Version May 2024
INTRODUCTION — Uterine fibroids (leiomyomas) are the most common pelvic neoplasm in females [1,2]. They are nonmalignant monoclonal tumors arising from the smooth muscle cells of the myometrium. The pathogenesis of leiomyomas is not well understood. Genetic predisposition, environmental factors, steroid hormones, and growth factors important in fibrotic processes and angiogenesis all play a role in the formation and growth of uterine fibroids [3]. The disease is heterogeneous, and different fibroids within the same uterus may have different etiologies and arise from different somatic mutations [4]. Leiomyoma-related effects on the function and structure of the endometrium are the final common pathways in the pathogenesis of excessive bleeding in myomatous uteri, and there is evidence of both histologic changes in the endometrium and endometrial vasculature in these uteri [5,6].
The pathogenesis of uterine leiomyomas is reviewed here. The diagnosis and management of leiomyomas as well as variants of leiomyomas are discussed separately. (See "Uterine fibroids (leiomyomas): Epidemiology, clinical features, diagnosis, and natural history" and "Uterine fibroids (leiomyomas): Treatment overview" and "Uterine fibroids (leiomyomas): Variants and smooth muscle tumors of uncertain malignant potential".)
HISTOLOGY — Uterine leiomyomas are noncancerous monoclonal neoplasms arising from uterine smooth muscle cells and fibroblasts [7,8]. They contain a large amount of extracellular matrix (including collagen, proteoglycan, fibronectin) and are surrounded by a thin pseudocapsule of areolar tissue and compressed muscle fibers.
Leiomyomas are nonmalignant lesions. However, there is a heterogeneous group of lesions which have some, but not all, characteristics of malignant disease termed leiomyoma variants. Leiomyoma variants are classified as benign, malignant, or of uncertain potential based upon histologic features and clinical behavior. (See "Uterine fibroids (leiomyomas): Variants and smooth muscle tumors of uncertain malignant potential".)
PATHOGENESIS — At least two distinct components contribute to leiomyoma development:
●Transformation of normal myocytes into abnormal myocytes, in most instances through somatic mutations.
●Growth of abnormal myocytes into clinically apparent neoplasms.
The first process appears to be quite common, in view of the high prevalence of microscopic myomas [9]. Myometrial and leiomyoma stem cells have been identified that transform and grow into leiomyomas under the influence of hormones. The subsequent growth of the neoplasm occurs via clonal expansion from a single cell and will likely be a better target for new therapeutic interventions [10,11].
GENETICS — Uterine leiomyomas are a common phenotype with differing genotypes. There appear to be multiple different genetic pathways to phenotypic leiomyomas [12].
Most fibroids arise from somatic mutations with mediator complex subunit 12 (MED12) being by far the most common group followed by high mobility group AT-hook (HMGA1 and HMGA2), and collagen type IV, alpha-5 and alpha-6 (COL4A5 and COL4A6) [12-15]. Inherited mutations in the fumarate hydratase gene (FH) also comprise a major fibroid subgroup with these individuals and their families at risk of hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC), a rare autosomal dominant syndrome characterized by cutaneous and uterine leiomyomas and an aggressive form of papillary renal cell cancer. Patients with HLRCC syndrome appear to be at an increased risk of uterine sarcoma. This is discussed in detail separately [15,16] (see "Hereditary leiomyomatosis and renal cell cancer (HLRCC)"). There are also rare cases of somatic FH mutations in fibroids [17]. A small group of fibroids have no recognized mutation.
There is some evidence of genotype/phenotype relationships in fibroids including the fact that MED12 mutations seem to be associated with fibroids of smaller size [13]. While it has been reported that MED12 and FH mutations do not coexist [18], due to the independent clonal nature of fibroids within the same uterus, multiple genotypes can exist simultaneously in the same uterus, and downstream signaling pathways appear redundant for all the groups with the exception of the FH group [19].
STEROID HORMONES — Gonadal steroid hormones are an important influence in leiomyoma pathogenesis. While traditional teaching has always highlighted the role of estrogen, progesterone appears to be the important hormone [20-22]. Progesterone receptors are upregulated in leiomyomas compared with normal myometrium, although the truncated PR-A isoform appears to predominate in both leiomyomas and myometrium [20,23,24].
Estrogens also influence fibroid development. Estrogen receptor alpha appears upregulated in all leiomyomas, and estrogen receptor beta is sometimes upregulated in various ethnic groups [25,26]. Myomas also appear to have a modest increase in the type 1 isotype of 17-beta hydroxysteroid dehydrogenase [27].
Biologically, the enzyme aromatase (coded for by the gene CYP19), which converts androgens to estrogens, appears to be an important regulator of estrogen response in leiomyomas. Aromatase is upregulated in leiomyoma cells compared with normal myometrium [28,29]. The transcription of CYP19 is controlled by a variety of promoters, and there appear to be differences in the promoter across ethnic and racial groups [30,31]. As an example, African American patients differentially use the proximal II aromatase promoter that appears to be correlated with higher expression of CYP19 mRNA [25].
The steroid hormone effect on leiomyomas is also evident in the role of endocrine-disrupting chemicals in increasing the risk of leiomyomas [32]. One study reported that a 20 to 39 percent probability of causation of fibroids could be attributed to diphenyl dichloroethene, an insecticide [33]. Also, early-life exposures such as diethylstilbestrol have been found to be associated with fibroid incidence in some studies [34,35] but not others [36]; recall bias may influence results [37,38].
