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Endometriosis

Endometriosis is a disease in which cells like those in the endometrium, the layer of tissue that normally covers the inside of the uterus, grow outside the uterus. It occurs in humans and a limited number of menstruating mammals. Lesions can be found on ovaries, fallopian tubes, tissue around the uterus and ovaries (peritoneum), intestines, bladder, and diaphragm; and may also occur in other parts of the body. Symptoms include pelvic pain, heavy and painful periods, pain with bowel movements, painful urination, pain during sexual intercourse and infertility. Nearly half of those affected have chronic pelvic pain, while 70% feel pain during menstruation. Up to half of affected individuals are infertile. About 25% of individuals have no symptoms and 85% of those seen with infertility in a tertiary center have no pain. Endometriosis can have both social and psychological effects.

Diagnosis is usually based on symptoms and medical imaging; however, a definitive diagnosis is made through laparoscopy and biopsy. Other causes of similar symptoms include pelvic inflammatory disease, irritable bowel syndrome, interstitial cystitis, and fibromyalgia. Endometriosis is often misdiagnosed and many patients report being incorrectly told their symptoms are trivial or normal. Patients with endometriosis see an average of seven physicians before receiving a correct diagnosis, with an average delay of 6.7 years between the onset of symptoms and surgically obtained biopsies, the gold standard for diagnosing the condition. This places endometriosis at the extreme end of diagnostic inefficiency.

Nearly 11 million women were affected by endometriosis, globally, in 2015. Other sources estimate 6 to 10% of the general female population might have endometriosis. Ethnic differences have been observed in endometriosis, as Southeast Asian and East Asian women are significantly more likely than White women to be diagnosed with endometriosis.

The main cause of endometriosis is exposure to elevated levels of the female sex hormone estrogen, as well as estrogen receptor sensitivity. Estrogen exposure worsens the inflammatory symptoms of endometriosis by stimulating an immune response.

While there is no cure for endometriosis, several treatments may improve symptoms. This may 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 active component of the birth control pill continuously or using an intrauterine device with progestogen may also be useful. Gonadotropin-releasing hormone agonist (GnRH agonist) may improve the ability of those who are infertile to conceive. Surgical removal of endometriosis may be used to treat those whose symptoms are not manageable with other treatments.

Signs and symptoms
Pain and infertility are common symptoms, although 20–25% of affected women are asymptomatic. Presence of pain symptoms are associated with the type of endometrial lesions as 50% of women with typical lesions, 10% of women with cystic ovarian lesions, and 5% of women with deep endometriosis do not have pain.

Pelvic pain
A major symptom of endometriosis is recurring pelvic pain. The pain can range from mild to severe cramping or stabbing pain that occurs on both sides of the pelvis, in the lower back and rectal area, and even down the legs. The amount of pain a person feels correlates weakly with the extent or stage (1 through 4) of endometriosis, with some individuals having little or no pain despite having extensive endometriosis or endometriosis with scarring, while others may have severe pain even though they have only a few small areas of endometriosis. The most severe pain is typically associated with menstruation. Pain can also start a week before a menstrual period, during and even a week after a menstrual period, or it can be constant. The pain can be debilitating and result in emotional stress. Symptoms of endometriosis-related pain may include:
 * Dysmenorrhea (64%) – painful, sometimes disabling cramps during the menstrual period; pain may get worse over time (progressive pain), also lower back pains linked to the pelvis
 * Chronic pelvic pain – typically accompanied by lower back pain or abdominal pain
 * Dyspareunia – painful sexual intercourse
 * Dysuria – urinary urgency, frequency, and sometimes painful voiding
 * Mittelschmerz – pain associated with ovulation
 * Bodily movement pain – present during exercise, standing, or walking

Compared with patients with superficial endometriosis, those with deep disease appear to be more likely to report shooting rectal pain and a sense of their insides being pulled down. Individual pain areas and pain intensity appear to be unrelated to the surgical diagnosis, and the area of pain unrelated to the area of endometriosis.

There are multiple causes of pain. Endometriosis lesions react to hormonal stimulation and may "bleed" during menstruation. The blood accumulates locally if it is not cleared shortly by the immune, circulatory, and lymphatic systems. This accumulation can lead to swelling, which triggers inflammation with the activation of cytokines, resulting in pain. Another source of pain is organ dislocation that arises from adhesion binding internal organs together. The ovaries, the uterus, the oviducts, the peritoneum, and the bladder can all be bound together. Pain triggered in this way can last throughout the menstrual cycle, not just during menstrual periods.

Additionally, endometriotic lesions can develop their own nerve supply, creating a direct and two-way interaction between lesions and the central nervous system. This interaction can produce a variety of individual differences in pain that, in some cases, become independent of the disease itself. Nerve fibers and blood vessels are thought to grow into endometriosis lesions by a process known as neuroangiogenesis.

Infertility
About a third of women with infertility have endometriosis. Among those with endometriosis, about 40% are infertile. The pathogenesis of infertility varies by disease stage: in early-stage disease, it is hypothesised to result from an inflammatory response that impairs various aspects of conception, whereas in later stages, distorted pelvic anatomy and adhesions contribute to impaired fertilisation.

Other
Other symptoms include diarrhea or constipation, chronic fatigue, nausea and vomiting, migraines, low-grade fevers, heavy (44%) and/or irregular periods (60%), and hypoglycemia. Endometriosis is associated with certain types of cancers, notably some types of ovarian cancer, non-Hodgkin's lymphoma and brain cancer. Endometriosis is however unrelated to endometrial cancer.

Rarely, endometriosis can cause endometrium-like tissue to be found in other parts of the body. Thoracic endometriosis occurs when endometrium-like tissue implants in the lungs or pleura. Manifestations of this include coughing up blood, a collapsed lung, or bleeding into the pleural space. Endometriosis may also affect the nearby colon which in rare situations may progress to partial obstruction requiring emergency surgery.

Stress may be a contributing factor or a consequence of endometriosis.

Physical health
Complications of endometriosis include internal scarring, adhesions, pelvic cysts, ovarian chocolate cysts, ruptured cysts, and bowel and ureter obstruction resulting from pelvic adhesions. Endometriosis-associated infertility may result from scar formation and anatomical distortions caused by the condition.

Ovarian endometriosis may complicate pregnancy through decidualization, abscess formation and/or rupture.

Thoracic endometriosis can be associated with recurrent thoracic endometriosis syndrome which manifests during menstrual periods. It includes catamenial pneumothorax in 73% of women, catamenial hemothorax in 14%, catamenial hemoptysis in 7%, and pulmonary nodules in 6%.

A 20-year study involving 12,000 women with endometriosis found that individuals under 40 are three times more likely to develop heart problems compared to their healthy peers.

Results of a 30-year study of reproductive and pregnancy outcomes, which included over 14,000+ women of child-bearing age, were presented at the 2015 European Society of Human Reproduction and Embryology (ESHRE) annual congress. The study indicated that 39% of women with surgically confirmed non-graded endometriosis had a 270% higher risk for ectopic pregnancy and a 76% higher risk for miscarriage compared to their peers. For women with deep endometriosis (>5 mm invasion, ASRM Stage II and higher), the risk of miscarriage increased to 298%.

Women with endometriosis also face a significantly increased risk of experiencing ante- and postpartum hemorrhage as well as a 170% increased risk of severe pre-eclampsia during pregnancy.

Endometriosis slightly increases the risk (about 1% or less) of developing ovarian, breast and thyroid cancers compared to women without the condition.

The mortality rates associated with endometriosis are low, with unadjusted and age-standardized death rates of 0.1 and 0.0 per 100,000, respectively.

Sciatic endometriosis also called catamenial or cyclical sciatica ,is a rare form where endometriosis affects the sciatic nerve. Diagnosis is usually confirmed through MRI or CT-myelography.

Endometriosis can also impact a woman's fetus or neonate, increasing the risks for congenital malformations, preterm delivery and higher neonatal death rates.

Mental health
"Endometriosis is associated with an elevated risk of developing depression and anxiety disorders". Studies suggest this is partially due to the pelvic pain experienced by endometriosis patients. "'It has been demonstrated that pelvic pain has significant negative effects on women's mental health and quality of life; in particular, women who suffer from pelvic pain report high levels of anxiety and depression, loss of working ability, limitations in social activities and a poor quality of life'"

Genetics
Endometriosis is a heritable condition influenced by both genetic and environmental factors, a genetic disorder of polygenic/multifactorial inheritance acquired via affected genes from either a person's father or mother. For example, children or siblings of women with endometriosis are at higher risk of developing endometriosis themselves; low progesterone levels may be genetic, and may contribute to a hormone imbalance. Individuals with an affected first-degree relative have an approximate six-fold increase incidence of endometriosis.

