Pathophysiology of Uterine Fibroids (Myomas)
Uterine fibroids are benign, monoclonal tumors that arise from myometrial smooth muscle cells and fibroblasts, characterized by a fundamental defect where these cells become "stuck" in a pregnancy-like differentiated state with hormonal hypersensitivity and inability to respond to normal apoptotic signals. 1
Cellular Origin and Clonal Nature
Fibroids originate as monoclonal neoplasms from individual myometrial smooth muscle cells that have undergone genetic alterations, with approximately one-third demonstrating clonal chromosomal aberrations 2, 1.
The tumors are characterized by increased smooth muscle cell proliferation combined with excessive collagen deposition, creating well-vascularized masses with significant extracellular matrix accumulation 1, 3.
These neoplastic cells represent clonal expansions of genetically altered myometrial cells, indicating that specific genetic mutations in individual cells initiate tumor development 2, 4.
Hormonal Hypersensitivity: The Central Pathophysiologic Mechanism
The American College of Obstetricians and Gynecologists identifies that fibroid cells exhibit an estrogen-driven pattern of gene expression similar to normal myometrium during pregnancy, with both estrogen and progesterone receptors required for growth 1.
The National Institute of Child Health and Human Development describes the core defect as hormonal hypersensitivity combined with defective cellular differentiation that prevents normal apoptosis 1.
Fibroid cells mimic differentiated myometrial cells at pregnancy and exhibit hypersensitivity to sex steroid hormones, preventing them from responding to normal apoptotic or dedifferentiation signals and returning to a non-gravid phenotype 2.
This explains why fibroids are not noted prior to puberty, typically regress after menopause, often enlarge dramatically during pregnancy, and can shrink with medically induced hypogonadism 2.
The Prostaglandin Defect: Why Fibroids Persist
The European Society of Human Reproduction and Embryology identifies a critical defect: fibroid cells lack the ability to produce or respond to prostaglandins, which are key signaling molecules that mediate parturition and postpartum myometrial involution 1.
In normal myometrium, prostaglandins induce either apoptosis or dedifferentiation in postpartum cells, allowing return to the non-gravid state 1.
Fibroid cells contain defects in this prostaglandin signaling pathway and thereby persist in a proliferative phenotype, unable to undergo the normal regression that occurs in postpartum myometrium 2.
This results in increased cellular proliferation and decreased apoptosis compared to normal myometrium, leading to tumor accumulation 2.
Growth Factor Dysregulation
The Society for Gynecologic Investigation reports that TGF-β3 is elevated 5-fold in leiomyomas compared to normal myometrium, while TGF-β1 shows no consistent pattern 1.
TGF-β signaling promotes increased extracellular matrix production and decreased collagenase production, contributing to the characteristic fibrotic nature of these tumors 1.
The American Society for Reproductive Medicine identifies multiple dysregulated growth factors in fibroids, including platelet-derived growth factor, heparin-binding epidermal growth factor, hepatoma-derived growth factor, and basic fibroblast growth factor, which play regulatory roles in smooth muscle cell proliferation and collagen production 1.
Genetic Alterations
Specific cytogenetic anomalies have been identified, including the 12:14 chromosomal translocation resulting in abnormal expression of the high-mobility group IC gene 4, 5.
Loss of the tuberous sclerosis 2 gene has been shown to result in leiomyoma development 4.
Fibroids with abnormal karyotypes tend to be larger than those with normal karyotypes, suggesting different genetic subgroups have distinct clinical behaviors 4.
MED12 mutations are frequently obtained at certain stages of fibroid development, often coinciding with cytogenetic aberrations 6.
Molecular Pathways
Mammalian target of rapamycin (mTOR), a master regulator of proliferation, is activated in many fibroids, possibly by mechanisms similar to human fibrosis syndromes or by mutation of upstream tumor suppressor genes 6.
Menstrual cycle-related injury and repair with coinciding hormonal cycling appears to affect myometrial stem cells that eventually obtain genetic aberrations 6.
Clinical Implications of the Pathophysiology
The American College of Obstetricians and Gynecologists notes that understanding this pathophysiology explains why only 20-50% of women with fibroids develop symptoms requiring treatment, despite prevalence reaching 70-80% by age 50 1.
The hormonal dependence accounts for the high incidence during reproductive years and the benign nature of these tumors 2.
The National Institute of Child Health and Human Development emphasizes that fibroids being "stuck" in a pregnancy-like differentiated state explains their responsiveness to hormonal therapies that reduce estrogen and progesterone signaling 1.
Race represents a major genetic risk factor, with Black women having over 80% incidence by age 50 compared to 70% in White women 4, 5.