Uterine fibroids, commonly known as fibroids, are benign tumors that develop from the smooth muscle tissue of the uterus, often during the reproductive years of women. Also referred to as leiomyomas or myomas, they consist of muscle cells and fibrous connective tissue and are the most common noncancerous gynecologic tumors, affecting up to 70% of white women and more than 80% of Black women by age 50.[1][2]These growths can vary in size, number, and location within or on the uterus—such as intramural (within the uterine wall), submucosal (inside the uterine cavity), or subserosal (on the outer surface)—and many remain asymptomatic throughout a woman's life.[3] When symptoms do occur, they frequently include heavy menstrual bleeding, pelvic pain or pressure, frequent urination, constipation, or infertility, and fibroids tend to enlarge under the influence of estrogen and progesterone before shrinking after menopause.[4]Several risk factors contribute to the development of fibroids, including African American race, family history, obesity, early onset of menstruation, and vitamin D deficiency, though the exact cause remains multifactorial, involving genetic, hormonal, and environmental influences.[4][5]Management of fibroids depends on symptom severity, fibroid characteristics, patient age, and fertility desires, with options spanning watchful waiting for mild cases, hormonal medications or intrauterine devices to alleviate bleeding, minimally invasive procedures like uterine artery embolization, and surgical approaches such as myomectomy (fibroid removal) or hysterectomy (uterus removal) for definitive treatment.[6][7]
Signs and symptoms
Common symptoms
Many uterine fibroids are asymptomatic and discovered incidentally during routine pelvic examinations or imaging for other conditions, with estimates indicating that 50% to 80% of affected women experience no noticeable symptoms.[8][9][10] Among those who do have symptoms, the manifestations primarily arise from the fibroids' size, number, and location within or near the uterus, often impacting daily activities and prompting medical consultation when severe.[11][12]The most prevalent symptom is heavy menstrual bleeding, known as menorrhagia, which can involve prolonged periods lasting more than seven days, passage of large blood clots, and soaking through sanitary products every hour or less.[8][10] This excessive blood loss frequently leads to iron-deficiency anemia, characterized by symptoms such as fatigue, weakness, and shortness of breath, significantly reducing quality of life and necessitating evaluation if it interferes with normal functioning.[9][12][11]Pelvic pain or a sensation of pressure is another common complaint, often described as a feeling of fullness or bloating in the lower abdomen, which may worsen during menstruation or intercourse (dyspareunia).[8][10] Larger fibroids can also cause referred pain, including lower backache or leg discomfort due to compression of nearby nerves or structures.[9][12]Compression of adjacent organs by enlarging fibroids may result in urinary symptoms such as frequent urination, urgency, or even incontinence, particularly when fibroids press on the bladder.[8][11] Similarly, pressure on the rectum can lead to constipation, bloating, or difficulty with bowel movements.[10][12] Fibroids, particularly submucosal ones, can also contribute to infertility by distorting the uterine cavity and impairing embryo implantation.[13] These symptoms collectively contribute to diminished physical and emotional well-being, with hormonal fluctuations potentially exacerbating their severity during the reproductive years.[9][11] Medical attention is advised if symptoms persist or intensify, as they can signal the need for intervention to alleviate discomfort and prevent complications like chronic anemia.[8][10]
Pregnancy-related complications
Uterine fibroids during pregnancy are associated with an increased risk of several adverse maternal and fetal outcomes, affecting approximately 10% to 30% of pregnancies in women with fibroids.[14] These complications arise primarily from fibroid growth, degeneration, or distortion of the uterine cavity, leading to heightened risks for both the mother and fetus.[15]One significant concern is the elevated risk of miscarriage, preterm labor, and placental abruption, often linked to fibroid degeneration. Fibroids in the uterine body are more likely to contribute to miscarriage compared to those in the lower uterine segment.[15] Preterm birth risk is also increased, with pooled analyses showing a consistent association across studies.[16]Placental abruption may occur due to degeneration-induced ischemia or mechanical interference by the fibroid.[4] Additionally, fibroid degeneration can precipitate these events by causing inflammation and vascular disruption within the uterus.[17]Pain during pregnancy is frequently caused by red degeneration, also known as carneous degeneration, which involves hemorrhagic infarction of the fibroid and typically occurs in the second trimester.[18] This degeneration leads to severe, localized abdominal pain due to ischemia and necrosis, distinguishing it from general pelvic discomfort.[14] The pain usually resolves within days to weeks with conservative management, but it can mimic other acute abdominal conditions.[19]Large fibroids that obstruct the uterine cavity can result in fetal malpresentation, such as breech or transverse lie, with risks rising to 13% in affected pregnancies compared to 4.5% in controls.[14] They may also cause intrauterine growth restriction by compressing placental blood flow or limiting space for fetal development.[17] These effects are more pronounced with fibroids exceeding 5 cm in diameter or those in submucosal locations.[20]Postpartum, fibroids increase the risk of hemorrhage due to uterine atony, where the uterus fails to contract effectively after delivery, leading to excessive bleeding.[20] This complication is exacerbated by multiple or large fibroids, which impair uterine contractility and can result in blood loss ranging from 900 to 3000 mL.[20] The presence of fibroids contributes to atony as a primary mechanism in these cases.[21]Fibroids are also linked to higher rates of cesarean section, particularly when located submucosally or retroplacentally, due to complications like malpresentation or obstructed labor.[22] Women with large fibroids (>5 cm) face an elevated cesarean risk compared to those without.[20]Management during pregnancy emphasizes monitoring to mitigate these risks, including serial ultrasounds to track fibroid size, location, and effects on fetal growth.[23]Ultrasound is recommended as the primary imaging modality for ongoing assessment, with frequency tailored to fibroid characteristics and pregnancy progression.[24] Close surveillance helps identify early signs of degeneration or obstruction.[25]
