Uterine fibroid

Some people with uterine fibroids do not experience any symptoms. However, abdominal pain, anemia, and heavy or increased bleeding can be signs of fibroids. bleeding, premature labor, or interference with the position of the fetus. A uterine fibroid can cause rectal pressure. The abdomen can grow larger, mimicking the appearance of pregnancy. The majority of people with uterine fibroids will have normal pregnancy outcomes. In cases of intercurrent uterine fibroids in infertility, a fibroid is typically located in a submucosal position. It is thought that this location may interfere with the function of the lining and the ability of the embryo to implant. ==Risk factors==

Some risk factors associated with the development of uterine fibroids are modifiable. Black women have a 3–9 times increased chance of developing uterine fibroids than white women. Only a few specific genes or cytogenetic deviations are associated with fibroids. 80–85% of fibroids have a mutation in the mediator complex subunit 12 (MED12) gene. Familial leiomyomata A syndrome (Reed's syndrome) that causes uterine leiomyomata along with cutaneous leiomyomata and renal cell cancer has been reported. This is associated with a mutation in the gene that produces the enzyme fumarate hydratase, located on the long arm of chromosome 1 (1q42.3-43). Inheritance is autosomal dominant. ==Pathophysiology==

Uterine fibroids are leiomyomas that occur in the uterus. Fibroids grossly appear as round, well-circumscribed (but not encapsulated), solid nodules that are white or tan and show a whorled appearance on histological section. The size varies, from microscopic to lesions of considerable size. Typically, lesions the size of a grapefruit or bigger are felt by the patient herself through the abdominal wall. Location and classification Growth and location are the main factors that determine whether a fibroid causes symptoms and problems. • Type 0: pedunculated submucosal, intracavitary (i.e., inside of the uterus) • Type 1: submucosal, Aromatase overexpression is particularly pronounced in African-American women. Genetic and hereditary causes are suspected, and several epidemiologic findings indicate considerable genetic influence, especially for early-onset cases. First-degree relatives have a 2.5-fold risk and nearly a 6-fold risk when considering early-onset cases. Monozygotic twins have double concordance rate for hysterectomy compared to dizygotic twins. Expansion of uterine fibroids occurs at a slow rate of cell proliferation combined with the production of copious amounts of extracellular matrix. A small population of the cells in a uterine fibroid has properties of stem cells or progenitor cells, and contributes significantly to ovarian steroid-dependent growth of fibroids. These stem-progenitor cells are deficient in estrogen receptor α and progesterone receptor and instead rely on substantially higher levels of these receptors in surrounding differentiated cells to mediate estrogen and progesterone actions via paracrine signaling. ==Diagnosis==

Physical examination and ultrasound are sufficient for diagnosing uterine fibroids in most people. When ultrasound findings are inconclusive, magnetic resonance imaging (MRI) can confirm the diagnosis of uterine fibroids in most cases. In addition, MRI can identify benign uterine fibroids with atypical imaging features and fibroids with variant growth patterns. MRI can also identify other uterine (e.g., adenomyosis, endometrial polyps, endometrial cancer) and extrauterine (e.g., benign and malignant ovarian tumors, endometriosis) disorders that may mimic the appearance of uterine fibroids and/or contribute to the patient's symptoms. Malignant tumors of the uterine wall (e.g., leiomyosarcoma) are very rare. Findings suggestive of a malignant uterine tumor rather than a benign fibroid include fast or unexpected growth (particularly after menopause), interruption/effacement of the endometrial stripe, lymph node enlargement, invasion of adjacent organs, and metastases to distant organs (e.g., lung). MRI findings suggestive of a malignancy include nodular/ill-circumscribed tumor margins, intermediate/high T2-weighted signal intensity of the solid tumor components, regions with high signal T1-weighted sequences in keeping with subacute hemorrhage, fine/wispy enhancement of the solid parts of the tumor, and restricted diffusion on diffusion-weighted imaging (DWI). File:9cmFibroidPelvicCongestionS.png|A very large (9 cm) fibroid of the uterus which is causing pelvic congestion syndrome as seen on CT File:9cmFibroidUS.png|A very large (9 cm) fibroid of the uterus, which is causing pelvic congestion syndrome as seen on ultrasound File:Leiomyoma of the Uterus.jpg|A relatively large submucosal leiomyoma; it fills out the major part of the endometrial cavity. File:UterineFirboid.png|A small uterine fibroid seen within the wall of the myometrium on a cross-sectional ultrasound view File:Calcifiedfibroids.PNG|Two calcified fibroids (in the uterus) File:Subserosal uterine fibroid.png|A subserosal uterine fibroid with a diameter of 5 centimeters File:Pelvic MRI 05 fibroids.jpg|MRI image with multiple uterine leiomyomas File:Giant Myoma.jpg|Giant leiomyomas almost filling the abdomen File:Histopathology of uterine leiomyoma.jpg|Histopathology of uterine fibroids typically show smooth muscle in a whorled (fascicular) pattern. File:Histopathology of uterine leiomyoma (Van Gieson's stain).jpg|This variant of Van Gieson's stain distinguishes muscle (yellow) from connective tissue (red). File:Beta-catenin immunohistochemistry in leiomyoma.jpg|Immunohistochemistry for β-catenin in uterine leiomyoma, which is negative as there is only staining of cytoplasm but not of cell nuclei. Negative immunohistochemistry staining for β-catenin in cell nuclei is a consistent finding in uterine leiomyomas, and helps distinguish such tumors from β-catenin-positive spindle cell tumors. Coexisting disorders Fibroids that lead to heavy vaginal bleeding lead to anemia and iron deficiency. Due to pressure effects, gastrointestinal problems such as constipation and bloatedness are possible. Compression of the ureter may lead to hydronephrosis. Fibroids may also present alongside endometriosis, which itself may cause infertility. Adenomyosis may be mistaken for or coexist with fibroids. In very rare cases, malignant (cancerous) growths, leiomyosarcoma, of the myometrium can develop. In extremely rare cases uterine fibroids may present as part or early symptom of the hereditary leiomyomatosis and renal cell cancer syndrome. ==Treatment==

