Root Causes of Uterine Fibroids
The root cause of uterine fibroids is multifactorial, involving a combination of genetic alterations, hormonal factors (particularly estrogen and progesterone), growth factors, and environmental influences, with race, age, parity, and body mass index playing significant roles in their development. 1
Genetic and Cellular Factors
- Monoclonal origin: Fibroids are benign monoclonal neoplasms of the myometrium, composed of smooth muscle cells embedded in an extracellular matrix of collagen, fibronectin, and proteoglycan 1
- Genetic alterations: Approximately 40% of uterine fibroids show cytogenetic alterations similar to those found in other tumor types 2
- Specific translocations: Chromosomal 12:14 translocation results in abnormal expression of the high mobility group IC gene in leiomyomas 1
- Gene loss: Loss of specific genes such as tuberous sclerosis 2 has been shown to result in leiomyoma development 1
Hormonal Influences
- Estrogen and progesterone: Fibroid development correlates with both the metabolism and levels of female sex hormones and the number of hormone receptors expressed on the myometrial surface 2
- Age-related patterns: Fibroid-associated symptoms peak during perimenopausal years and typically decline after menopause, highlighting the hormonal dependency 1
- Proliferative mechanisms: Hormonal effects may be exercised through:
- Proinflammatory factors (TNF alpha)
- Growth factors (IGF1, IGF2, TGF-beta3, and bFGF)
- Inhibitors of apoptosis (p53 suppression) 2
Growth Factor Dysregulation
- Elevated growth factors: Several growth factors have been identified in both normal myometrium and fibroid tumors, including:
- Platelet-derived growth factor
- Heparin-binding epidermal growth factor
- Hepatoma-derived growth factor
- Basic fibroblast growth factor 1
- TGF-β expression: TGF-β3 is consistently elevated in leiomyomas (approximately 5-fold higher) compared to corresponding myometrium, suggesting a key role in fibroid development 1
- Differential responses: Normal myometrial cells show inhibited proliferation in response to TGF-β1, while leiomyoma cells do not show this inhibitory effect, indicating altered growth factor signaling 1
Demographic and Environmental Risk Factors
- Race: Black women have an estimated incidence of fibroids by age 50 exceeding 80%, whereas White women have an incidence approaching 70% 1
- Age: Prevalence increases with age, occurring in 20-50% of women over 30 years 1
- Other risk factors: Early menarche, nulliparity, caffeine and alcohol consumption, chronic inflammation, and obesity have been identified as predisposing factors 2
Clinical Implications
- High prevalence: Uterine fibroids are the most common benign gynecological condition, with approximately one-third of affected women requiring treatment due to symptoms 3
- Economic impact: The societal economic burden of symptomatic fibroids is substantial, ranging from $5.9 to $34.4 billion annually, with lost work hours accounting for the largest proportion 1
- Treatment challenges: The limited understanding of molecular mechanisms underlying fibroid initiation and development has hampered the creation of long-term, non-invasive treatment options 4
Understanding these root causes is essential for developing targeted therapies that address the underlying mechanisms rather than just managing symptoms. Future research focusing on the complex interplay between genetic, hormonal, and environmental factors may lead to more effective interventions for this common condition.