Inheritance is significant, but not the sole risk factor for endometriosis. Studies attribute 50% of risk to genetics, the other 50% likely to environmental factors. It has been proposed that endometriosis may result from a series of multiple mutations, within target genes, in a mechanism similar to the development of cancer. In this case, the mutations may be either somatic or heritable.

A 2019 genome-wide association study (GWAS) review enumerated 36 genes with mutations associated with endometriosis development. Nine chromosome loci were robustly replicated: There are many findings of altered gene expression and epigenetics, but both of these can also be a secondary result of, for example, environmental factors and altered metabolism. Examples of altered gene expression include that of miRNAs.

Environmental toxins
Some factors associated with endometriosis include:
 * Prolonged exposure to naturally synthesized estrogen; for example, from late menopause or early menarche
 * Obstruction of menstrual outflow; for example, in Müllerian anomalies

Potential toxins:
 * Dioxins- Several studies have investigated the potential link between exposure to dioxins and endometriosis, but evidence is equivocal and potential mechanisms are poorly understood. A 2004 review of studies of dioxin and endometriosis concluded that "the human data supporting the dioxin-endometriosis association are scanty and conflicting", and a 2009 follow-up review also found that there was "insufficient evidence" in support of a link between dioxin exposure and developing endometriosis.
 * Endocrine-disrupting chemicals (EDCs)- A wider class of hormonally active agents, to which dioxin belongs, consists of both natural and manmade compounds, e.g., bisphenols, phthalates, pesticides (chlorpyrifos, hexachlorobenzene) and polychlorinated biphenyls (PCBs). Dietary uptake represents a significant source of EDC exposure via consumption of food, water and beverages, but exposure can also occur through ingestion of EDC dust and inhalation of its gases or particles in the air. Most EDCs are lipophilic, allowing them to bioaccumulate in adipose tissue (body fat) and increase in concentration. Bisphenol A (BPA), bisphenol S (BPS), phthalates, pesticides and PCBs all have a suspected linkage to endometriosis, though have not been definitively proven as being causative.

Vaginal dysbiosis
A growing body of evidence has shown a correlation between an imbalance in the vaginal microbiome and the appearance of endometriosis. This correlation is mediated by an immune system overload in the context of retrograde menstruation, in which it fails to detect and kill cells that come outside of the vaginal environment. By disrupting normal immune function, dysbiosis leads to elevated levels of proinflammatory cytokines, a compromised immunosurveillance system and altered immune cell profiles. Indeed, the activation of Toll-like receptors in macrophages leads to a greater activity of this immune cell type. They, in turn, secrete factors (such as the pro-inflammatory cytokine interleukin 8) that help creating an inflammatory environment, ultimately favoring the proliferation and adhesion of endometrial cells.

Pathophysiology
While the exact cause of endometriosis remains unknown, many theories have been presented to better understand and explain its development. These concepts do not necessarily exclude each other. The pathophysiology of endometriosis is likely to be multifactorial and to involve an interplay between several factors.

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.

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 (ROS) (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
Most often, endometriosis is found on the: Less common pelvic sites are:
 * Ovaries
 * Fallopian tubes
 * Tissues that hold the uterus in place (ligaments)
 * Outer surface of the uterus
 * 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.

Male endometriosis
Endometriosis has been reported in people assigned male at birth. Prostate endometriosis has been reported following estrogen therapy for prostate cancer and feminizing hormone therapy.

Abdominal endometriosis also happens in men following cirrhosis.

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
A health history and a physical examination can lead the health care practitioner to suspect endometriosis. There is a clear benefit for performing a transvaginal ultrasound (TVUS) as a first step of testing for endometriosis.

Definitive diagnosis is based on the morphology (form and structure) of the pelvic region, determined by observation (surgical or non-invasive imaging), classified into four different stages of endometriosis. The American Society of Reproductive Medicine's scale, revised in 1996, gives higher scores to deep, thick lesions or intrusions on the ovaries and dense, enveloping adhesions on the ovaries or fallopian tubes. Additionally, histological studies, when performed, should show specific findings.

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
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 surgery. 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. A 2020 article recommended administering an anti-spasmodic agent (i.e. hyoscine butylbromide) and a big glass of water (if the bladder is empty), and scanning in the supine position with an abdominal strap, for better image quality. It also recommended using pelvic-phased array coils and T1 (spin-lattice) weighted scanning, with and without suppression of fat for endometriomas, and sagittal, axial and oblique 2D T2 (spin-spin) weighting for deep infiltrating endometriosis.

Stages of disease
By surgical observation, endometriosis can be classified as stage I–IV by the 1996 scale of the American Society of Reproductive Medicine (ASRM). The scale uses a point system that assesses lesions and adhesions in the pelvic organs. It is important to note that staging assesses physical disease only, not the level of pain or infertility. A person with Stage I endometriosis may have a little disease and severe pain, while a person with Stage IV endometriosis may have severe disease and no pain or vice versa. The various stages are summarized by:

Stage I (Minimal)
 * Findings restricted to only superficial lesions and possibly a few filmy adhesions.

Stage II (Mild)
 * In addition, some deep lesions are present in the cul-de-sac.

Stage III (Moderate)
 * As above, plus the presence of endometriomas on the ovary and more adhesions.

Stage IV (Severe)
 * As above, plus large endometriomas, extensive adhesions. Implants and adhesions may be found beyond the uterus. Large ovarian cysts are common.

Markers
An area of research is the search for endometriosis markers.

In 2010, essentially all proposed biomarkers for endometriosis were of unclear medical use, although some appear to be promising. The one biomarker that has been in use over the last 20 years is CA-125. A 2016 review found that this biomarker was present in those with symptoms of endometriosis; and, once ovarian cancer has been ruled out, a positive CA-125 may confirm the diagnosis. Its performance in ruling out endometriosis is low. CA-125 levels appear to fall during endometriosis treatment, but it has not shown a correlation with disease response.

Another review in 2011 identified several putative biomarkers upon biopsy, including findings of small sensory nerve fibers or defectively expressed β3 integrin subunit. It has been postulated a future diagnostic tool for endometriosis will consist of a panel of several specific and sensitive biomarkers, including both substance concentrations and genetic predisposition.

A 2016 review of endometrial biomarkers for diagnosing endometriosis was unable to draw conclusions due to the low quality of the evidence.

MicroRNAs have the potential to be used in diagnostic and therapeutic decisions.

Histopathology
For a histopathological diagnosis, at least two of the following three criteria should be present:
 * Endometrial type stroma
 * Endometrial epithelium with glands
 * Evidence of chronic hemorrhage, mainly hemosiderin deposits

Immunohistochemistry has been found to be useful in diagnosing endometriosis as stromal cells have a peculiar surface antigen, CD10, thus allowing the pathologist go straight to a staining area and confirm the presence of stromal cells and sometimes glandular tissue is identified that was missed on routine H&E staining.

Pain quantification
The most common pain scale for quantification of endometriosis-related pain is the visual analogue scale (VAS); VAS and numerical rating scale (NRS) were the best adapted pain scales for pain measurement in endometriosis. For research purposes, and for more detailed pain measurement in clinical practice, VAS or NRS for each type of typical pain related to endometriosis (dysmenorrhea, deep dyspareunia and non-menstrual chronic pelvic pain), combined with the clinical global impression (CGI) and a quality of life scale, are used.

Prevention
Limited evidence indicates that the use of combined oral contraceptives is associated with a reduced risk of endometriosis, as is regular exercise and the avoidance of alcohol and caffeine. There is little known information on preventing endometriosis.

Management
While there is no cure for endometriosis, there are two types of interventions; treatment of pain and treatment of endometriosis-associated infertility. In many cases, menopause (natural or surgical) will abate the process. In the reproductive years, endometriosis is merely managed: the goal is to provide pain relief, to restrict progression of the process, and to restore or preserve fertility where needed. In younger individuals, some surgical treatment attempts to remove endometriotic tissue and preserve the ovaries without damaging normal tissue.

Pharmacotherapy for pain management can be initiated based on the presence of symptoms and examination and ultrasound findings that rule out other potential causes.

In general, the diagnosis of endometriosis is confirmed during surgery, at which time removal can be performed. Further steps depend on circumstances: someone without infertility can manage symptoms with pain medication and hormonal medication that suppresses the natural cycle, while an infertile individual may be treated expectantly after surgery, with fertility medication, or with in vitro fertilisation (IVF).

A 2020 Cochrane systematic review found that for all types of endometriosis, "it is uncertain whether laparoscopic surgery improves overall pain compared to diagnostic laparoscopy".

Surgery
Based on strong evidence, experts recommend that surgery be performed laparoscopically (through keyhole surgery) rather than open. Treatment consists of the ablation or excision of the endometriosis, electrocoagulation, lysis of adhesions, resection of endometriomas, and restoration of normal pelvic anatomy as much as is possible. When laparoscopic surgery is used, small instruments are inserted through the incisions to remove the endometriosis tissue and adhesions. Because the incisions are very small, there will only be small scars on the skin after the procedure, and most individuals recover from surgery quickly and have a reduced risk of adhesions. Many endometriosis specialists believe that excision is the ideal surgical method to treat endometriosis. A 2017 literature review found excision improved some outcomes over ablation. 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.

