this reflect health inequities, rather than true differences in prevalence.[81]

History

The earliest references to what may have been endometriosis are from Ancient Egypt, nearly 4,000 years ago.[85] In Ancient Greece, the Hippocratic Corpus outlines symptoms similar to endometriosis, including adhesions, and infertility.[86] 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. The now discredited diagnosis of hysteria may have been endometriosis in many cases.[87]

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,[88] even though other authors consider it more likely he was describing malignant tissue.[89] Around 1896, Thomas Cullen and others described endometriosis and adenomyosis under the single name adenomyomas. Between 1903 and 1920, Cullen showed that the tissue in adenomyomas was endometrial.[90] John A. Sampson defined endometriosis. He studied its pathogenesis and was the first to propose the theory of retrograde menstruation as a cause. He also suggested that endometrial tissue could be inadvertently transplanted during surgery, such as a cesarean section. During operations, he observed that endometriotic lesions would bleed in sync with a woman's menstrual cycle.[89]

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).[91] In the 1940s, the only available hormonal therapies for endometriosis were high-dose testosterone and high-dose estrogen therapy.[92] 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.[91]

Pseudopregnancy (high-dose estrogen–progestogen therapy) for endometriosis was first described by Kistner and Andrews in the late 1950s, and become widely employed.[91] Danazol, was first described for endometriosis in 1971.[93] It was used for some 40 years, but had masculizing side effects, including weight gain, excessive body hair growth and shrinking of breasts.[94] 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 they were slow to act.[95] Oral fast-acting GnRH antagonists such as elagolix were introduced for endometriosis in 2018.[95][96]

Society and culture

Stigma and medical culture

Endometriosis is affected by multiple forms of stigma related to fertility, pain and menstruation, contributing to patient dismissal, delayed diagnosis, and adverse mental health outcomes.[97] Menstrual stigma contributes by discouraging discussion among peers and by casting doubt on accounts of period pain.[97][98] There can also be stigma around painful sex.[99] Cultural norms can reinforce these barriers. In India, unmarried women are often not offered a transvaginal ultrasound, because taboos about sex before marriage and cultural ideas about virginity produce anxiety about vaginal penetration of any kind. In other countries, women who are unmarried, have unperforated hymens, or not sexually active may also be denied transvaginal ultrasounds due to similar beliefs. This causes delays in diagnosis.[100][101][102][103][104]

Race and ethnicity can impact how endometriosis affects one's life. For instance, the stereotype that black women have a higher pain threshold may reduce quality of care.[105] Cultural attitudes also play a role; in a 2020 Puerto Rican study, stigma led to endometriosis pain being dismissed as "changuería" or "changas" by friends and family, local terms for whining or complaining, often directed at children.[106]

Further barriers come from outdated standards for laparoscopic evaluation and lack of understanding of the disease.[99] Healthcare providers sometimes dismiss described symptoms as normal menstruation, or psychologize the issue.[97] Menstrual disorders generally do not get covered extensively in medical education, leading to gaps in knowledge of healthcare professionals.[107]

Economic burden

The economic burden of endometriosis is substantial.[108] 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.[109] Surgery is the main component of medical cost.[108] Costs vary greatly between countries.[110] 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 patient.[108] Some women are unable to work due to endometriosis: a survey of Puerto Rican women showed a 20% absence from work,[111] whereas a survey of Swedish patients found that 32% did not work.[112]

Research funding

Like many conditions mainly affecting women, endometriosis is underfunded in relation to its disease burden.[113] For example, in the US, the NIH spends 5 to 10 times less on endometriosis research than on other conditions, relative to the number of healthy life years lost to each disease.[114] In the EU, endometriosis got significantly less funding than 9 comparator conditions, including psoriasis and male infertility.[115]

Research directions

A priority area of research is the search for endometriosis biomarkers, which can help with earlier diagnoses.[116] 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 cannot be used on its own. MicroRNAs might be most promising, but levels are not consistent among studies, making them a challenging target.[117]

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.[118]

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