Risk factors and causes
Genetic and familial factors
Uterine fibroids, also known as leiomyomas, originate as monoclonal tumors from a single myometrial smooth musclecell, leading to clonal expansion driven by genetic alterations.[26] Cytogenetic abnormalities, including chromosomal rearrangements and deletions, are detectable in approximately 40% of fibroid cases, underscoring their genetic basis.[27] The most prevalent mutation occurs in the MED12 gene, affecting approximately 70% of fibroids and disrupting mediator complex function to promote tumorigenesis.[28] Recent multiomic analyses (as of 2024) show higher proportions of MED12-mutated fibroids in Black women (meta-analysis: 74.5%) compared to White women (65.8%), contributing to racial disparities.[29]Familial predisposition significantly influences fibroid development, with women having an affected first-degree relative experiencing a 2- to 3-fold increased risk compared to those without such history.[30] Heritability estimates for fibroids range from 20% to 50%, based on twin and family studies highlighting shared genetic liability.[31] These patterns suggest polygenic inheritance, where multiple variants contribute to susceptibility.A notable hereditary syndrome linked to fibroids is hereditary leiomyomatosis and renal cell cancer (HLRCC), caused by germline mutations in the FH gene encoding fumarate hydratase.[32] Individuals with HLRCC often develop early-onset, symptomatic, and aggressive uterine leiomyomas, sometimes necessitating hysterectomy at a young age, alongside risks for cutaneous leiomyomas and renal cell carcinoma.[33]Additional genetic drivers include rearrangements of the HMGA2 gene on chromosome 12q14-15, observed in 10-20% of fibroids and associated with overexpression that alters chromatin structure and cell proliferation.[34] Disruptions in the COL4A5 and COL4A6 genes, encoding type IV collagen chains, occur in a subset of cases, often through chromothripsis, and are linked to familial clustering.[34]Racial genetic disparities are evident, particularly in women of African ancestry, who exhibit higher overall fibroid prevalence and severity, with elevated proportions of MED12 mutations compared to other populations.[29]
Hormonal and lifestyle factors
Uterine fibroids, also known as leiomyomas, are estrogen- and progesterone-dependent tumors, with fibroid cells expressing higher levels of estrogen and progesterone receptors compared to normal myometrial cells.[35] This dependency drives their growth primarily during the reproductive years, when ovarian hormone production is elevated, and leads to regression in most cases following menopause due to declining steroid hormone levels.[36]Estrogen promotes fibroid proliferation by stimulating cell division and vascularization, while progesterone enhances extracellular matrix production and inhibits apoptosis, further supporting tumor expansion.[37]Reproductive history significantly influences fibroid risk through hormonal exposure duration. Early menarche (≤11 years) is not significantly associated with increased fibroid risk compared to menarche at ages 12–13 (HR 0.96, 95% CI 0.62–1.48), though later menarche (≥16 years) reduces risk (HR 0.68, 95% CI 0.47–0.99). Nulliparity is associated with approximately 150% higher risk (HR 2.5 for nulliparous vs. parous women), as pregnancy and childbirth appear to exert a protective effect, possibly through postpartum hormonal changes or mechanical alterations in the uterus.[38]Among lifestyle factors, obesity markedly heightens fibroid susceptibility via elevated systemic estrogen levels. Excess adipose tissue facilitates the aromatization of androgens to estrogens, increasing circulating estrogen independently of ovarian production; women with a BMI greater than 30 kg/m² face approximately 19% higher risk (OR 1.19, 95% CI 1.09–1.31) compared to those with normal BMI.[39] Dietary patterns also play a role, with high intake of red meat linked to a 20–70% higher risk, potentially due to heme iron promoting oxidative stress and inflammation that foster fibroid development.[40] Conversely, diets low in fruits and vegetables correlate with elevated risk, as these foods provide antioxidants and fiber that may mitigate estrogen excess; regular consumption of such produce is associated with 20–30% risk reduction.[41]Vitamin D deficiency further compounds vulnerability, with deficient women showing approximately 140% higher odds of fibroids (OR 2.4, 95% CI 1.2–4.9), attributable to vitamin D's role in modulating cell growth and anti-proliferative effects on myometrium.[42]Smoking exhibits a protective association, reducing fibroid risk by 20–30%, attributed to polycyclic aromatic hydrocarbons in tobacco smoke acting as anti-estrogens by inhibiting aromatase activity and accelerating estrogen metabolism.[43] In contrast, moderate alcohol consumption slightly elevates risk, with current drinkers facing a 12–16% higher incidence of new-onset fibroids, possibly through alcohol's enhancement of estrogen receptor activity and disruption of liver detoxification pathways.[44]
Pathophysiology
Classification and locations