As for deep endometriosis, a segmental resection or shaving of nodules is effective but is associated with an increased rate of complications, of which about 4.6% are major.

Historically, a hysterectomy (removal of the uterus) was thought to be a cure for endometriosis in individuals who do not wish to conceive. Removal of the uterus may be beneficial as part of the treatment, if the uterus itself is affected by adenomyosis. However, this should only be done in combination with removal of the endometriosis by excision. If endometriosis is not also removed at the time of hysterectomy, pain may persist. A study of hysterectomy patients found those with endometriosis were not using less pain medication 3 years after the procedure.

Presacral neurectomy may be performed where the nerves to the uterus are cut. However, this technique is not usually used due to the high incidence of associated complications including presacral hematoma and irreversible problems with urination and constipation.

Recurrence
The underlying process that causes endometriosis may not cease after a surgical or medical intervention. A study has shown that dysmenorrhea recurs at a rate of 30 percent within a year following laparoscopic surgery. Resurgence of lesions tend to appear in the same location if the lesions were not completely removed during surgery. It has been shown that laser ablation resulted in higher and earlier recurrence rates when compared with endometrioma cystectomy; and recurrence after repetitive laparoscopy was similar to that after the first surgery. Endometriosis has a 10% recurrence rate after hysterectomy and bilateral salpingo-oophorectomy.

Endometriosis recurrence following conservative surgery is estimated as 21.5% at 2 years and 40-50% at 5 years.

Recurrence rate for DIE after surgery is less than 1%.

Risks and safety of pelvic surgery
Risk of developing complications following surgery depend on the type of the lesion that has undergone surgery. 55% to 100% of individuals develop adhesions following pelvic surgery, which can result in infertility, chronic abdominal and pelvic pain, and difficult reoperative surgery. Trehan's temporary ovarian suspension, a technique in which the ovaries are suspended for a week after surgery, may be used to reduce the incidence of adhesions after endometriosis surgery. Removal of cysts on the ovary without removing the ovary is a safe procedure.

Hormonal medications

 * Hormonal birth control therapy: Birth control pills reduce the menstrual pain and recurrence rate for endometrioma following conservative surgery for endometriosis. A 2018 Cochrane systematic review found that there is insufficient evidence to make a judgement on the effectiveness of the combined oral contraceptive pill compared with placebo or other medical treatment for managing pain associated with endometriosis partly because of lack of included studies for data analysis (only two for COCP vs placebo).
 * Progestogens: Progesterone counteracts estrogen and inhibits the growth of the endometrium. Danazol and gestrinone are suppressive steroids with some androgenic activity. Both agents inhibit the growth of endometriosis but their use has declined, due in part to virilizing side effects such as excessive hair growth and voice changes. There is tentative evidence based on cohort studies that dienogest and norethisterone acetate (NETA) may help patients with DIE in terms of pain. There is tentative evidence based on a prospective study that vaginal danazol reduces pain in those affected by DIE.
 * Gonadotropin-releasing hormone (GnRH) modulators: These drugs include GnRH agonists such as leuprorelin and GnRH antagonists such as elagolix and are thought to work by decreasing estrogen levels. A 2010 Cochrane review found that GnRH modulators were more effective for pain relief in endometriosis than no treatment or placebo, but were not more effective than danazol or intrauterine progestogen, and had more side effects than danazol. A 2018 Swedish systematic review found that GnRH modulators had similar pain-relieving effects to gestagen, but also decreased bone density.
 * Aromatase inhibitors are medications that block the formation of estrogen and have become of interest for researchers who are treating endometriosis. Examples of aromatase inhibitors include anastrozole and letrozole. Evidence for aromatase inhibitors is confirmed by numerous controlled studies that show benefit in terms of pain control and quality of life when used in combination with gestagens or oral contraceptives with less side-effects when used in combination with oral contraceptives like norethisterone acetate. Despite multiple benefits, there are lot of things to consider before using aromatase inhibitors for endometriosis, as it is common for them to induce functional cysts as an adverse effects. Moreover, dosages, treatment length, appropriate add-back therapies and mode of administration is still being investigated.
 * Progesterone receptor modulators like mifepristone and gestrinone have the potential (based on only one randomized controlled trial each) to be used as a treatment to manage pain caused by endometriosis.

Other medicines

 * Melatonin, there is tentative evidence for its use (at a dose of 10 mg) in reducing pain related to endometriosis.
 * Vitamin C and E antioxidant supplementation may significantly reduce pain symptoms in endometriosis.
 * Opioids: Morphine sulphate tablets and other opioid painkillers work by mimicking the action of naturally occurring pain-reducing chemicals called "endorphins". There are different long acting and short acting medications that can be used alone or in combination to provide appropriate pain control.
 * Chinese herbal medicine was reported to have comparable benefits to gestrinone and danazol in patients who had had laparoscopic surgery, though the review notes that the two trials were small and of "poor methodological quality" and results should be "interpreted cautiously" as better quality research is needed.
 * Serrapeptase, a digestive enzyme found in the intestines of silkworms. Serrapeptase is widely used in Japan and Europe as an anti-inflammatory treatment. More research is needed but serrapeptase may be used by endometriosis patients to reduce inflammation.
 * Angiogenesis inhibitors lack clinical evidence of efficacy in endometriosis therapy. Under experimental in vitro and in vivo conditions, compounds that have been shown to exert inhibitory effects on endometriotic lesions include growth factor inhibitors, endogenous angiogenesis inhibitors, fumagillin analogues, statins, cyclo-oxygenase-2 inhibitors, phytochemical compounds, immunomodulators, dopamine agonists, peroxisome proliferator-activated receptor agonists, progestins, danazol and gonadotropin-releasing hormone agonists. However, many of these agents are associated with undesirable side effects and more research is necessary. An ideal therapy would diminish inflammation and underlying symptoms without being contraceptive.
 * Pentoxifylline, an immunomodulating agent, has been theorized to improve pain as well as improve pregnancy rates in individuals with endometriosis. There is not enough evidence to support the effectiveness or safety of either of these uses. Current American Congress of Obstetricians and Gynecologists (ACOG) guidelines do not include immunomodulators, such as pentoxifylline, in standard treatment protocols.
 * NSAIDs are anti-inflammatory medications commonly used for endometriosis patients despite unproven efficacy and unintended adverse effects.
 * Neuromodulators like gabapentin did not prove to be superior to placebo in managing pain caused by endometriosis.

The overall effectiveness of manual physical therapy to treat endometriosis has not yet been identified.

Comparison of interventions
A 2021 meta-analysis found that GnRH analogues and combined hormonal contraceptives were the best treatment for reducing dyspareunia, menstrual and non menstrual pelvic pain. A 2018 Swedish systematic review found a large number of studies but a general lack of scientific evidence for most treatments. There was only one study of sufficient quality and relevance comparing the effect of surgery and non-surgery. Cohort studies indicate that surgery is effective in decreasing pain. Most complications occurred in cases of low intestinal anastomosis, while risk of fistula occurred in cases of combined abdominal or vaginal surgery, and urinary tract problems were common in intestinal surgery. The evidence was found to be insufficient regarding surgical intervention.

The advantages of physical therapy techniques are decreased cost, absence of major side-effects, it does not interfere with fertility, and near-universal increase of sexual function. Disadvantages are that there are no large or long-term studies of its use for treating pain or infertility related to endometriosis.

Treatment of infertility
Surgery is more effective than medicinal intervention for addressing infertility associated with endometriosis. Surgery attempts to remove endometrium-like tissue and preserve the ovaries without damaging normal tissue. Receiving hormonal suppression therapy after surgery might be positive regarding endometriosis recurrence and pregnancy. In-vitro fertilization (IVF) procedures are effective in improving fertility in many individuals with endometriosis.

During fertility treatment, the ultralong pretreatment with GnRH-agonist has a higher chance of resulting in pregnancy for individuals with endometriosis, compared to the short pretreatment.

Research
Preliminary research on mouse models showed that monoclonal antibodies, as well as inhibitors of MyD88 downstream signaling pathway, can reduce lesion volume. Thanks to that, clinical trials are being done on using a monoclonal antibody directed against IL-33 and using anakinra, an IL-1 receptor antagonist.

Promising preclinical outcomes is pushing clinical trials into testing cannabinoid extracts, dichloroacetic acid and curcuma capsules.

Epidemiology
Determining how many people have endometriosis is challenging because definitive diagnosis requires surgical visualization through laparoscopic surgery. Criteria that are commonly used to establish a diagnosis include pelvic pain, infertility, surgical assessment, and in some cases, magnetic resonance imaging. An ultrasound can identify large clumps of tissue as potential endometriosis lesions and ovarian cysts but it is not effective for all patients, especially in cases with smaller, superficial lesions.

