Uterine Fibroids — Leiomyoma

Uterine leiomyomas (fibroids) are benign smooth muscle tumors of the uterus that arise from the myometrium and represent the most common pelvic tumor in women of reproductive age. They have a prevalence of 70–80% by age 50 years, though only 20–25% are clinically symptomatic. Leiomyomas affect women of all races but demonstrate a 3–9 fold increased prevalence in Black women compared to white women, with earlier onset and more aggressive phenotypes in this population. Despite being benign, fibroids are clinically significant because they cause substantial morbidity (heavy menstrual bleeding, anemia, infertility, pelvic pain), represent a leading indication for hysterectomy in the United States, and frequently appear on Step 2 CK requiring knowledge of diagnostic criteria, imaging interpretation, and management algorithms.

The development and growth of uterine leiomyomas involve complex interactions between genetic mutations, aberrant growth factor signaling, altered estrogen and progesterone receptor expression, and abnormal myometrial stem cell differentiation. The following mechanisms drive fibroid pathogenesis and explain their clinical behavior:

- Clonal Origin and Somatic Mutations: Leiomyomas arise from a single smooth muscle cell that acquires genetic mutations, conferring them a monoclonal origin. The most frequent mutations involve HMGA2 (10–40% of cases), MED12 (40–50% of cases affecting codon 44), and FUBP1 (1–3% of cases). MED12 mutations are particularly associated with intramural fibroids and appear to confer growth advantages by disrupting normal mediator complex function and transcriptional regulation. These mutations create a selective growth advantage, leading to clonal expansion of the mutated cell population. Notably, the same mutations are not found in morphologically normal myometrium from affected women, confirming the acquired (somatic) rather than germline nature of these genetic alterations.

- Altered Estrogen and Progesterone Signaling: Leiomyomas exist in an estrogen-rich microenvironment created through multiple mechanisms. Fibroid tissue exhibits increased expression of aromatase (CYP19A1), the enzyme catalyzing the final step of estrogen synthesis from androgens, resulting in local estrogen production up to 2–3 fold higher than in normal myometrium. Additionally, leiomyomas show increased expression of estrogen receptor-β (ER-β) relative to estrogen receptor-α (ER-α), altering the balance toward ER-β-mediated proliferative signaling. Concurrently, progesterone resistance develops through multiple mechanisms: decreased progesterone receptor-B (PR-B) to progesterone receptor-A (PR-A) ratio, impaired co-activator recruitment, and altered expression of progesterone response element genes. This progesterone resistance explains the incomplete response to progestin-based therapies in some women. The altered estrogen-progesterone milieu drives smooth muscle proliferation, reduces apoptosis, and promotes the accumulation of extracellular matrix.

- Growth Factor and Cytokine Dysregulation: Leiomyomas produce elevated levels of multiple growth factors that promote both autocrine (self-stimulating) and paracrine (stimulating surrounding tissue) proliferation. Transforming growth factor-beta (TGF-β), particularly TGF-β3, is markedly elevated in fibroids and drives excessive extracellular matrix deposition while promoting smooth muscle proliferation. Basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) are upregulated, promoting angiogenesis and nutrient delivery to growing fibroids. Dysregulated expression of cytokines (IL-6, IL-8, IL-11) and chemokines creates a pro-inflammatory microenvironment that recruits immune cells and further perpetuates growth signaling. This growth factor-rich environment explains why fibroids continue to grow even when estrogen levels are suppressed, indicating growth factor signaling can function independently of classical hormone pathways.

- Abnormal Myometrial Stem Cell Biology: Emerging evidence indicates that leiomyomas may arise from dysfunction of bone marrow-derived stem cells or resident myometrial progenitor cells. Altered homing of stem cells to the myometrium, combined with impaired differentiation and increased self-renewal capacity, may establish a "niche" favoring tumor initiation and growth. The fibroid microenvironment itself becomes dysregulated, with altered perivascular cells and abnormal interactions between smooth muscle cells and fibroblasts that perpetuate proliferation.

- Extracellular Matrix Remodeling and Fibrosis: Leiomyomas contain excessive and abnormally organized extracellular matrix (ECM), which comprises up to 40% of fibroid tissue compared to 10% of normal myometrium. Elevated TGF-β drives fibroblasts and myofibroblasts to produce abundant collagen (types I, III, and IV) and other ECM components. The ECM becomes increasingly cross-linked and organized into fibrous bands, creating the characteristic firm, whorled appearance of fibroids. This ECM accumulation contributes to the mechanical distortion of the uterus and has critical implications for treatment—mechanical removal via myomectomy may be necessary when fibroids are large enough to cause significant ECM-based structural deformity.