Uterine fibroids, also known as leiomyomas, are classified primarily by their anatomical location within or on the uterus using the FIGO (International Federation of Gynecology and Obstetrics) system, which standardizes nomenclature for clinical and research purposes. This system categorizes fibroids into types 0–8 based on their relationship to the endometrial cavity, myometrium, and serosa, with hybrid types indicated by hyphens (e.g., 2-5 for those impacting both endometrium and serosa). The classification highlights how location influences symptoms, such as bleeding from cavity distortion or pressure from external growth.[45]Submucosal fibroids (types 0–2) comprise 5–10% of cases and arise from the myometrium beneath the endometrium, protruding into the uterine cavity and often causing heavy menstrual bleeding and infertility due to impaired endometrial function and vascular disruption. Type 0 is a pedunculated intracavitary fibroid with no myometrial involvement; type 1 involves less than 50% intramural extension; and type 2 involves 50% or more but less than 100% intramural extension while distorting the cavity. Type 3 fibroids are fully intramural but contact the endometrium without cavity distortion.[45][46]Intramural fibroids (type 4) are the most common, accounting for approximately 70% of cases, and develop entirely within the myometrium without contacting the endometrium or serosa, leading to uterine enlargement that can cause pelvic pain, heavy bleeding, and pressure symptoms.[1][47]Subserosal fibroids (types 5–7) represent about 20% of cases and project outward from the serosal surface, potentially compressing adjacent structures like the bladder or rectum and causing urinary frequency, constipation, or back pain. Type 5 has 50% or more intramural extension; type 6 has less than 50%; and type 7 is pedunculated subserosal, attached by a narrow stalk (defined as ≤10% of the fibroid's mean diameter).[45][47]Type 8 encompasses other locations, such as cervical or parasitic fibroids, which are rare and lack direct myometrial attachment; parasitic variants detach from the uterus and derive blood supply from omentum or bowel, risking torsion or infarction. Pedunculated variants (types 0 and 7) carry a risk of torsion due to their stalk, leading to acute pain. Multiple fibroids are typical, with an average of 3–5 per affected uterus, exacerbating symptoms through cumulative mass effect. Fibroid growth is primarily driven by estrogen and progesterone.[45][48]
Cellular and molecular mechanisms
Uterine fibroids, also known as leiomyomas, arise from the transformation of myometrial smooth muscle cells through somaticmutations, resulting in the formation of monoclonal tumors. These mutations, particularly in genes such as MED12, occur in approximately 70% of fibroids and drive clonal expansion by altering cellular proliferation and survival pathways.[26] Evidence from genetic analyses confirms the monoclonal origin, where a single mutated cell proliferates to form the tumor mass, distinguishing fibroids from polyclonal growths in normal myometrium.[49]A hallmark of fibroid progression is the overproduction of extracellular matrix (ECM), characterized by excessive deposition of collagen types I and III, as well as fibronectin, which contributes to tissue fibrosis and rigidity. This ECM remodeling is mediated by upregulated matrix metalloproteinases and tissue inhibitors, leading to a disordered, stiff microenvironment that further promotes smooth muscle cell hypertrophy and inhibits apoptosis.[50] The resulting fibrosis not only supports tumor growth but also enhances mechanotransduction signals that sustain the fibrotic phenotype.[51]Dysregulation of growth factors plays a central role in fibroid proliferation and angiogenesis. Transforming growth factor-β (TGF-β) isoforms, particularly TGF-β3, stimulate ECM synthesis and smooth muscle cell differentiation while promoting vascular endothelial growth factor (VEGF) expression to support neovascularization.[52] Epidermal growth factor (EGF) and insulin-like growth factor-1 (IGF-1) enhance cell cycle progression via receptor tyrosine kinase signaling, amplifying mitogenic responses and contributing to the hypercellular regions within fibroids.[53] These factors collectively create a pro-proliferative niche that sustains tumor expansion.[54]Steroid hormone signaling is pivotal in fibroid maintenance, with upregulated estrogen receptor α (ERα) and progesterone receptors A and B (PR-A/B) driving cell cycle activation. Estrogen binding to ERα induces PR expression, forming a feed-forward loop where progesterone further amplifies ERα activity, leading to increased cyclin D1 and c-Myc expression that promotes G1/S transition.[35] This heightened sensitivity to ovarian steroids results in hormone-dependent growth, explaining the regression of fibroids post-menopause.[55]In larger fibroids, hypoxia-inducible factors (HIFs), especially HIF-1α, are activated due to inadequate vascularization, contributing to central necrosis and degenerative changes. Hypoxic conditions stabilize HIF-1α, which translocates to the nucleus to induce genes involved in glycolysis and angiogenesis, such as VEGF, as a compensatory mechanism; however, persistent hypoxia leads to cell death in avascular cores.[56] This process underscores the role of tumor size in exacerbating metabolic stress.[57]Emerging evidence implicates myometrial stem cells in fibroid initiation, where these progenitor cells acquire somatic mutations and expand clonally to form tumors. Myometrial stem/progenitor cells, identified by markers like CD34 and Sca-1, exhibit self-renewal capacity and differentiate into smooth muscle lineages, potentially serving as the cellular origin when transformed by genetic alterations.[58] This stem cell involvement explains the multicentric nature of fibroids and their responsiveness to hormonal cues.[59]
Diagnosis
Clinical evaluation
