the pathophysiology of endometriosis is likely to be multifactorial and to involve an interplay between several factors. formation the main theories for the formation of the ectopic endometrium-like tissue include retrograde menstruation, müllerianosis, coelomic metaplasia, vascular dissemination of stem cells, and surgical transplantation were postulated as early as 1870. each is further described below. retrograde menstruation theory the theory of retrograde menstruation (also called the implantation theory or transplantation theory) is the most commonly accepted theory for the dissemination and transformation of ectopic endometrium into endometriosis. it suggests that during a woman's menstrual flow, some of the endometrial debris flow backward through the fallopian tubes and into the peritoneal cavity, attaching itself to the peritoneal surface (the lining of the abdominal cavity) where it can proceed to invade the tissue as or transform into endometriosis. it is not clear at what stage the transformation of endometrium, or any cell of origin such as stem cells or coelomic cells (see those theories below), to endometriosis begins. proofs in support of the theory are based on retrospective epidemiological studies that an association with endometrial implants attached to the peritoneal cavity, which would develop into endometrial lesions and retrograde menstruation; and the fact that animals like rodents and non-human primates whose endometrium is not shed during the estrous cycle don't develop naturally endometriosis contrary to animals that have a natural menstrual cycle like rhesus monkeys and baboons. retrograde menstruation alone is not able to explain all instances of endometriosis, and additional factors such as genetics, immunology, stem cell migration, and coelomic metaplasia (see "other theories" on this page) are needed to account for disseminated disease and why many individuals with retrograde menstruation are not diagnosed with endometriosis. in addition, endometriosis has shown up in people who have never experienced menstruation including cisgender men, fetuses, and prepubescent girls. further theoretical additions are needed to complement the retrograde menstruation theory to explain why cases of endometriosis show up in the brain and lungs. this theory has numerous other associated issues. researchers are investigating the possibility that the immune system may not be able to cope with the cyclic onslaught of retrograde menstrual fluid. in this context there is interest in studying the relationship of endometriosis to autoimmune disease, allergic reactions, and the impact of toxic materials. it is still unclear what, if any, causal relationship exists between toxic materials or autoimmune disease and endometriosis. there are immune system changes in people with endometriosis, such as an increase of macrophage-derived secretion products, but it is unknown if these are contributing to the disorder or are reactions from it. endometriotic lesions differ in their biochemistry, hormonal response, immunology, inflammatory response when compared to endometrium. this is likely because the cells that give rise to endometriosis are a side population of cells. similarly, there are changes in, for example, the mesothelium of the peritoneum in people with endometriosis, such as loss of tight junctions, but it is unknown if these are causes or effects of the disorder. in rare cases where imperforate hymen does not resolve itself prior to the first menstrual cycle and goes undetected, blood and endometrium are trapped within the uterus until such time as the problem is resolved by surgical incision. many health care practitioners never encounter this defect, and due to the flu-like symptoms it is often misdiagnosed or overlooked until multiple menstrual cycles have passed. by the time a correct diagnosis has been made, endometrium and other fluids have filled the uterus and fallopian tubes with results similar to retrograde menstruation resulting in endometriosis. the initial stage of endometriosis may vary based on the time elapsed between onset and surgical procedure. the theory of retrograde menstruation as a cause of endometriosis was first proposed by john a. sampson. other theories stem cells: endometriosis may arise from stem cells from bone marrow and potentially other sources. in particular, this theory explains endometriosis found in areas remote from the pelvis such as the brain or lungs. stem cells may be from local cells such as the peritoneum (see coelomic metaplasia below) or cells disseminated in the blood stream (see vascular dissemination below) such as those