Ethnic differences in endometriosis have been observed. The condition is more common in women of East Asian and Southeast Asian descent than in White women. Risk factors include having a family history of the condition.

One estimate is that 10.8 million people are affected globally. Other sources estimate 6 to 10% of the general female population and 2 to 11% of asymptomatic women are affected. In addition, 11% of women in a general population have undiagnosed endometriosis that can be seen on magnetic resonance imaging (MRI). Endometriosis is most common in those in their thirties and forties; however, it can begin in girls as early as eight years old. It results in few deaths with unadjusted and age-standardized death rates of 0.1 and 0.0 per 100,000. Endometriosis was first determined to be a separate condition in the 1920s. Before that time, endometriosis and adenomyosis were considered together. It is unclear who first described the disease.

It chiefly affects adults from premenarche to postmenopause, regardless of race or ethnicity or whether or not they have had children and is estimated to affect over 190 million women in their reproductive years. Incidences of endometriosis have occurred in postmenopausal individuals, and in less common cases, individuals may have had endometriosis symptoms before they even reach menarche.

The rate of recurrence of endometriosis is estimated to be 40-50% for adults over a 5-year period. The rate of recurrence has been shown to increase with time from surgery and is not associated with the stage of the disease, initial site, surgical method used, or post-surgical treatment.

History
Endometriosis was first discovered microscopically by Karl von Rokitansky in 1860, although the earliest antecedents may have stemmed from concepts published almost 4,000 years ago. The Hippocratic Corpus outlines symptoms similar to endometriosis, including uterine ulcers, adhesions, and infertility. Historically, women with these symptoms were treated with leeches, straitjackets, bloodletting, chemical douches, genital mutilation, pregnancy (as a form of treatment), hanging upside down, surgical intervention, and even killing due to suspicion of demonic possession. Hippocratic doctors recognized and treated chronic pelvic pain as a true organic disorder 2,500 years ago, but during the Middle Ages, there was a shift into believing that women with pelvic pain were mad, immoral, imagining the pain, or simply misbehaving. The symptoms of inexplicable chronic pelvic pain were often attributed to imagined madness, female weakness, promiscuity, or hysteria. The historical diagnosis of hysteria, which was thought to be a psychological disease, may have indeed been endometriosis. The idea that chronic pelvic pain was related to mental illness influenced modern attitudes regarding individuals with endometriosis, leading to delays in correct diagnosis and indifference to the patients' true pain throughout the 20th and into the 21st century.

Hippocratic doctors believed that delaying childbearing could trigger diseases of the uterus, which caused endometriosis-like symptoms. Women with dysmenorrhea were encouraged to marry and have children at a young age. The fact that Hippocratics were recommending changes in marriage practices due to an endometriosis-like illness implies that this disease was likely common, with rates higher than the 5-15% prevalence that is often cited today. If indeed this disorder was so common historically, this may point away from modern theories that suggest links between endometriosis and dioxins, PCBs, and chemicals.

The early treatment of endometriosis was surgical and included oophorectomy (removal of the ovaries) and hysterectomy (removal of the uterus). In the 1940s, the only available hormonal therapies for endometriosis were high-dose testosterone and high-dose estrogen therapy. High-dose estrogen therapy with diethylstilbestrol for endometriosis was first reported by Karnaky in 1948 and was the main pharmacological treatment for the condition in the early 1950s. Pseudopregnancy (high-dose estrogen–progestogen therapy) for endometriosis was first described by Kistner in the late 1950s. Pseudopregnancy as well as progestogen monotherapy dominated the treatment of endometriosis in the 1960s and 1970s. These agents, although efficacious, were associated with intolerable side effects. Danazol was first described for endometriosis in 1971 and became the main therapy in the 1970s and 1980s. In the 1980s GnRH agonists gained prominence for the treatment of endometriosis and by the 1990s had become the most widely used therapy. Oral GnRH antagonists such as elagolix were introduced for the treatment of endometriosis in 2018.

Public figures
A number of public figures have spoken about their experience with endometriosis, including:

 * RuthAnne
 * Emma Barnett
 * Emma Bunton
 * Alexa Chung
 * Danielle Collins
 * Olivia Culpo
 * Lena Dunham
 * Abby Finkenauer
 * Bethenny Frankel
 * Whoopi Goldberg
 * Mel Greig
 * Halsey
 * Emma Hayes
 * Julianne Hough
 * Bridget Hustwaite
 * Bindi Irwin
 * Jaime King
 * Padma Lakshmi
 * Cyndi Lauper
 * Jillian Michaels
 * Monica
 * Marilyn Monroe
 * Tia Mowry
 * Sinéad O'Connor
 * Dolly Parton
 * Daisy Ridley
 * Emma Roberts
 * Susan Sarandon
 * Amy Schumer
 * Kirsten Storms
 * Gabrielle Union
 * Lacey Schwimmer
 * Chrissy Teigen
 * Emma Watkins
 * Mae Whitman
 * Jessica Williams
 * Leah Williamson

Economic burden
The economic burden of endometriosis is widespread and multifaceted. Endometriosis is a chronic disease that has direct and indirect costs which include loss of work days, direct costs of treatment, symptom management, and treatment of other associated conditions such as depression or chronic pain. One factor which seems to be associated with especially high costs is the delay between onset of symptoms and diagnosis.

Costs vary greatly between countries. Two factors that contribute to the economic burden include healthcare costs and losses in productivity. A Swedish study of 400 endometriosis patients found "Absence from work was reported by 32% of the women, while 36% reported reduced time at work because of endometriosis". An additional cross sectional study with Puerto Rican women, "found that endometriosis-related and coexisting symptoms disrupted all aspects of women's daily lives, including physical limitations that affected doing household chores and paid employment. The majority of women (85%) experienced a decrease in the quality of their work; 20% reported being unable to work because of pain, and over two-thirds of the sample continued to work despite their pain."

Medical culture
There are a number of barriers that those affected face to receiving diagnosis and treatment for endometriosis. Some of these include outdated standards for laparoscopic evaluation, stigma about discussing menstruation and sex, lack of understanding of the disease, primary-care physicians' lack of knowledge, and assumptions about typical menstrual pain. On average, those later diagnosed with endometriosis waited 2.3 years after the onset of symptoms before seeking treatment and nearly three quarters of women receive a misdiagnosis prior to endometriosis. Self-help groups say practitioners delay making the diagnosis, often because they do not consider it a possibility. There is a typical delay of 7–12 years from symptom onset in affected individuals to professional diagnosis. There is a general lack of knowledge about endometriosis among primary care physicians. Half of general health care providers surveyed in a 2013 study were unable to name three symptoms of endometriosis. Health care providers are also likely to dismiss described symptoms as normal menstruation. Younger patients may also feel uncomfortable discussing symptoms with a physician.

Race and ethnicity
Race and ethnicity may play a role in how endometriosis affects one's life. Endometriosis is less thoroughly studied among Black people, and the research that has been done is outdated. Cultural differences among ethnic groups also contribute to attitudes toward and treatment of endometriosis, especially in Hispanic or Latino communities. A study done in Puerto Rico in 2020 found that health care and interactions with friends and family related to discussing endometriosis were affected by stigma. The most common finding was a referral to those expressing pain related to endometriosis as "changuería" or "changas", terms used in Puerto Rico to describe pointless whining and complaining, often directed at children.

Stigma
The existing stigma surrounding women's health, specifically endometriosis, can lead to patients not seeking diagnoses, lower quality of healthcare, increased barriers to care and treatment, and negative reception from members of society. Additionally, it is crucial to note that menstrual stigma significantly contributes to the broader issue of endometriosis stigma, creating an interconnected challenge that extends beyond reproductive health. Widespread awareness campaigns, developments and implementations aimed to multilevel anti-stigma organizational and structural changes, as well as more qualitative studies of the endometriosis stigma, help to overcome the harm of the phenomenon.

title: Endometriosis


text:
Pope Cornelius

Pope Cornelius (Κορνήλιος) was the bishop of Rome from 6th or 13th March 251 until his martyrdom in June 253. He was pope during and following a period of persecution of the church, while a schism occurred over how repentant church members who had practiced pagan sacrifices to protect themselves could be readmitted to the church. He agreed with Cyprian of Carthage that those who had lapsed could be restored to communion after varying forms of Reinitiation and Penance. This position was in contrast to the Novatianists, who held that those who failed to maintain their confession of faith under persecution would not be received again into communion with the church. This resulted in a short-lived schism in the Church of Rome that spread as each side sought to gather support. Cornelius held a synod that confirmed his election and excommunicated Novatian, but the controversy regarding lapsed members continued for years.

The persecutions resumed in 251 under Emperor Trebonianus Gallus. Cornelius was sent into exile and may have died from the rigours of his banishment, possibly beheaded.