The clinical evaluation of uterine fibroids begins with a comprehensive medical history to identify symptoms and risk factors. Patients are queried about menstrual patterns, including heavy menstrual bleeding (menorrhagia), prolonged menses, or irregular cycles, which are common presenting complaints. Additional history focuses on pelvic pain or pressure, fertility challenges such as infertility or recurrent miscarriages, and family history of fibroids, as genetic factors increase susceptibility.[1][60]A bimanual pelvic examination is performed to assess for uterine enlargement, irregularity, or tenderness, which may indicate fibroid presence; the uterus may feel firm, nodular, or asymmetrically enlarged depending on fibroid location. Signs of anemia, such as pallor, are also noted during the general physical exam.[1][61]Symptom severity and impact on quality of life are quantified using validated tools like the Uterine Fibroid Symptom and Quality of Life (UFS-QOL) questionnaire, which assesses bleeding, pain, and health-related quality of life domains through patient-reported items.[62]Differential diagnoses are considered based on history, including adenomyosis (suggested by dysmenorrhea and heavy bleeding without discrete masses) and endometrial cancer (prompted by postmenopausal bleeding or atypical patterns).[1][60]Referral to a specialist is indicated for severe anemia (hemoglobin <10 g/dL) due to chronic blood loss or rapid fibroid growth, which may signal complications requiring urgent assessment.[1][60]
Imaging and laboratory tests
Diagnosis should incorporate standardized systems such as the FIGO classification for fibroid mapping and MUSA guidelines for sonographic assessment to ensure precise reporting of size, number, location, and vascularity.[45]Transvaginal ultrasound (TVUS) is the initial imaging modality of choice for confirming the presence of uterine fibroids due to its accessibility, cost-effectiveness, and high diagnostic accuracy, with sensitivity ranging from 90% to 99% for detecting fibroids greater than 1 cm in diameter.[63] This technique allows for real-time assessment of fibroid size, location, and number, while color Doppler enhances evaluation by identifying vascularity, which can help differentiate fibroids from other pelvic masses and guide treatment planning.[64] TVUS is particularly useful in symptomatic patients, providing essential information for initial management decisions without the need for more invasive procedures in straightforward cases.For complex presentations involving multiple fibroids or suspected complications such as degeneration, magnetic resonance imaging (MRI) serves as the gold standard, offering superior soft-tissue contrast and multiplanar capabilities for precise mapping.[65] MRI demonstrates higher sensitivity (up to 99%) and specificity compared to ultrasound, enabling detailed characterization of fibroid location relative to the endometrial cavity, assessment of degeneration types (e.g., hyaline or red degeneration), and evaluation of uterine distortion, which is critical for preoperative planning in surgical or interventional therapies.[66] T2-weighted sequences are particularly valuable, as they highlight fibroids as well-defined, hypointense masses against the brighter myometrium, facilitating accurate volume estimation and identification of atypical features.[67]Submucosal fibroids, which protrude into the uterine cavity and often cause heavy bleeding, are better delineated with saline infusion sonohysterography (SIS), an adjunct to TVUS that involves instilling sterile saline to distend the endometrium for enhanced visualization.[68]SIS improves detection sensitivity for intracavitary lesions, accurately quantifying the degree of fibroid protrusion into the cavity (e.g., types 0-2 per FIGO classification) and identifying associated polyps or adhesions, thereby informing decisions for hysteroscopic resection.[69]Hysteroscopy complements these imaging tools by providing direct endoscopic visualization of the endometrial cavity, allowing real-time assessment of distortion or submucosal involvement and enabling simultaneous biopsy or resection if indicated.[8] This procedure is especially beneficial for confirming imaging findings in patients with abnormal uterine bleeding, with high specificity for ruling out malignancy in accessible lesions.[70]Laboratory evaluations support imaging by assessing associated complications and excluding mimics. A complete blood count (CBC) is routinely performed to detect anemia from chronic heavy menstrual bleeding, with anemia present in approximately 54% of women with uterine fibroids.[61][71] Serum follicle-stimulating hormone (FSH) levels, typically elevated above 30 mIU/mL in postmenopausal women, help confirm menopausal status in ambiguous presentations, as fibroids rarely persist or grow after menopause without hormonal influence.[36] Beta-human chorionic gonadotropin (beta-hCG) testing is essential to exclude pregnancy prior to imaging or invasive procedures, given the potential for fibroid-related complications in gestation.[72]Endometrial biopsy is reserved for cases with suspicious features, such as rapid fibroid growth (e.g., doubling in size within six months) or postmenopausal bleeding, to exclude rare malignancies like leiomyosarcoma or endometrial hyperplasia/carcinoma.[73] These indications warrant histopathological evaluation, as postmenopausal bleeding carries a 10% risk of endometrial cancer, and rapid enlargement deviates from the typical slow growth of benign fibroids.[74]Biopsy via office-based aspiration or hysteroscopy-guided sampling provides definitive tissue diagnosis, influencing whether conservative management or surgical intervention is pursued.[75]
Treatment
Medical management
Medical management of uterine fibroids primarily involves pharmacological interventions aimed at alleviating symptoms such as heavy menstrual bleeding and pelvic pain, while potentially reducing fibroid size to improve quality of life without invasive procedures.[61] These treatments target the hormonal dependency of fibroids, focusing on estrogen and progesterone modulation, and are often used for short-term symptom control or as a bridge to other therapies.[76]Nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, and tranexamic acid are first-line options for managing abnormal uterine bleeding associated with fibroids. NSAIDs inhibit prostaglandin synthesis to reduce menstrual blood loss and cramping, typically achieving a 30-50% decrease in bleeding volume.[77]Tranexamic acid, an antifibrinolytic agent, promotes blood clotting and further reduces heavy menstrual bleeding by approximately 40%, with dosing limited to heavy flow days to minimize side effects like gastrointestinal upset.