Most fibroids do not require treatment unless they are causing symptoms. After menopause, fibroids shrink and usually do not cause problems. Uterine fibroids that cause symptoms can be treated by: • medication to control symptoms (i.e., symptomatic management) • medication aimed at shrinking tumors • ultrasound fibroid destruction • surgical removal of fibroids (myomectomy) or using heat to reduce size (radiofrequency ablation) • surgical removal of the womb (hysterectomy) • blocking the blood supply of fibroids (uterine artery embolization) In those who have symptoms, uterine artery embolization and surgical options have similar outcomes with respect to satisfaction. For decades, a common approach to treating symptomatic fibroids was "either get a hysterectomy or wait until menopause diminishes the symptoms," but minimally invasive (small incision) and noninvasive (no incision) options were often not offered. Especially since the 2010s, minimally invasive and noninvasive options are increasingly being offered as they have advanced on their technological journey from being new and unusual to being common clinical practice. While most levonorgestrel-IUD studies concentrated on the treatment of women without fibroids, a few reported good results specifically for women with fibroids, including a substantial regression of fibroids. Cabergoline, when given in a moderate and well-tolerated dose, has been shown in two studies to shrink fibroids effectively. The mechanism of action of how it shrinks fibroids is unclear. Long-term UPA-treated fibroids have shown volume reduction of about 70%. In some cases UPA alone is used to relieve symptoms without surgery, and to allow successful pregnancies without fibroid regrowth. Indeed, in the tumor cells, the molecule blocks the cell proliferation, induces their apoptosis and stimulates the remodeling of the extensive fibrosis by matrix metalloproteinases, hence explaining the long-term benefit. Yet, due to some rare but severe hepatic injuries after UPA treatment, the licence was suspended in 2020 in the EU and voluntarily removed in Canada. Danazol is an effective treatment for fibroids and controls symptoms. Unpleasant side effects limit its use. The mechanism of action is thought to be antiestrogenic effects. Recent experience indicates that the safety and side effect profile can be improved by more cautious dosing. Progesterone antagonists such as mifepristone have been tested; there is evidence that they improve some symptoms and quality of life, but because of adverse histological changes observed in several trials, they can not currently be recommended outside of a research setting. Fibroid growth has recurred after antiprogestin treatment was stopped. Long-term outcomes with respect to how happy people are with the procedure are similar to those of surgery. UAE also appears to require more repeat procedures than if surgery was done initially. A person will usually recover from the procedure within a few days. Uterine artery ligation, sometimes also laparoscopic occlusion of uterine arteries, is a minimally invasive method to limit the blood supply of the uterus by a small surgery that can be performed transvaginally or laparoscopically. The principal mechanism of action may be similar to that in UAE, but it is easier to perform and has fewer expected side effects. The 2016 NICE (National Institute of Clinical Excellence – the non-governmental public body that publishes guidelines in the use of health technologies and good clinical practice in the United Kingdom) guidelines state UAE/UFE can be offered to people with symptomatic fibroids (fibroids being usually >30mm in size). Patients should be informed that UAE and myomectomy (the surgical removal of fibroids) may potentially allow them to retain their fertility. Myomectomy Myomectomy is a surgery to remove one or more fibroids. It is usually recommended when more conservative treatment options fail for patients who want fertility-preserving surgery or who want to retain the uterus. There are three types of myomectomy: • In a hysteroscopic myomectomy (also called transcervical resection), the fibroid can be removed by either the use of a resectoscope, an endoscopic instrument inserted through the vagina and cervix that can use high-frequency electrical energy to cut tissue, or a similar device. • A laparoscopic myomectomy is done through a small incision near the navel. The physician uses a laparoscope and surgical instruments to remove the fibroids. Studies have suggested that laparoscopic myomectomy is associated with lower morbidity rates and faster recovery than laparotomic myomectomy. • A laparotomic myomectomy (also known as an open or abdominal myomectomy) is the most invasive surgical procedure to remove fibroids. The physician makes an incision in the abdominal wall and removes the fibroids from the uterus. Laparoscopic myomectomy has less pain and a shorter time in the hospital than open surgery. An analysis of 15,000 patients found that those who had myomectomy required fewer additional procedures to manage fibroids (including hysterectomies) over the next 5 years than those who had UAE. Hysterectomy Hysterectomy was the classical method of treating fibroids. Although it is now recommended only as a last option, fibroids are still the leading cause of hysterectomies in the US. Endometrial ablation Endometrial ablation can be used if the fibroids are only within the uterus and not intramural and are relatively small. High failure and recurrence rates are expected in the presence of larger or intramural fibroids. Other procedures Radiofrequency ablation is a minimally invasive treatment for fibroids. In this technique the fibroid is shrunk by inserting a needle-like device into the fibroid through the abdomen and heating it with radio-frequency (RF) electrical energy to cause necrosis of cells. The treatment is a potential option for people who have fibroids, have completed childbearing, and want to avoid a hysterectomy. Magnetic resonance guided focused ultrasound is a non-invasive intervention (requiring no incision) that uses high-intensity focused ultrasound waves to destroy tissue and magnetic resonance imaging (MRI), which guides and monitors the treatment. During the procedure, delivery of focused ultrasound energy is guided and controlled using MR thermal imaging. Patients who have symptomatic fibroids, who desire a non-invasive treatment option, and who do not have contraindications for MRI are candidates for MRgFUS. About 60% of patients qualify. It is an outpatient procedure and takes one to three hours, depending on the size of the fibroids. It is safe and about 75% effective. Symptomatic improvement is sustained for two plus years. Need for additional treatment varies from 16 to 20% and is largely dependent on the amount of fibroid that can be safely ablated; the higher the ablated volume, the lower the re-treatment rate. There are currently no randomized trials between MRgFUS and UAE. A multi-center trial is underway to investigate the efficacy of MRgFUS vs. UAE. ==Prognosis==