Christian persecution
Emperor Decius, who ruled from 249 to 251 AD, persecuted Christians in the Roman Empire rather sporadically and locally, but starting in January of the year 250, he ordered all citizens to perform a religious sacrifice in the presence of commissioners, or else face death. Many Christians refused and were martyred, (including Pope Fabian on 20 January 250), while others partook in the sacrifices in order to save their own lives.

Two schools of thought arose after the persecution. One side, led by Novatian, a priest in the diocese of Rome, said those who had stopped practising Christianity during the persecution could not be accepted back into the church, even if they repented. He held that idolatry was an unpardonable sin, and that the Church had no authority to forgive apostates, but that their forgiveness must be left to God; it could not be pronounced in this world. The opposing side, including Cornelius and Cyprian of Carthage, said the lapsi could be restored to communion through repentance, demonstrated by a period of penance.

During the persecution it proved impossible to elect a successor, and the papal seat remained vacant for a year. During this period the church was governed by several priests, including Novatian. When Decius left Rome to fight the invading Goths, the Roman clergy chose a new bishop. In the fourteen months without a pope, the leading candidate, Moses, had died under the persecution. The more moderate Cornelius was unwillingly elected over Novatian and others as the twenty-first pope in March 251.

Papacy
Those who supported a more rigorist position had Novatian consecrated bishop and refused to recognize Cornelius as Bishop of Rome. Both sides sent out letters to other bishops seeking recognition and support. Cornelius had the support of Cyprian, Dionysius, and most African and Eastern bishops while Novatian had the support of a minority of clergy and laymen in Rome. Cornelius's next action was to convene a synod of 60 bishops to acknowledge him as the rightful pope and the council excommunicated Novatian as well as all Novatianists. Also addressed in the synod was that Christians who stopped practising during Emperor Decius's persecution could be re-admitted into the Christian community only after doing penance.

The verdict of the synod was sent to the Christian bishops, most notably the bishop of Antioch, a fierce Novatian supporter, in order to convince him to accept Cornelius as bishop of Rome. The letters that Cornelius sent to surrounding bishops provide information of the size of the church in Rome at that time. Cornelius mentions that the Roman Church had, "forty six priests, seven deacons, seven sub-deacons, forty two acolytes, fifty two ostiarii, and over one thousand five hundred widows and persons in distress." His letters also inform that Cornelius had a staff of over 150 clergy members and the church fed over 1,500 people daily. From these numbers, it has been estimated that there were at least 50,000 Christians in Rome during the papacy of Pope Cornelius.

Death and letters
In June 251, Decius was killed in battle with the Goths; and persecutions resumed under his successor, Trebonianus Gallus. Cornelius was exiled to Centumcellae, Italy, where he died in June 253. The Liberian catalogue ascribes his death to the hardships of banishment; later sources say he was beheaded. He was entombed in a catacomb near the chapel of the popes, behind a Latin inscription, not Greek like his predecessor Pope Fabian and successor Lucius I. It translates to "Cornelius Martyr". The letters he sent while in exile are all written in the colloquial Latin of the period instead of the classical style used by the educated such as Cyprian, a theologian as well as a bishop, and Novatian, who was also a philosopher. This suggests that Cornelius came from a financially average family and thus was given an ordinary education as a child. One letter mentions an office of "exorcist" in the church for the first time. Canon law has since then required each diocese to have an exorcist.

Veneration
Some of his relics were taken to Germany during the Middle Ages; his head was claimed by Kornelimünster Abbey near Aachen. In the Rhineland, he was also a patron saint of lovers. A legend associated with Cornelius tells of a young artist who was commissioned to decorate the Corneliuskapelle in the Selikum quarter of Neuss. The daughter of a local townsman fell in love with the artist, but her father forbade the marriage, remarking that he would only consent if the pope did as well. Miraculously, the statue of Cornelius leaned forward from the altar and blessed the pair, and the two lovers were thus married.

Cornelius, along with Quirinus of Neuss, Hubertus and Anthony the Great, was venerated as one of the Four Holy Marshals in the Rhineland during the late Middle Ages.

A legend told at Carnac states that its stones were once pagan soldiers who had been turned into stone by Cornelius, who was fleeing from them.

The Catholic Church commemorated Cornelius by venerating him, with his Saint's Day on 16 September, which he shares with his friend Cyprian. His Saint's Day was originally on 14 September, the date on which both Cyprian and Cornelius were martyred, according to Jerome. Cornelius's saintly name means "battle horn", and he is represented in icons by a pope either holding some form of cow's horn or with a cow nearby. He is the patron against earache, epilepsy, fever, twitching, and also of cattle, domestic animals, earache sufferers, epileptics, and the town of Kornelimünster, Germany, where his head is enshrined.

license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/

title: Pope Cornelius


text:
Cervical cancer

Cervical cancer is a cancer arising from the cervix or in the any layer of the wall of the cervix. It is due to the abnormal growth of cells that have the ability to invade or spread to other parts of the body. Early on, typically no symptoms are seen. Later symptoms may include abnormal vaginal bleeding, pelvic pain or pain during sexual intercourse. While bleeding after sex may not be serious, it may also indicate the presence of cervical cancer.

Human papillomavirus infection (HPV) causes more than 90% of cases; most  who have had HPV infections, however, do not develop cervical cancer. HPV 16 and 18 strains are responsible for nearly 50% of high grade cervical pre-cancers. Other risk factors include smoking, a weak immune system, birth control pills, starting sex at a young age, and having many sexual partners, but these are less important. Genetic factors also contribute to cervical cancer risk. Cervical cancer typically develops from precancerous changes called cervical intraepithelial neoplasia over 10 to 20 years. About 90% of cervical cancer cases are squamous cell carcinomas, 10% are adenocarcinoma, and a small number are other types. Diagnosis is typically by cervical screening followed by a biopsy. Medical imaging is then done to determine whether or not the cancer has spread.

HPV vaccines protect against two to seven high-risk strains of this family of viruses and may prevent up to 90% of cervical cancers. As a risk of cancer still exists, guidelines recommend continuing regular Pap tests. Other methods of prevention include having few or no sexual partners and the use of condoms. Cervical cancer screening using the Pap test or acetic acid can identify precancerous changes, which when treated, can prevent the development of cancer. Treatment may consist of some combination of surgery, chemotherapy, and radiation therapy. Five-year survival rates in the United States are 68%. Outcomes, however, depend very much on how early the cancer is detected.

Worldwide, cervical cancer is both the fourth-most common type of cancer and the fourth-most common cause of death from cancer in women. In 2012, an estimated 528,000 cases of cervical cancer occurred, with 266,000 deaths. This is about 8% of the total cases and total deaths from cancer. About 70% of cervical cancers and 90% of deaths occur in developing countries. In low-income countries, it is one of the most common causes of cancer death with an incidence rate of 47.3 per 100,000 women. In developed countries, the widespread use of cervical screening programs has dramatically reduced rates of cervical cancer. Expected scenarios for the reduction of mortality due to cervical cancer worldwide (and specially in low-income countries) have been reviewed, given assumptions with respect to the achievement of recommended prevention targets using triple-intervention strategies defined by WHO. In medical research, the most famous immortalized cell line, known as HeLa, was developed from cervical cancer cells of a woman named Henrietta Lacks.

Signs and symptoms
The early stages of cervical cancer may be completely free of symptoms. Vaginal bleeding, contact bleeding (one most common form being bleeding after sexual intercourse), or (rarely) a vaginal mass may indicate the presence of malignancy. Also, moderate pain during sexual intercourse and vaginal discharge are symptoms of cervical cancer. In advanced disease, metastases may be present in the abdomen, lungs, or elsewhere.

Symptoms of advanced cervical cancer may include loss of appetite, weight loss, fatigue, pelvic pain, back pain, leg pain, swollen legs, heavy vaginal bleeding, bone fractures, and (rarely) leakage of urine or faeces from the vagina. Bleeding after douching or after a pelvic exam is a common symptom of cervical cancer.

Causes
Infection with some types of HPV is the greatest risk factor for cervical cancer, followed by smoking. HIV infection is also a risk factor. Not all of the causes of cervical cancer are known, however, and several other contributing factors have been implicated.

Human papillomavirus
HPV types 16 and 18 are the cause of 75% of cervical cancer cases globally, while 31 and 45 are the causes of another 10%.

Women who have multiple sexual partners, or have partners who have multiple sexual partners, regardless of sex are at higher risk of cervical cancer.

Over 200 types of HPV known, 12 are classified as high-risk types (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59), three as probable high-risk (26, 53, and 66), and 12 as low-risk (6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81, and CP6108).

Genital warts, which are a form of benign tumor of epithelial cells, are also caused by various strains of HPV. However, these serotypes are usually not related to cervical cancer. Having multiple strains at the same time is common, including those that can cause cervical cancer along with those that cause warts. Infection with HPV is generally believed to be required for cervical cancer to occur.