[78]For women with mild symptoms, hormonal therapies including combined oral contraceptives or progestins can help regulate menstrual cycles and lessen bleeding. Combined oral contraceptives suppress endometrial proliferation, thereby reducing blood loss in fibroid-related menorrhagia, particularly suitable for younger patients desiring contraception.[77] Progestins, administered orally or via intrauterine devices, provide similar benefits by stabilizing the endometrium, though their efficacy may vary based on fibroid size and location.[79]Gonadotropin-releasing hormone (GnRH) agonists, such as leuprolide, induce a hypoestrogenic state that shrinks fibroids by 30-50% in volume after 3-6 months of use, making them useful preoperatively.[80] However, treatment is generally limited to 6 months due to side effects mimicking menopause, including hot flashes, bone density loss, and mood changes.[81]Selective progesterone receptor modulators (SPRMs), exemplified by ulipristal acetate, offer targeted therapy by partially agonizing and antagonizing progesterone receptors, leading to amenorrhea in about 70% of patients and fibroid volume reduction of up to 25%. Approved for intermittent preoperative use in the European Union since 2012 in women unable to undergo surgery or embolization, ulipristal requires liver function monitoring due to rare risks of hepatotoxicity, with treatment cycles not exceeding 3 months each.[82]Newer oral GnRH antagonists, such as elagolix (in combination as ORIAHNN), linzagolix, and relugolix (as Myfembree), provide rapid symptom relief with dose-dependent estrogen suppression and fewer hypoestrogenic effects when combined with add-back therapy. Elagolix (in combination as ORIAHNN), approved by the FDA in 2020, reduces heavy menstrual bleeding volume by 50-77% and fibroid size by 20-40% over 6 months, with common side effects limited to headache and hot flashes.[83] Relugolix (as Myfembree), approved by the FDA in 2021, similarly reduces bleeding in about 70% of patients and fibroid volume by up to 50% over 6 months with add-back therapy.[84] Linzagolix, approved in the EU and UK in 2022 with a licensing agreement signed in Canada in October 2025 to pursue approval, and a new drug application submitted in Japan in February 2025 pending approval, similarly achieves bleeding reduction in 70-80% of cases at 100-200 mg doses, offering flexible dosing to balance efficacy and tolerability.[85]Iron supplementation is essential for addressing anemia resulting from chronic heavy bleeding, restoring hemoglobin levels and preventing fatigue. Oral iron therapy, typically 325 mg ferrous sulfate daily, corrects iron deficiency in most patients within 3 months when combined with dietary adjustments, though gastrointestinal tolerance may necessitate intravenous alternatives in severe cases.[9]
Surgical and procedural interventions
Surgical and procedural interventions for uterine fibroids are employed when medical management fails to control symptoms or when patients seek definitive treatment, particularly for larger or symptomatic tumors affecting quality of life or fertility. These options range from uterus-preserving procedures to complete removal of the uterus, with selection influenced by fibroid size, number, location, patient age, and desire for future pregnancy. Minimally invasive approaches are preferred when feasible to reduce recovery time and complications compared to traditional open surgery.[86][61]Hysterectomy, the surgical removal of the uterus, serves as the definitive treatment for symptomatic fibroids, eliminating the possibility of recurrence and providing complete symptom resolution. It is the leading indication for hysterectomy in premenopausal women, accounting for over 50% of cases, and can be performed via abdominal, vaginal, laparoscopic, or robotic-assisted routes, with minimally invasive methods associated with shorter hospital stays and faster recovery. Total hysterectomy removes the uterus and cervix, while subtotal spares the cervix; ovaries may be preserved to avoid surgical menopause unless indicated otherwise. However, this procedure ends fertility and is generally reserved for women who have completed childbearing.[86][87]Myomectomy involves the excision of fibroids while preserving the uterus, making it the preferred option for women desiring future fertility or uterine conservation. Approaches include hysteroscopic myomectomy for submucosal fibroids, accessed through the vagina and cervix; laparoscopic or robotic-assisted for intramural or subserosal types, using small incisions; and abdominal open surgery for very large or numerous fibroids. These procedures reduce symptoms effectively but carry a recurrence risk of 15-33% within five years, with approximately 10-21% of patients requiring subsequent hysterectomy. Uterine rupture risk in subsequent pregnancies is low (0.5-2%) with proper counseling and deliveryplanning. Fibroid location, such as submucosal versus intramural, guides the choice of approach to optimize outcomes.[86][88][61]Uterine artery embolization (UAE) is a minimally invasive, uterus-preserving procedure that blocks blood supply to fibroids via catheter insertion in the femoral artery, leading to ischemia and subsequent shrinkage. Performed under local anesthesia on an outpatient basis, it achieves fibroid volume reduction of 40-60% within three to six months and provides symptom relief in about 85% of patients, with low rates of major complications (under 5%). It is suitable for women not seeking immediate fertility, though pregnancy outcomes post-UAE require careful monitoring due to potential placental issues. Long-term reintervention rates are around 20-30% over five years.[61][89][90]MRI-guided focused ultrasound surgery (MRgFUS) offers a noninvasive alternative, using high-intensity ultrasound waves focused under real-time MRI guidance to thermally ablate fibroid tissue without incisions. This outpatient procedure targets specific fibroids, achieving volume reductions of up to 50-70% at one year in recent studies, with symptom improvement in 70-80% of patients and minimal recovery time. It preserves the uterus and is ideal for those avoiding surgery, though efficacy depends on fibroid accessibility and size (typically under 10 cm), and availability remains limited. Re-treatment rates are approximately 15-20% over three years, with rare skin burns or nerve effects.