- Angiogenesis and Neovascularization: Fibroids require increased blood supply to sustain growth. Elevated VEGF and placental growth factor (PlGF) promote formation of new blood vessels. However, these vessels are often structurally abnormal with increased permeability and shunting, explaining the tendency toward heavy bleeding. The vessel architecture is chaotic compared to normal myometrial vessels, predisposing to both excessive menstrual bleeding and potentially to placental abnormalities in pregnancy.

Leiomyomas are acquired benign tumors with multifactorial pathogenesis. Unlike many other gynecologic conditions, there is no single definable "cause," but rather identified risk factors and conditions that increase susceptibility:

- Age (Peak Incidence 40–50 Years): Leiomyomas increase in incidence and prevalence with advancing reproductive age. The cumulative risk of developing clinically detectable fibroids by age 50 approaches 70–80%. This age-related increase reflects both the time required for somatic mutations to accumulate and occur and the prolonged duration of estrogen and progesterone exposure over decades of reproductive life. Fibroids rarely present before age 20 and typically do not develop or grow substantially after menopause when steroid hormone levels decline, though pre-existing fibroids may persist as estrogen-producing tumors.

- Race and Ethnicity (Black > White > Asian populations): Black women have a 3–9 fold higher prevalence of leiomyomas compared to white women and experience fibroids at younger ages (mean age at diagnosis 40 years in Black women vs 44 years in white women). Fibroids in Black women tend to be more numerous, larger at diagnosis, and more symptomatic. The biological basis for this striking disparity remains incompletely understood but likely involves genetic polymorphisms affecting growth factor signaling, stem cell biology, and hormone metabolism, combined with potential environmental and socioeconomic factors. This disparity represents one of the most significant health inequities in gynecology and is a critical board concept.

- Obesity (BMI >30 kg/m²): Obesity increases fibroid risk, likely through multiple mechanisms including elevated circulating and adipose tissue-derived estrogen, chronic systemic inflammation, and altered immune function. Some studies suggest a 2–3 fold increased risk in obese versus normal-weight women, though the relationship is not uniformly linear across all studies.

- Nulliparity and Reduced Parity: Nulliparous women (never pregnant) have increased leiomyoma risk compared to women with completed pregnancies. Each pregnancy is associated with a modest reduction in fibroid risk, with parity acting as a protective factor. This may relate to pregnancy-associated involution and remodeling of the myometrium, which may suppress fibroid development or growth. The protective effect is most pronounced after full-term pregnancies.

- Hormonal Factors: Prolonged estrogen and progesterone exposure increases fibroid risk. Early menarche (age <12 years) and late menopause are associated with increased risk due to extended reproductive years of hormone exposure. Use of estrogen-only hormone replacement therapy may increase fibroid risk, though combined estrogen-progestin regimens and oral contraceptives show variable or neutral effects. Conversely, long-acting reversible contraceptives (LARCs) like the levonorgestrel intrauterine device (LUD) may reduce fibroid growth.

- Genetic Predisposition: While individual fibroids are clonal (monoclonal origin), familial clustering occurs, suggesting genetic susceptibility. Twin studies suggest heritability of approximately 40%. Polymorphisms in genes regulating estrogen metabolism (CYP19, ESR1), TGF-β signaling, and cell cycle regulation may predispose to fibroid development. However, no single germline mutation accounts for the majority of cases; inheritance appears polygenic.

- Metabolic and Inflammatory States: Emerging evidence suggests insulin resistance, metabolic syndrome, and chronic inflammation may increase fibroid risk or growth. Elevated circulating inflammatory markers (CRP, IL-6) correlate with fibroid presence and growth, suggesting a pro-inflammatory state contributes to pathogenesis.

The clinical presentation of uterine leiomyomas ranges from asymptomatic incidental findings to severe symptoms causing substantial disability. Symptomatology depends on fibroid location, size, and relation to the endometrium and adjacent pelvic structures. The mechanisms underlying symptoms are distinct based on fibroid phenotype:

- Heavy Menstrual Bleeding (Menorrhagia) — Most Common Symptom: Occurs in 30–40% of women with fibroids and represents the leading reason for medical intervention. The mechanism is multifactorial: (1) increased surface area of endometrium overlying submucosal fibroids exposes a larger vascular bed; (2) abnormal angiogenesis within fibroids and surrounding myometrium creates structurally abnormal, leaky vessels prone to excessive bleeding; (3) alteration of hemostatic mechanisms—fibroid tissue exhibits reduced expression of tissue factor pathway inhibitor (TFPI) and altered thrombin generation, impairing localized hemostasis; (4) mechanical distortion preventing normal myometrial contraction needed for hemostasis; (5) elevated local prostaglandins and inflammatory mediators (IL-6, IL-8) that promote vasodilation and inhibit vasoconstriction. Bleeding is typically cyclical (worse in first 1–2 days of menses) but can be continuous in severe cases, leading to iron deficiency anemia in 20–40% of symptomatic women.