Smoking
Cigarette smoking, both active and passive, increases the risk of cervical cancer. Among HPV-infected women, current and former smokers have roughly two to three times the incidence of invasive cancer. Passive smoking is also associated with increased risk, but to a lesser extent.

Smoking has also been linked to the development of cervical cancer. Smoking can increase the risk in women a few different ways, which can be by direct and indirect methods of inducing cervical cancer. A direct way of contracting this cancer is a smoker has a higher chance of cervical intraepithelial neoplasia (CIN3) occurring, which has the potential of forming cervical cancer. When CIN3 lesions lead to cancer, most of them have the assistance of the HPV virus, but that is not always the case, which is why it can be considered a direct link to cervical cancer. Heavy smoking and long-term smoking seem to have more of a risk of getting the CIN3 lesions than lighter smoking or not smoking at all. Although smoking has been linked to cervical cancer, it aids in the development of HPV, which is the leading cause of this type of cancer. Also, not only does it aid in the development of HPV, but also if the woman is already HPV-positive, she is at an even greater likelihood of contracting cervical cancer.

Oral contraceptives
Long-term use of oral contraceptives is associated with increased risk of cervical cancer in women who have had HPV. Women who have used oral contraceptives for 5 to 9 years have about three times the incidence of invasive cancer, and those who used them for 10 years or longer have about four times the risk.

Multiple pregnancies
Having many pregnancies is associated with an increased risk of cervical cancer. Among HPV-infected women, those who have had seven or more full-term pregnancies have around four times the risk of cancer compared with women with no pregnancies, and two to three times the risk of women who have had one or two full-term pregnancies.

Biopsy
The Pap test can be used as a screening test, but produces a false negative in up to 50% of cases of cervical cancer. Other concerns is the cost of doing Pap tests, which make them unaffordable in many areas of the world.

Confirmation of the diagnosis of cervical cancer or precancer requires a biopsy of the cervix. This is often done through colposcopy, a magnified visual inspection of the cervix aided by using a dilute acetic acid (e.g. vinegar) solution to highlight abnormal cells on the surface of the cervix, with visual contrast provided by staining the normal tissues a mahogany brown with Lugol's iodine. Medical devices used for biopsy of the cervix include punch forceps. Colposcopic impression, the estimate of disease severity based on the visual inspection, forms part of the diagnosis. Further diagnostic and treatment procedures are loop electrical excision procedure and cervical conization, in which the inner lining of the cervix is removed to be examined pathologically. These are carried out if the biopsy confirms severe cervical intraepithelial neoplasia.

Often before the biopsy, the doctor asks for medical imaging to rule out other causes of woman's symptoms. Imaging modalities such as ultrasound, CT scan, and MRI have been used to look for alternating disease, spread of the tumor, and effect on adjacent structures. Typically, they appear as heterogeneous mass on the cervix.

Interventions such as playing music during the procedure and viewing the procedure on a monitor can reduce the anxiety associated with the examination.

Precancerous lesions
Cervical intraepithelial neoplasia (CIN) means the development of abnormal cells on the surface of the cervix. It is caused by an HPV infection but in most cases it is resolved by the immune system. However a small percentage of people might develop a more serious CIN which, if left untreated, can develop into cervical cancer. CIN is often diagnosed during routine Pap smear examination or colposcopy.

The naming and histologic classification of cervical carcinoma precursor lesions has changed many times over the 20th century. The World Health Organization classification system was descriptive of the lesions, naming them mild, moderate, or severe dysplasia or carcinoma in situ (CIS). The term cervical intraepithelial neoplasia (CIN) was developed to place emphasis on the spectrum of abnormality in these lesions, and to help standardize treatment. For premalignant dysplastic changes, cervical intraepithelial neoplasia grading (CIN 1–3) is used. It classifies mild dysplasia as CIN1, moderate dysplasia as CIN2, and severe dysplasia and CIS as CIN3. More recently, CIN2 and CIN3 have been combined into CIN2/3. These results are what a pathologist might report from a biopsy.

These should not be confused with the Bethesda system terms for Pap test (cytopathology) results. Among the Bethesda results: Low-grade squamous intraepithelial lesion (LSIL) and high-grade squamous intraepithelial lesion (HSIL). An LSIL Pap may correspond to CIN1, and HSIL may correspond to CIN2 and CIN3, but they are results of different tests, and the Pap test results need not match the histologic findings.

Cancer subtypes
Histologic subtypes of invasive cervical carcinoma include:
 * Squamous cell carcinoma (about 80–85% )
 * adenocarcinoma (about 15% of cervical cancers in the UK )
 * Adenosquamous carcinoma
 * Small cell carcinoma
 * Neuroendocrine tumour
 * Glassy cell carcinoma
 * Villoglandular adenocarcinoma

Though squamous cell carcinoma is the cervical cancer with the most incidence, the incidence of adenocarcinoma of the cervix has been increasing in recent decades. Endocervical adenocarcinoma represents 20–25% of the histological types of cervical carcinoma. Gastric-type mucinous adenocarcinoma of the cervix is a rare type of cancer with aggressive behavior. This type of malignancy is not related to high-risk human papillomavirus (HPV). Noncarcinoma malignancies which can rarely occur in the cervix include melanoma and lymphoma. The International Federation of Gynecology and Obstetrics (FIGO) stage does not incorporate lymph node involvement in contrast to the TNM staging for most other cancers. For cases treated surgically, information obtained from the pathologist can be used in assigning a separate pathologic stage, but is not to replace the original clinical stage.

Staging
Cervical cancer is staged by the FIGO system, which is based on clinical examination rather than surgical findings. Prior to the 2018 revisions to FIGO staging, the system allowed only these diagnostic tests to be used in determining the stage: palpation, inspection, colposcopy, endocervical curettage, hysteroscopy, cystoscopy, proctoscopy, intravenous urography, and X-ray examination of the lungs and skeleton, and cervical conization. However, the current system allows use of any imaging or pathological methods for staging.

Screening

Checking cervical cells with the Papanicolaou test (Pap test) for cervical pre-cancer has dramatically reduced the number of cases of, and mortality from, cervical cancer. Liquid-based cytology may reduce the number of inadequate samples. Pap test screening every three to five years with appropriate follow-up can reduce cervical cancer incidence up to 80%.

Pap test screening can reveal abnormal cells on the surface of the cervix called cervical intraepithelial neoplasia (CIN) that in a small percentage can develop into cervical cancer. These precancerous changes can be confirmed with further examination known as colposcopy.

Personal invitations encouraging women to get screened are effective at increasing the likelihood they will do so. Educational materials also help increase the likelihood women will go for screening, but they are not as effective as invitations.

According to the 2010 European guidelines, the age at which to start screening ranges between 20 and 30 years of age, but preferentially not before age 25 or 30 years, and depends on burden of the disease in the population and the available resources.

In the United States, screening is recommended to begin at age 21, regardless of age at which a woman began having sex or other risk factors. Pap tests should be done every three years between the ages of 21 and 65. In women over the age of 65, screening may be discontinued if no abnormal screening results were seen within the previous 10 years and no history of CIN2 or higher exists. HPV vaccination status does not change screening rates.

A number of recommended options exist for screening those 30 to 65. This includes cervical cytology every 3 years, HPV testing every 5 years, or HPV testing together with cytology every 5 years. Screening is not beneficial before age 25, as the rate of disease is low. Screening is not beneficial in women older than 60 years if they have a history of negative results. The American Society of Clinical Oncology guideline has recommend for different levels of resource availability.

Pap tests have not been as effective in developing countries. This is in part because many of these countries have an impoverished health care infrastructure, too few trained and skilled professionals to obtain and interpret Pap tests, uninformed women who get lost to follow-up, and a lengthy turn-around time to get results. Visual inspection with acetic acid and HPV DNA testing have been tried, though with mixed success.

Barrier protection
Barrier protection or spermicidal gel use during sexual intercourse decreases, but does not eliminate risk of transmitting the infection, though condoms may protect against genital warts. They also provide protection against other sexually transmitted infections, such as HIV and Chlamydia, which are associated with greater risks of developing cervical cancer.

Vaccination
Three HPV vaccines (Gardasil, Gardasil 9, and Cervarix) reduce the risk of cancerous or precancerous changes of the cervix and perineum by about 93% and 62%, respectively. The vaccines are between 92% and 100% effective against HPV 16 and 18 up to at least 8 years.

HPV vaccines are typically given to age 9 to 26, as the vaccine is most effective if given before infection occurs. The duration of effectiveness and whether a booster will be needed is unknown. The high cost of this vaccine has been a cause for concern. Several countries have considered (or are considering) programs to fund HPV vaccination. The American Society of Clinical Oncology guideline has recommendations for different levels of resource availability.