[61][91][92]Radiofrequency ablation (RFA) employs heat generated by radiofrequency energy to destroy fibroid tissue, delivered laparoscopically, transcervically, or transvaginally, allowing precise targeting of individual fibroids while sparing the uterus. This minimally invasive option results in 46% volume reduction at three months and up to 65% at longer follow-up, with rapid symptom relief and return to activities within days. It is effective for smaller fibroids causing pain or bleeding, offering fertility preservation, though data on pregnancy outcomes are emerging. Complication rates are low (under 5%), including minor pain or infection.[61][93][94]Endometrial ablation destroys the uterine lining to control heavy menstrual bleeding associated with fibroids, using techniques like thermal balloon, radiofrequency, or cryoablation, but does not remove fibroids themselves and is unsuitable for large tumors. Performed hysteroscopically or non-hysteroscopically in an office or outpatient setting, it reduces bleeding by 80-90% in appropriately selected patients with small submucosal fibroids, often eliminating periods entirely. It is not recommended for women desiring fertility, as it increases ectopic pregnancy risk, and reintervention may be needed in 10-20% of cases over five years.[95][96][97]
Prognosis and complications
Natural history and outcomes
Uterine fibroids typically exhibit slow growth during the reproductive years, influenced by hormonal factors such as estrogen. Studies indicate that approximately 34% of fibroids demonstrate growth exceeding 20% in volume over a 6-month period, while the median annual growth rate is around 35% in premenopausal women.[73][98] This variability underscores the benign, hormone-dependent nature of fibroids, with many remaining stable or even regressing spontaneously in up to 21% of cases during this phase.[98] Untreated symptomatic fibroids can lead to complications such as iron-deficiency anemia from heavy bleeding, though many remain asymptomatic.[4]Post-menopause, fibroids often regress due to the decline in estrogen levels, with volume reductions typically ranging from 20% to 50% in many cases, though variability exists.[8] This natural involution typically alleviates symptoms, though persistence can occur in some women, particularly those with obesity. Recurrence is a key aspect of the disease course following interventions like myomectomy, with rates ranging from 10-30% within 5 years, depending on surgical approach and patient factors such as age.[88][99]Submucosal fibroids particularly impact fertility, reducing conception rates by approximately 70% (relative risk 0.3) compared to women without fibroids, primarily through distortion of the endometrial cavity.[100] Post-treatment pregnancy rates vary but generally range from 40-60% in women pursuing fertility preservation, with live birth outcomes reaching up to 75% after procedures like myomectomy.[101] Quality-of-life improvements are substantial following interventions, with approximately 80% of women experiencing symptom relief, as measured by enhancements in Uterine Fibroid Symptom and Health-Related Quality of Life (UFS-QOL) scores, including reductions in symptom severity by 25-30 points.[102]A 2025 randomized trial showed that transcervical fibroid ablation offers faster early recovery and reduced pain compared to minimally invasive myomectomy, with comparable short-term safety. As of 2025, studies continue to evaluate long-term recurrence risks with minimally invasive treatments.[103]
Uterine fibroids, or leiomyomas, carry a low risk of malignant transformation into leiomyosarcoma, estimated at 0.1% to 0.5% among presumed benign cases.[104] This risk underscores the importance of monitoring clinical features such as rapid growth or persistence and enlargement after menopause, which serve as key indicators prompting further evaluation.[105][106] Such changes deviate from the typical benign behavior of fibroids and may signal underlying sarcoma, though most rapid-growth cases remain nonmalignant.[73]Certain fibroid variants, including cellular leiomyomas and mitotically active leiomyomas, exhibit atypical features like increased cell density or elevated mitotic activity yet are histologically benign.[107][108] These variants, along with atypical leiomyomas showing bizarre nuclei, are distinguished from leiomyosarcoma primarily through histopathological examination, which reveals low mitotic rates and absence of necrosis despite the concerning morphology.[109][110]Diagnosing malignancy in suspicious fibroids presents challenges due to overlapping imaging and clinical features with benign tumors, often necessitating advanced modalities like PET-CT for metabolic assessment or core biopsy for tissue analysis.[111] Immunohistochemical markers such as Ki-67 for proliferation index and p53 for tumor suppressor dysfunction aid in differentiation, with elevated expression favoring sarcoma over benign variants.[112][113] According to 2025 clinical guidelines, enhanced MRI criteria—including irregular borders, central necrosis, and restricted diffusion—improve suspicion for malignancy, guiding selective use of invasive diagnostics.[45][114][115]Leiomyosarcoma outcomes remain poor, with 5-year survival rates ranging from 20% to 50% depending on stage at diagnosis, and total hysterectomy is the standard initial intervention to achieve local control.[116][117][118] Early detection through vigilant monitoring of high-risk features is critical to improving prognosis in these rare malignant transformations.[119]
Epidemiology
Prevalence and demographics