from the bone marrow. vascular dissemination: vascular dissemination is a 1927 theory that has been revived with new studies of bone-marrow stem cells involved in pathogenesis. environment: environmental toxins (e.g., dioxin, nickel) may cause endometriosis. toxins such as dioxins and dioxin-like compounds tend to bioaccumulate within the human body. further research is needed but "it is plausible that inflammatory-like processes, caused by dioxin-like environmental chemicals, can alter normal endometrial and immune cell physiology allowing persistence and development of endometrial tissue within the peritoneal cavity, normally cleared by immune system cells". müllerianosis: a theory supported by foetal autopsy is that cells with the potential to become endometrial, which are laid down in tracts during embryonic development called the female reproductive (müllerian) tract as it migrates downward at 8–10 weeks of embryonic life, could become dislocated from the migrating uterus and act like seeds or stem cells. coelomic metaplasia: coelomic cells which are the common ancestor of endometrial and peritoneal cells may undergo metaplasia (transformation) from one type of cell to the other, perhaps triggered by inflammation. vasculogenesis: up to 37% of the microvascular endothelium of ectopic endometrial tissue originates from endothelial progenitor cells, which result in de novo formation of microvessels by the process of vasculogenesis rather than the conventional process of angiogenesis. neural growth: an increased expression of new nerve fibres is found in endometriosis but does not fully explain the formation of ectopic endometriotic tissue and is not definitely correlated with the amount of perceived pain. autoimmune: graves disease is an autoimmune disease characterized by hyperthyroidism, goiter, ophthalmopathy, and dermopathy. people with endometriosis had higher rates of graves disease. one of these potential links between graves disease and endometriosis is autoimmunity. oxidative stress: influx of iron is associated with the local destruction of the peritoneal mesothelium, leading to the adhesion of ectopic endometriotic cells. peritoneal iron overload has been suggested to be caused by the destruction of erythrocytes, which contain the iron-binding protein hemoglobin, or a deficiency in the peritoneal iron metabolism system. oxidative stress activity and reactive oxygen species (such as superoxide anions and peroxide levels) are reported to be higher than normal in people with endometriosis. oxidative stress and the presence of excess ros can damage tissue and induce rapid cellular division. mechanistically, there are several cellular pathways by which oxidative stress may lead to or may induce proliferation of endometriotic lesions, including the mitogen activated protein (map) kinase pathway and the extracellular signal-related kinase (erk) pathway. activation of both of the map and erk pathways lead to increased levels of c-fos and c-jun, which are proto-oncogenes that are associated with high-grade lesions. localization possible locations of endometriosis most often, endometriosis is found on the: ovaries fallopian tubes tissues that hold the uterus in place (ligaments) outer surface of the uterus less common pelvic sites are: vagina cervix vulva bowel bladder rectum endometriosis may spread to the cervix and vagina or to sites of a surgical abdominal incision, known as "scar endometriosis." rectovaginal or bowel endometriosis affects approximately 5-12% of those with endometriosis, and can cause severe pain with bowel movements. deep infiltrating endometriosis (die) has been defined as the presence of endometrial glands and stroma infiltrating more than 5 mm in the subperitoneal tissue. the prevalence of die is estimated to be 1 to 2% in women of reproductive age. deep endometriosis typically presents as a single nodule in the vesicouterine fold or in the lower 20 cm of the bowel. deep endometriosis can be associated with severe pain. however, it can be present without severe levels of pain. extrapelvic endometriosis rarely, endometriosis appears in extrapelvic parts of the body, such as the lungs, brain, and skin. "scar endometriosis" can occur in surgical abdominal incisions. risk factors for scar endometriosis include previous abdominal surgeries, such as a hysterotomy or cesarean section, or ectopic pregnancies, salpingostomy puerperal sterilization, laparoscopy, amniocentesis, appendectomy, episiotomy, vaginal hysterectomies, and hernia repair. endometriosis may also present with skin lesions in cutaneous endometriosis. less commonly lesions can be found on the diaphragm