Since 2010, young women in Japan have been eligible to receive the cervical cancer vaccination for free. In June 2013, the Japanese Ministry of Health, Labor and Welfare mandated that, before administering the vaccine, medical institutions must inform women that the ministry does not recommend it. However, the vaccine is still available at no cost to Japanese women who choose to accept the vaccination.

Nutrition
Vitamin A is associated with a lower risk as are vitamin B12, vitamin C, vitamin E, and beta-Carotene.

Treatment
The treatment of cervical cancer varies worldwide, largely due to access to surgeons skilled in radical pelvic surgery and the emergence of fertility-sparing therapy in developed nations. Less advanced stages of cervical cancer typically have treatment options that allow fertility to be maintained if the patient desires.

Because cervical cancers are radiosensitive, radiation may be used in all stages where surgical options do not exist. Surgical intervention may have better outcomes than radiological approaches. In addition, chemotherapy can be used to treat cervical cancer and is more effective than radiation alone. Chemoradiotherapy may increase overall survival and reduce the risk of disease recurrence compared to radiotherapy alone.

Precancerous cells (cervical intraepithelial neoplasia) that would lead to cancer and early-stage cervical cancer (IA1) can be treated effectively by various surgical techniques. Surgical treatment methods include excision, where a cone-shaped portion of the cervix is removed, and ablation which removes only the parts with abnormal tissues. While these effectively reduce the risk of cancer developing or spreading, they cause an increased risk of premature birth in future pregnancies. Surgical techniques that remove more cervical tissue come with less risk of the cancer recurring but a higher chance of giving birth prematurely. Due to this risk, taking into account the age, childbearing plans of the woman, the size and location of the cancer cells are crucial for choosing the right procedure. There is low-certainty evidence that peri-operative care approaches, such as 'fast-track surgery' or 'enhanced recovery programmes' may lower surgical stress and improve recovery after gynaecological cancer surgery.

Microinvasive cancer (stage IA) may also be treated by hysterectomy (removal of the whole uterus, including part of the vagina). For stage IA2, the lymph nodes are removed as well. Alternatives include local surgical procedures such as a loop electrical excision procedure or cone biopsy. A systematic review concluded that more evidence is needed to inform decisions about different surgical techniques for women with cervical cancer at stage IA2.

If a cone biopsy does not produce clear margins (findings on biopsy showing that the tumor is surrounded by cancer free tissue, suggesting all of the tumor is removed), one more possible treatment option for women who want to preserve their fertility is a trachelectomy. This attempts to surgically remove the cancer while preserving the ovaries and uterus, providing for a more conservative operation than a hysterectomy. It is a viable option for those in stage I cervical cancer which has not spread; however, it is not yet considered a standard of care, as few doctors are skilled in this procedure. Even the most experienced surgeon cannot promise that a trachelectomy can be performed until after surgical microscopic examination, as the extent of the spread of cancer is unknown. If the surgeon is not able to microscopically confirm clear margins of cervical tissue once the woman is under general anaesthesia in the operating room, a hysterectomy may still be needed. This can only be done during the same operation if the woman consented. Due to the possible risk of cancer spreading to the lymph nodes in stage 1B cancers and some stage 1A cancers, the surgeon may also need to remove some lymph nodes from around the uterus for pathologic evaluation.

A radical trachelectomy can be performed abdominally or vaginally and opinions are conflicting as to which is better. A radical abdominal trachelectomy with lymphadenectomy usually only requires a two- to three-day hospital stay, and most women recover very quickly (about six weeks). Complications are uncommon, although women who can conceive after surgery are susceptible to preterm labour and possible late miscarriage. A wait of at least one year is generally recommended before attempting to become pregnant after surgery. Recurrence in the residual cervix is rare if the trachelectomy has cleared the cancer. Yet, women are recommended to practice vigilant prevention and follow-up care, including Pap screenings/colposcopy, with biopsies of the remaining lower uterine segment as needed (every 3–4 months for at least 5 years) to monitor for any recurrence in addition to minimizing any new exposures to HPV through safe sex practices until one is actively trying to conceive.

Early stages (IB1 and IIA less than 4 cm) can be treated with radical hysterectomy with removal of the lymph nodes or radiation therapy. Radiation therapy is given as external beam radiotherapy to the pelvis and brachytherapy (internal radiation). Women treated with surgery who have high-risk features found on pathologic examination are given radiation therapy with or without chemotherapy to reduce the risk of relapse. A Cochrane review has found moderate-certainty evidence that radiation decreases the risk of disease progression in people with stage IB cervical cancer, when compared to no further treatment. However, little evidence was found on its effects on overall survival.

Larger early-stage tumors (IB2 and IIA more than 4 cm) may be treated with radiation therapy and cisplatin-based chemotherapy, hysterectomy (which then usually requires adjuvant radiation therapy), or cisplatin chemotherapy followed by hysterectomy. When cisplatin is present, it is thought to be the most active single agent in periodic diseases. Such addition of platinum-based chemotherapy to chemoradiation seems not only to improve survival but also reduces risk of recurrence in women with early stage cervical cancer (IA2–IIA). A Cochrane review found a lack of evidence on the benefits and harms of primary hysterectomy compared to primary chemoradiotherapy for cervical cancer in stage IB2.

Advanced-stage tumors (IIB-IVA) are treated with radiation therapy and cisplatin-based chemotherapy. On 15 June 2006, the US Food and Drug Administration approved the use of a combination of two chemotherapy drugs, hycamtin and cisplatin, for women with late-stage (IVB) cervical cancer treatment. Combination treatment has significant risk of neutropenia, anemia, and thrombocytopenia side effects.

There is insufficient evidence whether anticancer drugs after standard care help women with locally advanced cervical cancer to live longer.

For surgery to be curative, the entire cancer must be removed with no cancer found at the margins of the removed tissue on examination under a microscope. This procedure is known as exenteration.

No evidence is available to suggest that any form of follow‐up approach is better or worse in terms of prolonging survival, improving quality of life or guiding the management of problems that can arise because of the treatment and that in the case of radiotherapy treatment worsen with time. A 2019 review found no controlled trials regarding the efficacy and safety of interventions for vaginal bleeding in women with advanced cervical cancer.

Tisotumab vedotin (Tivdak) was approved for medical use in the United States in September 2021.

Stage
Prognosis depends on the stage of the cancer. For intraepithelial cervical neoplasmas the prognosis is good. With treatment, the five-year relative survival rate for the earliest stage of invasive cervical cancer is 92%, and the overall (all stages combined) five-year survival rate is about 66%. These statistics may be improved when applied to women newly diagnosed, bearing in mind that these outcomes may be partly based on the state of treatment five years ago when the women studied were first diagnosed.

With treatment, 80–90% of women with stage I cancer and 60–75% of those with stage II cancer are alive 5 years after diagnosis. Survival rates decrease to 58% for women with stage III cancer and 17% or fewer of those with stage IV cancer five years after diagnosis. Recurrent cervical cancer detected at its earliest stages might be successfully treated with surgery, radiation, chemotherapy, or a combination of the three. About 35% of women with invasive cervical cancer have persistent or recurrent disease after treatment.

By country
Five-year survival in the United States for White women is 69% and for Black women is 57%.

Regular screening has meant that precancerous changes and early-stage cervical cancers have been detected and treated early. Figures suggest that cervical screening is saving 5,000 lives each year in the UK by preventing cervical cancer. About 1,000 women per year die of cervical cancer in the UK. All of the Nordic countries have cervical cancer-screening programs in place. The Pap test was integrated into clinical practice in the Nordic countries in the 1960s.

In Africa outcomes are often worse as diagnosis is frequently at a latter stage of disease. In a scoping review of publicly-available cervical cancer prevention and control plans from African countries, plans tended to emphasize survivorship rather than early HPV diagnosis and prevention.

Epidemiology
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Worldwide, cervical cancer is both the fourth-most common cause of cancer and deaths from cancer in women. In 2018, 570,000 cases of cervical cancer were estimated to have occurred, with over 300,000 deaths. It is the second-most common cause of female-specific cancer after breast cancer, accounting for around 8% of both total cancer cases and total cancer deaths in women. About 80% of cervical cancers occur in developing countries. It is the most frequently detected cancer during pregnancy, with an occurrence of 1.5 to 12 for every 100,000 pregnancies.

Australia
In 2022, it is estimated that 942 new cases of cervical cancer will be diagnosed in Australia. In 2022, it is estimated that a female has a 1 in 180 (or 0.56%) risk of being diagnosed with cervical cancer by the age of 85.

In 2020, there were 165 women aged 25–74 who died from cervical cancer, which is a mortality rate of 2 deaths per 100,000 women in the population. Over the 5 years 2016–2020, there were 62 Aboriginal and Torres Strait Islander women aged 25–74 who died from cervical cancer, which is a mortality rate of 7 deaths per 100,000 Indigenous women in the population. Over the 5 years 2016–2020, the age-standardised mortality rate among Aboriginal and Torres Strait Islander women was 3.8 times the rate of non-Indigenous Australians.