Uterine fibroids, also known as leiomyomas, affect a significant proportion of women during their reproductive years, with lifetime prevalence estimates indicating that 70-80% of women develop them by age 50.[120][27] This cumulative incidence is derived from histopathological and imaging studies, reflecting both symptomatic and asymptomatic cases.[121]The age distribution of fibroid development shows they are rare before age 20, with incidence increasing during reproductive years and peaking between 35 and 45 years.[122][123] Most new diagnoses occur in women aged 30 to 44, after which rates stabilize or decline post-menopause due to hormonal changes.Racial disparities are pronounced, with Black women experiencing higher prevalence, earlier onset, and more severe manifestations compared to White women. By age 50, over 80% of Black women are affected versus approximately 70% of White women, and Black women are diagnosed at younger ages—often 3 years earlier on average—with larger fibroids and symptoms requiring intervention.[27][124]Black women also face 2-3 times the risk of fibroid-related surgery, such as hysterectomy, contributing to disproportionate health burdens.[125]Socioeconomic factors influence fibroid prevalence and outcomes, with higher rates observed in lower-income groups linked to early-life disadvantages and barriers to preventive care. Women from low socioeconomic backgrounds, including those with childhood economic hardship, show elevated risk, potentially due to cumulative exposures like stress and limited healthcare access that exacerbate undetected growth.[126][127]As of 2025, ultrasound-based prevalence estimates vary widely from 5% to 77% depending on detection methods and populations studied, highlighting challenges in asymptomatic case identification. In the United States, fibroids impact an estimated 26 million women aged 15 to 50, underscoring their public health significance.[128][129]
Global trends and burden
Uterine fibroids affect an estimated 119 million women globally as of 2021, with prevalent cases rising from 66 million in 1990, reflecting a substantial increase driven by population growth and improved detection methods.[130] The age-standardized prevalence rate has shown a slight annual uptick, with an average annual percentage change (AAPC) of 0.078% over the past decade, while the age-standardized incidence rate has increased at an AAPC of 0.27%.[131] This upward trend in diagnoses is partly attributed to advancements in imaging technologies, such as ultrasound and MRI, which enhance early identification of asymptomatic cases.[132]Regional variations highlight disparities influenced by genetic ancestry and environmental factors, with prevalence notably higher among women of African descent, affecting up to 80% by age 50 compared to 70% in white women.[133] In sub-Saharan Africa, the burden is particularly pronounced, with studies indicating elevated rates in urban settings like Ghana's Greater Accra Region, where prevalence reaches 36.9%, potentially due to lifestyle and access differences.[134]The economic burden of uterine fibroids is significant, encompassing direct medical costs, surgical interventions, and indirect losses from reduced productivity. In the United States, the total annual cost reached $41.4 billion in 2022, up from $34.4 billion in 2010, including expenses for treatments and absenteeism.[135] Globally, symptoms such as heavy bleeding and pain contribute to productivity losses, with affected women reporting up to 33% impairment at work, equating to approximately $387 per week in lost output per individual.[136]As a leading cause of hysterectomy worldwide, uterine fibroids account for 40-60% of such procedures, with approximately 200,000 performed annually in the U.S. due to this condition.[137] In low-resource settings, particularly in low- and middle-income countries, disparities exacerbate the burden, including delayed diagnoses and limited access to non-surgical options, leading to higher rates of invasive treatments among underserved populations.[121]
Research and future directions
Ongoing clinical studies
As of 2025, phenome-wide association studies (PheWAS) have advanced the understanding of uterine fibroids by systematically linking them to a broad spectrum of comorbidities. A multicenter PheWAS conducted using electronic health records from approximately 79,000 women identified more than 380 conditions associated with fibroids, including circulatory disorders such as hypertension, as well as issues in skin, genital, urinary, musculoskeletal, and sensory systems.[138] This research, published in May 2025, highlights the extensive health burden beyond reproductive symptoms and underscores the need for integrated care approaches.[139]Research on patient-reported outcome measures (PROMs) is actively validating tools to assess treatment efficacy for uterine fibroids from a patient-centered perspective. A systematic evaluation in 2025 applied the Consensus-based Standards for the selection of health Measurement INstruments (COSMIN) methodology to review existing PROMs, finding that while several instruments cover symptom severity and quality of life, few meet high standards for reliability, validity, and responsiveness specific to fibroid-related outcomes.[140] Another scoping review from July 2025 mapped PROMs literature, revealing gaps in disease-specific measures and recommending development of comprehensive tools to better capture impacts on daily functioning and fertility.[141] These efforts aim to standardize outcome assessment in clinical trials and practice.Economic analyses from 2024 to 2025 have quantified the escalating financial burden of uterine fibroids, emphasizing the need for cost-effective interventions. A comparative cost-analysis updated estimates from 2010 to 2022, projecting total annual costs in the United States at $42.2 billion when including expenses for magnetic resonance-guided focused ultrasoundsurgery (MRgFUS) and infertility treatments, a rise driven by increased utilization of advanced procedures and indirect costs like lost productivity.[135] This study notes a shift toward higher direct medical costs despite reductions in some surgical expenses, highlighting disparities in access that amplify the overall economic impact.[142]Longitudinal cohort studies are tracking fibroid recurrence following minimally invasive treatments to inform long-term management strategies. Ongoing research, including a 2024 cohort, monitors non-perfused volume ratios (NPVR) after ultrasound-guided high-intensity focused ultrasound (USgHIFU), demonstrating sustained efficacy with NPVR ≥80% correlating to low recurrence rates over 2-5 years in over 500 participants.