STEM CELLS — Stem cells appear to play a key role in fibroid pathogenesis [39-41]. Stem cells have few receptors for steroid hormone compared with mature myometrial cells and paracrine interactions such as from the Wnt/beta-catenin signaling pathway may also play a key role in fibroid pathogenesis [40,42].
VASCULAR ABNORMALITIES — Abnormalities in uterine blood vessels and angiogenic growth factors appear to play a role in the pathobiology of myoma formation. The myomatous uterus has increased numbers of arterioles and venules, as well as venular ectasia (dilation) [43]. Molecular alterations leading to increased vessel number or abnormal function are the likely mechanisms for these abnormalities, although the venous changes were originally thought to be induced by physical compression of the vascular structures by bulky myomas [5].
It is possible that myoma formation is a response to injury, much like an atherosclerotic plaque that forms in response to hypoxia of arterial muscle [44]. Hypoxia of myometrial cells during menstruation may promote transformation of normal myocytes to abnormal myocytes and subsequently to leiomyomas. The fact that atherogenic risk factors appear to be more common in patients with leiomyomas supports this hypothesis [45].
The effect of vascular factors is also demonstrated at a molecular level. The angiogenic growth factor fibroblast growth factor-2 (also called basic fibroblast growth factor) and its receptor appear significantly altered in the leiomyomatous uterus [46-48].
FIBROTIC FACTORS — Leiomyomas can be viewed as a fibrotic process with abnormalities of the extracellular matrix at many levels. There is upregulation of the mRNA and protein for major extracellular matrix (ECM) components, particularly type I and III collagen [49]. Decreased expression of the collagen-binding protein dermatopontin is seen both in leiomyomas and in keloid scars, possibly suggesting a link between both of these abnormalities in Black patients [50]; however, no association was found between keloids and fibroids in the prospective Study of Environment, Life-style & Fibroids cohort [51]. There is also increasing information that the morphologic arrangement of extracellular components is abnormal in myomas and that the increased stiffness of these ECM alterations leads to altered gene expression through solid-state signaling [52,53].
Fibrotic growth factors are also dysregulated in leiomyomas. Transforming growth factor-beta (TGF-beta) and granulocyte-macrophage colony-stimulating factor (GM-CSF), which are involved in other fibrotic processes, may also contribute to the pathophysiology of leiomyomas. When obtained from the secretory phase of the menstrual cycle, leiomyomas appear to have higher levels of TGF-beta and TGF-beta receptor mRNA and protein than myometrium [54]. In addition, there is a substantial reduction in TGF-beta levels in the leiomyomas of patients treated with a gonadotropin-releasing hormone agonist to diminish the size of their tumors prior to surgical extirpation [54]. The association between vitamin D deficiency and uterine fibroids may be mediated in part by the effect of vitamin D on the TGF-beta pathways [55].
GM-CSF may differentially stimulate leiomyomas and normal myometrium both on its own and through an increase in expression of TGF-beta [56]. A TGF-beta homologue, endometrial bleeding-associated factor (EBAF, now called LEFTY-A), which is normally expressed in the endometrium only in the luteal phase of the menstrual cycle, is expressed throughout the cycle in patients with abnormal uterine bleeding of various etiologies, including leiomyomas [57].
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Beyond the Basics topic (see "Patient education: Uterine fibroids (Beyond the Basics)")
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Uterine fibroids (leiomyomas)".)
SUMMARY
●Histology – Uterine fibroids (leiomyomas) are noncancerous monoclonal neoplasms arising from the smooth muscle cells of the myometrium. They contain a large amount of extracellular matrix (including collagen, proteoglycan, fibronectin) and are surrounded by a thin pseudocapsule of areolar tissue and compressed muscle fibers. (See 'Histology' above.)
●Pathogenesis – Two distinct components contribute to leiomyoma development: transformation of normal myocytes into abnormal myocytes and growth of abnormal myocytes into clinically apparent tumors. Multiple factors likely play a role in both this transformation and growth acceleration for leiomyomas. (See 'Pathogenesis' above.)
●Genetics – Uterine leiomyomas are a common phenotype with many underlying genotypes. Both somatic and inherited mutations account for the majority of uterine fibroids, with the most common mutations occurring in the MED12, HMGA1 and HMGA2, FH, collagen type IV, alpha-5 (COL4A5) and collagen type IV alpha-6 (COL4A6) genes. (See 'Genetics' above.)
●Role of different factors – Genetic predisposition, environmental factors, steroid hormones, and growth factors important in fibrotic processes and angiogenesis all play a role in the formation and growth of uterine fibroids. (See 'Introduction' above.)
•Steroid hormones – Steroid hormone factors that influence leiomyoma development include upregulation of aromatase, estrogen, and progesterone receptors as well as a potential role of gonadotropins. (See 'Steroid hormones' above.)
•Stem cells – Stem cells appear to also play a key role in fibroid pathogenesis. (See 'Stem cells' above.)
•Vascular abnormalities – The myomatous uterus has increased numbers of arterioles and venules, as well as venular ectasia (dilation). In addition, the angiogenic growth factor fibroblast growth factor-2 and its receptor appear significantly altered in the leiomyomatous uterus. (See 'Vascular abnormalities' above.)
•Fibrotic factors – Leiomyomas can be viewed as a fibrotic process with abnormalities of the extracellular matrix at many levels. (See 'Fibrotic factors' above.)
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