About 1 out of 1,000 lesions are or become malignant, typically as a leiomyosarcoma on histology. A sign that a lesion may be malignant is growth after menopause. There is no consensus among pathologists regarding the transformation of leiomyoma into a sarcoma. Metastasis There are rare conditions in which fibroids metastasize, for example, extrauterine fibroids. They still grow benignly, but can be dangerous depending on their location. ==Epidemiology==

About 20% to 80% of women develop fibroids by the age of 50. Up to 50% of people with uterine fibroids have no symptoms. The prevalence of uterine fibroids among teenagers is 0.4%. African American women are two to three times more likely to get fibroids than Caucasian women. In African American women fibroids seem to occur at a younger age, grow more quickly, and are more likely to cause symptoms. This leads to higher rates of surgery for African Americans, both myomectomy, and hysterectomy. Increased risk of fibroids in African Americans causes them to fare worse in in-vitro fertility treatments and raises their risk of premature births and delivery by Caesarean section. It is unclear why fibroids are more common in African American women. Some studies suggest that black women who have obesity and high blood pressure are more likely to have fibroids. Other suggested causes include the tendency of African American women to consume food with less than the daily requirements for vitamin D. ==Related legislation==

United States The 2005 S.1289 bill was read twice and referred to the committee on Health, Labor, and Pensions but never passed for a Senate or House vote; the proposed Uterine Fibroid Research and Education Act of 2005 mentioned that $5 billion is spent annually on hysterectomy surgeries each year, which affect 22% of African Americans and 7% of Caucasian women. The bill also called for additional funding for research and educational purposes. It also states that of the $28 billion issued to NIH, $5 million was allocated for uterine fibroids in 2004. ==Other animals==

Uterine fibroids are rare in other mammals, although they have been observed in certain dogs and Baltic grey seals. ==Research==

Selective progesterone receptor modulators, such as progenta, have been under investigation. Another selective progesterone receptor modulator asoprisnil is being tested with promising results as a possible treatment for fibroids, intended to provide the advantages of progesterone antagonists without their adverse effects. Myomectomy and uterine artery embolisation seem to be equally effective in improving quality of life, as measured 4 years after surgery. == Notes ==