[143] These cohorts also evaluate reintervention needs post-uterine artery embolization (UAE) and myomectomy, reporting variable recurrence rates within 5 years, with factors like fibroid size and location influencing outcomes.Disparity-focused trials, particularly NIH initiatives, are addressing higher risks among Black women through targeted research. The Collaboration for Equity in Uterine Leiomyomas (CEQUAL) project, funded by the NIH since 2023 and ongoing in 2025, examines genetic, environmental, and socioeconomic factors exacerbating fibroid prevalence and severity in Black/African American women, aiming to reduce health inequities via community-engaged interventions.[144] Complementary efforts, including the 2025 Society for Women's Health Research (SWHR) agenda, prioritize uterine fibroids in Black populations, supporting trials on early detection and culturally tailored treatments to mitigate disproportionate symptom burdens.[145]Animal models for uterine fibroids remain limited, primarily utilizing spontaneous occurrences in dogs and seals for comparative pathology insights. In dogs, leiomyomas are documented in breeds like poodles, providing models for benign uterine tumors with histological similarities to human fibroids, though prevalence is low (under 10% in intact females).[146] Gray seals exhibit high incidence rates of up to 65% in older individuals (ages 22-41 years), offering a unique marine mammal model to study environmental influences on fibroid development and pathology.[147] These non-rodent models aid in preclinical testing but are constrained by ethical and logistical challenges in scaling for therapeutic research.[148]
Emerging therapies and prevention
Recent advancements in gene therapy for uterine fibroids focus on targeting recurrent mutations such as those in MED12 and fumarate hydratase (FH), which drive approximately 70% and 10% of cases, respectively. Engineered models have demonstrated that MED12 mutations promote fibroid-like phenotypes in myometrial cells, paving the way for CRISPR-based editing to correct these alterations and prevent tumor initiation.[149] In 2025, Vanderbilt University Medical Center (VUMC) researchers identified 11 previously unpublished fibroid-associated genes and 46 novel loci through a genome-wide meta-analysis, expanding the known total from 72 genes and enabling precision medicine approaches to stratify risk and tailor therapies.[150][31] These discoveries highlight genes like HEATR3, whose dysregulation influences fibroid growth, supporting future gene-targeted interventions to reduce hysterectomy rates in high-risk populations.[150]Emerging pharmacological strategies emphasize novel drugs that disrupt hypoxia-inducible factor (HIF) pathways and angiogenesis, key drivers of fibroid vascularization and proliferation. Selective HIF-1α inhibitors, such as echinomycin and PX-478, have shown preclinical promise by reducing HIF-1α expression, attenuating cell growth, and inducing apoptosis in fibroid models.[56] Anti-angiogenic agents like simvastatin inhibit Wnt/β-catenin signaling to curb proliferation; a phase II trial (NCT03400826) is evaluating its efficacy over three months in symptomatic patients.[56][151] These therapies aim to offer non-hormonal alternatives with fewer side effects than current options, with ongoing refinements targeting fibroid-specific hypoxia signatures identified in 2024 studies.[56]Noninvasive technologies are advancing with refinements in high-intensity focused ultrasound (HIFU), guided by MRI or ultrasound for precise ablation of fibroid tissue while sparing surrounding structures. Updated protocols in 2024-2025 incorporate radiomics and machine learning to predict treatment outcomes and minimize complications like skin burns, achieving symptom relief in many patients within days and supporting fertility preservation.[142][152] Clinical data indicate HIFU efficacy rates of 70-80% for volume reduction in eligible fibroids, particularly types 0-II submucosal lesions, with combined post-treatment management enhancing durability.[153] Laser-guided interstitial thermaltherapy is under exploration as a complementary approach, offering targeted coagulation with real-time imaging, though larger trials are needed to confirm long-term benefits.[154]Prevention strategies center on modifiable factors, with vitamin D supplementation emerging as a key intervention based on trials linking deficiency to increased fibroid risk. A 2024 meta-analysis of randomized controlled trials found that supplementation (e.g., 50,000 IU weekly for 8-12 weeks) reduced fibroid volume by 5.7% (95% CI -10.63 to -0.76) over 2-6 months in deficient women.[155] Another meta-analysis confirmed lower serumvitamin D levels (-5.50 ng/mL) and higher deficiency odds (OR 3.71) in fibroid patients.[156] Lifestyle interventions, including high-fiber diets rich in fruits, vegetables, omega-3s, and green tea catechins (EGCG), show protective effects by lowering estrogen levels and inflammation, particularly in high-risk groups like Black women with earlier onset and higher prevalence.[157]Weight management through exercise and reduced saturated fat intake addresses obesity-related aromatization, potentially mitigating progression in genetically predisposed individuals.[157]Stem cell research underscores the role of myometrial stem cells (MMSCs) in fibroid origins, with 2025 studies revealing that mediator kinase (CDK8/19) inhibition promotes MMSC differentiation into fibroid-like cells via super-enhancer reprogramming. This modulation mimics MED12-mutant phenotypes, affecting ~40% of differentially expressed genes and extracellular matrix production, suggesting therapeutic targeting to block initiation at the progenitor level.[158] Three-dimensional organoid models derived from human MMSCs further enable testing of interventions that restore normal myometrial identity and halt aberrant growth.[159]The 2025 Society for Women's Health Research (SWHR) agenda prioritizes uterine health research, emphasizing fibroids alongside autoimmune conditions like lupus to explore potential inflammatory and immunological links influencing disease burden. This framework advocates for integrated studies on environmental triggers and metabolic factors to advance preventive and therapeutic equity.[160][161]