- Dysmenorrhea (Menstrual Cramps and Pelvic Pain): Occurs in 15–30% of women with fibroids, particularly submucosal and intramural fibroids that distort the endometrial cavity. Pain results from increased uterine contractions and elevated prostaglandins and leukotriene production. Myometrial contractions intensify as the uterus attempts to expel fibroid tissue or compensate for abnormal cavity shape. Pain is typically crampy and colicky, worse during menses, and may be accompanied by passage of clots.

- Chronic Pelvic Pain and Pressure: Intramural and subserosal fibroids, particularly when large (>4 cm), cause mechanical distortion and expansion of the uterus, creating a sensation of pelvic heaviness, pressure, or fullness. This is distinct from dysmenorrhea and may be constant or worsen with prolonged standing, physical activity, or menses. The pain arises from stretching of the uterine serosa (visceral peritoneum) and mechanical compression of adjacent structures.

- Urinary Symptoms (Frequency and Urgency): Large anterior fibroids may compress the bladder, reducing bladder capacity and causing urinary frequency (>8 times daily), urgency, and occasionally urinary retention. On examination, abdominal mass may be palpable. Rarely, large fibroids can compress the urethra causing obstructive uropathy with elevated creatinine, though this is uncommon.

- Bowel Symptoms (Constipation): Posterior and subserosal fibroids may compress the rectosigmoid colon, causing constipation, incomplete evacuation, and rarely fecal incontinence if nerve plexuses are compressed. These symptoms typically develop insidiously and improve following fibroid removal.

- Infertility and Reproductive Dysfunction: Fibroids are implicated in 2–3% of infertility cases, with submucosal fibroids having the most significant impact on fertility. Mechanisms include: (1) endometrial cavity distortion impairing embryo implantation or causing mechanical miscarriage; (2) altered endometrial receptivity with impaired stromal development and abnormal secretory response; (3) reduced endometrial blood flow to areas overlying fibroids; (4) abnormal uterine contractions preventing normal sperm transport and embryo placement; (5) tubal compression or obstruction by fibroids in the cornual region. Fibroids may also increase miscarriage rates (odds ratio approximately 1.5–2.0) through similar mechanisms. Fertility preservation is an important consideration in reproductive-aged women, influencing treatment decisions toward myomectomy over hysterectomy.

- Dysfunctional Uterine Bleeding (DUB) Pattern: Some women present with irregular, prolonged, or continuous bleeding rather than simple heavy menstrual bleeding, attributed to altered prostaglandin and cytokine production and abnormal endometrial vascular architecture. Distinguishing DUB from heavy cyclic bleeding has implications for treatment selection.

- Asymptomatic/Incidental Finding: 20–25% of women with leiomyomas are asymptomatic and discovered incidentally on pelvic ultrasound obtained for other indications or during routine pelvic examination. Asymptomatic fibroids do not require treatment.

Diagnosis of uterine leiomyomas combines clinical suspicion (based on symptoms and examination findings) with imaging confirmation. No laboratory tests are pathognomonic; diagnosis is primarily radiological.

- Clinical History and Physical Examination: Detailed menstrual history including cycle length, duration of menses, number of pads/tampons used daily (soaking >1 pad per hour suggests heavy bleeding), presence of clots, dysmenorrhea severity, and impact on quality of life. Assessment for infertility, pelvic pain, and pressure symptoms. Bimanual pelvic examination revealing an enlarged, firm, irregularly nodular uterus with preserved mobility (unless fibroids very large) strongly suggests leiomyomas. The examination should also assess for cervical masses (unlikely) and exclude other masses.

- Transvaginal Ultrasound (TVUS) — First-Line Imaging: Transvaginal ultrasound is the initial imaging modality of choice due to superior resolution of fibroid size, location, and relationship to the endometrial cavity. A complete ultrasound assessment includes:

Management follows ACOG's Practice Bulletin on management of symptomatic uterine leiomyomas and is driven by symptoms, fibroid location (FIGO type), and desire for future fertility — not by size alone.