The number of women diagnosed with cervical cancer has dropped on average by 4.5% each year since organised screening began in 1991 (1991–2005). Regular twice-yearly Pap tests can reduce the incidence of cervical cancer up to 90% in Australia, and save 1,200 Australian women from dying from the disease each year. It is predicted that because of the success of the primary HPV testing programme there will be fewer than four new cases per 100 000 women annually by 2028.

Canada
An estimated 1,450 Canadians will be diagnosed with cervical cancer in 2022. An estimated 380 will die from it.

India
In India, the number of people with cervical cancer is rising, but overall the age-adjusted rates are decreasing. Usage of condoms in the female population has improved the survival of women with cancers of the cervix.

European Union
As of 2022, the World Health Organization announced that "each year in the WHO European Region more than 66 000 women are newly diagnosed with cervical cancer and more than 30 000 die from this preventable disease."

United Kingdom
Cervical cancer is the 12th-most common cancer in women in the UK (around 3,100 women were diagnosed with the disease in 2011), and accounts for 1% of cancer deaths (around 920 died in 2012). With a 42% reduction from 1988 to 1997, the NHS-implemented screening programme has been highly successful, screening the highest-risk age group (25–49 years) every 3 years, and those ages 50–64 every 5 years.

United States
An estimated 13,170 new cervical cancers and 4,250 cervical cancer deaths will occur in the United States in 2019. The median age at diagnosis is 50. The rates of new cases in the United States was 7.3 per 100,000 women, based on rates from 2012 to 2016. Cervical cancer deaths decreased by approximately 74% in the last 50 years, largely due to widespread Pap test screening. The annual direct medical cost of cervical cancer prevention and treatment prior to introduction of the HPV vaccine was estimated at $6 billion.

Nigeria
The Nigerian Institute of Medical Research (NIMR) reports that 28 Nigerian women lose their lives daily due to this disease. This alarming statistic underscores the pressing need for better awareness, prevention, and treatment efforts across the country. Numerous Nigerian women lack access to these preventive measures. In many regions of the country, screening tests such as Pap tests and HPV tests are not easily accessible or affordable

History

 * 400 BCE: Hippocrates noted that cervical cancer was incurable.
 * 1925: Hinselmann invented the colposcope.
 * 1928: Papanicolaou developed the Papanicolaou technique.
 * 1941: Papanicolaou and Traut: Pap test screening began.
 * 1946: Aylesbury spatula was developed to scrape the cervix, collecting the sample for the Pap test.
 * 1951: First successful in-vitro cell line, HeLa, derived from biopsy of cervical cancer of Henrietta Lacks.
 * 1976: Harald zur Hausen and Gisam found HPV DNA in cervical cancer and genital warts; Hausen later won the Nobel Prize for his work.
 * 1988: Bethesda System for reporting Pap results was developed.
 * 2006: First HPV vaccine was approved by the FDA.
 * 2015: HPV Vaccine shown to protect against infection at multiple body sites.
 * 2018: Evidence for single-dose protection with HPV vaccine.

Epidemiologists working in the early 20th century noted that cervical cancer behaved like a sexually transmitted disease. In summary:

 * 1) Cervical cancer was noted to be common in female sex workers.
 * 2) It was rare in nuns, except for those who had been sexually active before entering the convent (Rigoni in 1841).
 * 3) It was more common in the second wives of men whose first wives had died from cervical cancer.
 * 4) It was rare in Jewish women.
 * 5) In 1935, Syverton and Berry discovered a relationship between RPV (Rabbit Papillomavirus) and skin cancer in rabbits. (HPV is species-specific and therefore cannot be transmitted to rabbits).

These historical observations suggested that cervical cancer could be caused by a sexually transmitted agent. Initial research in the 1940s and 1950s attributed cervical cancer to smegma. During the 1960s and 1970s it was suspected that infection with herpes simplex virus was the cause of the disease. In summary, HSV was seen as a likely cause because it is known to survive in the female reproductive tract, to be transmitted sexually in a way compatible with known risk factors, such as promiscuity and low socioeconomic status. Herpes viruses were also implicated in other malignant diseases, including Burkitt's lymphoma, Nasopharyngeal carcinoma, Marek's disease and the Lucké renal adenocarcinoma. HSV was recovered from cervical tumour cells.

A description of human papillomavirus (HPV) by electron microscopy was given in 1949, and HPV-DNA was identified in 1963. It was not until the 1980s that HPV was identified in cervical cancer tissue. It has since been demonstrated that HPV is implicated in virtually all cervical cancers. Specific viral subtypes implicated are HPV 16, 18, 31, 45 and others.

In work that was initiated in the mid-1980s, the HPV vaccine was developed, in parallel, by researchers at Georgetown University Medical Center, the University of Rochester, the University of Queensland in Australia, and the U.S. National Cancer Institute. In 2006, the U.S. Food and Drug Administration (FDA) approved the first preventive HPV vaccine, marketed by Merck & Co. under the trade name Gardasil.

In November 2020, the World Health Organization, under backing from the World Health Assembly, set out a strategy to eliminate cervical cancer by 2050. The strategy involves vaccinating 90% of girls by the age of 15, screening 70% of women by the age of 35 and again by the age of 45, and treating 90% of women identified with cervical disease.

Australia
In Australia, Aboriginal women are more than five times more likely to die from cervical cancer than non-Aboriginal women, suggesting that Aboriginal women are less likely to have regular Pap tests. There are several factors that may limit indigenous women from engaging in regular cervical screening practices, including sensitivity in discussing the topic in Aboriginal communities, embarrassment, anxiety and fear about the procedure. Difficulty in accessing screening services (for example, transport difficulties) and a lack of female GPs, trained Pap test providers and trained female Aboriginal Health Workers are also issues.

The Australian Cervical Cancer Foundation (ACCF), founded in 2008, promotes 'women's health by eliminating cervical cancer and enabling treatment for women with cervical cancer and related health issues, in Australia and in developing countries.' Ian Frazer, one of the developers of the Gardasil cervical cancer vaccine, is the scientific advisor to ACCF. Janette Howard, the wife of the then-Prime Minister of Australia, John Howard, was diagnosed with cervical cancer in 1996, and first spoke publicly about the disease in 2006.

United States

A 2007 survey of American women found 40% had heard of HPV infection and less than half of those knew it causes cervical cancer. Over a longitudinal study from 1975 to 2000, it was found that people of lower socioeconomic census brackets had higher rates of late-stage cancer diagnosis and higher morbidity rates. After controlling for stage, there still existed differences in survival rates. Women in the US experience stigma around HPV infection, vaccination and cervical cancer. This is predominantly driven by fear of social judgment and rejection, self-blame, and shame, with notable negative influences from gender and social norms, as both human papillomavirus infection and cervical cancer were stigmatized due to the perception that they arise from reckless behavior such as having multiple sexual partners or neglecting screening.

LGBTQ populations
Transgender men and gender-diverse people who have a cervix (even if partially intact) or have a prior history of cervical cancer or precancerous conditions, and are age 21 or older who has ever had sex with anyone need to get screened for cervical cancer. Transmasculine people are just as likely as cisgender women to have cervical cancer, but are less likely to undergo cervical screening, because of dysphoria, gender disaffirmation or disempowerment of the individual by healthcare providers, or being misinformed of HPV and cervical cancer risks as well as many healthcare providers perceiving transmasculine individuals to be at low risk of cervical cancer.

Transgender women who have not had bottom surgery have no risk of cervical cancer, as they do not have a cervix. Trans women who have had bottom surgery to create a vagina (vaginoplasty) and possibly a cervix, are at a very small risk to develop cancer in the tissues of their neo-vagina or neo-cervix as these tissues are made up of different cells than a cervix in a cisgender woman Cervical cancer screening is not necessary in trans women who have undergone vaginoplasty because they do not have a cervix.

Intersex people with a cervix are also able to have cervical cancer.

title: Cervical cancer


text:
Pope Eutychian

Pope Eutychian, also called Eutychianus (Ευτυχιανός), was the bishop of Rome from 4 January 275 to his death on 7 December 283.

Eutychian's original epitaph was discovered in the catacomb of Callixtus (see Kraus, Roma sotterranea, p. 154 et seq.), but almost nothing more is known of him. Even the date of his reign is uncertain. Liber Pontificalis gives a reign of 8 years and 11 months, from 275 to 283. Eusebius, on the other hand says his reign was only 10 months.

Eutychian is said to have allowed the blessing of grapes and beans on the altar and to have buried 324 martyrs with his own hands. Some historians doubt these traditions, but others assert that persecutions continued until the Edict of Serdica was proclaimed in 311 by Emperor Galerius, making Christianity a legal and acceptable religion. The blessing of produce of the fields is believed by some to belong to a later period, but this cannot be verified.

Eutychian's feast day is 8 December.

title: Pope Eutychian