What is the pathophysiology of uterine fibroids?

Pathophysiology of Uterine Fibroids

Uterine fibroids are benign, monoclonal smooth muscle tumors that arise from myometrial cells and exhibit a unique pathophysiology characterized by hormonal hypersensitivity, defective cellular differentiation, and dysregulated growth factor signaling that prevents normal apoptosis.

Cellular Origin and Monoclonal Nature

• Fibroids originate as benign, monoclonal tumors derived from uterine smooth muscle cells (myometrium) and fibroblasts 1.
• These tumors are characterized by increased smooth muscle cell proliferation and excessive collagen deposition, making them well-vascularized masses 1.
• Recent evidence demonstrates that fibroid stem cells have been isolated and appear necessary for tumor growth, representing a fundamental component of fibroid pathogenesis 2.

Hormonal Mechanisms: The Pregnancy Phenotype Model

The central pathophysiologic concept is that fibroid cells mimic differentiated myometrial cells of pregnancy but fail to respond to normal regression signals 1.

Estrogen and Progesterone Dependence

• Fibroids exhibit an estrogen-driven pattern of gene expression similar to normal myometrium during pregnancy, with both estrogen and progesterone receptors (PR-A and PR-B) required for growth 1, 3.
• The tumors demonstrate hypersensitivity to sex steroid hormones due to aberrant expression levels or signaling via estrogen and progesterone receptors 1.
• This hormonal responsiveness explains why fibroids occur predominantly during reproductive years and often regress after menopause 1.

Defective Prostaglandin Signaling

• A critical pathophysiologic defect is that 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, causing them to persist in a proliferative, differentiated phenotype indefinitely 1.

Abnormal Cell Cycle Regulation

• Unlike normal smooth muscle cells, fibroid cells undergo irreversible differentiation that is uncoupled from growth arrest 1.
• These cells continue to proliferate despite being in a differentiated state, with blocked apoptotic pathways allowing accumulation of differentiated, proliferating cells 1.
• This explains the benign nature of fibroids—they are well-differentiated but fail to undergo normal programmed cell death 1.

Growth Factor Dysregulation

Transforming Growth Factor-β (TGF-β)

• TGF-β3 is elevated 5-fold in leiomyomas compared to normal myometrium, while TGF-β1 shows no consistent pattern 1.
• In normal myometrium, TGF-β1 inhibits cell proliferation, but fibroid cells show no inhibitory response to TGF-β1 1.
• TGF-β signaling promotes increased extracellular matrix production and decreased collagenase production, contributing to the fibrotic nature of these tumors 1.

Other Growth Factors

• Multiple growth factors are present and dysregulated in fibroids, including platelet-derived growth factor (PDGF), heparin-binding epidermal growth factor, hepatoma-derived growth factor, and basic fibroblast growth factor 1.
• These growth factors play regulatory roles in smooth muscle cell proliferation and collagen production 1, 4.

Genetic Abnormalities

• Heterogeneous cytogenetic abnormalities are associated with fibroids, including chromosomal 12:14 translocation resulting in abnormal expression of the high mobility group IC gene 1.
• Loss of the tuberous sclerosis 2 gene has been shown to result in leiomyoma development 1.
• Recent discoveries include somatic mutations involving MED12 (mediator subunit complex 12) or HMGA2 (high-mobility group AT-hook 2) in the majority of fibroids 2.

Extracellular Matrix Accumulation

• A defining feature is excessive collagen deposition, particularly types I and III collagen, contributing to the firm, fibrotic nature of these tumors 1.
• The dysregulated TGF-β signaling directly promotes this excessive matrix production while simultaneously decreasing matrix degradation 1.

Clinical Implications of Pathophysiology

• The pathophysiology explains why only 20-50% of women with fibroids develop symptoms requiring treatment—the tumors are benign and slow-growing 3.
• The hormonal dependence accounts for the high incidence during reproductive years, with prevalence reaching 70-80% by age 50 3.
• Understanding that fibroids are "stuck" in a pregnancy-like differentiated state explains their responsiveness to hormonal therapies that reduce estrogen and progesterone signaling 1.

Common Pitfall

A critical caveat is that fibroids cannot be prevented due to multifactorial causes including genetic alterations, hormonal factors, and non-modifiable risk factors such as race and age 3. The pathophysiology involves both cell-intrinsic genetic factors and systemic hormonal influences that are not amenable to primary prevention strategies.