or lungs. diaphragmatic endometriosis is rare, almost always on the right hemidiaphragm, and may inflict the cyclic pain of the right scapula (shoulder) or cervical area (neck) during a menstrual period. pulmonary endometriosis can be associated with a thoracic endometriosis syndrome that can include catamenial (occurs during menstruation) pneumothorax seen in 73% of women with the syndrome, catamenial hemothorax in 14%, catamenial hemoptysis in 7%, and pulmonary nodules in 6%. diagnosis laparoscopic image of endometriotic lesions in the pouch of douglas and on the right sacrouterine ligament a health history and a physical examination can lead the health care practitioner to suspect endometriosis. there is a clear benefit for undergoing an ultrasound diagnostic procedure (tvus) as a first step of testing for endometriosis. for many patients, there are significant delays in diagnosis. studies show an average delay of 11.7 years in the united states. patients in the uk have an average delay of 8 years and in norway of 6.7 years. a third of women had consulted their gp six or more times before being diagnosed. the most common sites of endometriosis are the ovaries, followed by the douglas pouch, the posterior leaves of the broad ligaments, and the sacrouterine ligaments. as for deep infiltrating endometriosis, tvus, trus and mri are the techniques of choice for non-invasive diagnosis with a high sensitivity and specificity. laparoscopy transvaginal ultrasonography showing a 67 x 40 mm endometrioma as distinguished from other types of ovarian cysts by a somewhat grainy and not completely anechoic content laparoscopy, a surgical procedure where a camera is used to look inside the abdominal cavity, is the only way to accurately diagnose the extent and severity of pelvic/abdominal endometriosis. laparoscopy is not an applicable test for extrapelvic sites such as umbilicus, hernia sacs, abdominal wall, lung, or kidneys. reviews in 2019 and 2020 concluded that 1) with advances in imaging, endometriosis diagnosis should no longer be considered synonymous with immediate laparoscopy for diagnosis, and 2) endometriosis should be classified a syndrome that requires confirmation of visible lesions seen at laparoscopy in addition to characteristic symptoms. laparoscopy permits lesion visualization unless the lesion is visible externally (e.g., an endometriotic nodule in the vagina) or is extra-abdominal. if the growths (lesions) are not visible, a biopsy must be taken to determine the diagnosis. surgery for diagnoses also allows for surgical treatment of endometriosis at the same time. during a laparoscopic procedure lesions can appear dark blue, powder-burn black, red, white, yellow, brown or non-pigmented. lesions vary in size. some within the pelvis walls may not be visible, as normal-appearing peritoneum of infertile women reveals endometriosis on biopsy in 6–13% of cases. early endometriosis typically occurs on the surfaces of organs in the pelvic and intra-abdominal areas. health care providers may call areas of endometriosis by different names, such as implants, lesions, or nodules. larger lesions may be seen within the ovaries as endometriomas or "chocolate cysts", "chocolate" because they contain a thick brownish fluid, mostly old blood. frequently during diagnostic laparoscopy, no lesions are found in individuals with chronic pelvic pain, a symptom common to other disorders including adenomyosis, pelvic adhesions, pelvic inflammatory disease, congenital anomalies of the reproductive tract, and ovarian or tubal masses. ultrasound vaginal ultrasound can be used to diagnosis endometriosis, or for localizing endometrioma before surgury. this can be used to identify the spread of disease in individuals with well-established clinical suspicion of endometriosis. vaginal ultrasound is inexpensive, easily accessible, has no contraindications and requires no preparation. by extending the ultrasound assessment into the posterior and anterior pelvic compartments a sonographer is able to evaluate structural mobility and look for deep infiltrating endometriotic nodules. better sonographic detection of deep infiltrating endometriosis could reduce the number of diagnostic laparoscopies, as well as guide disease management and enhance patient quality of life. magnetic resonance imaging mri is another means of detecting lesions in a non-invasive manner. mri is not widely used due to its cost and limited availability, although it can be used to detect the most common form of endometriosis (endometrioma) with a sufficient accuracy. it is recommended for the patient to receive an anti-spasmodic agent(i.e.