What is the etiology of myomas (uterine fibroids) in women of reproductive age?

Etiology of Uterine Myomas (Fibroids)

Uterine myomas arise from monoclonal expansion of individual myometrial smooth muscle cells through a multifactorial process involving genetic alterations, hormonal influences (particularly estrogen and progesterone), and demographic risk factors including race, age, parity, and body mass index. 1

Cellular Origin and Clonal Nature

• Myomas represent benign clonal neoplasms originating from single myometrial smooth muscle cells that undergo transformation and proliferation 1, 2
• Each fibroid develops from an individual cell that has acquired genetic alterations, explaining why multiple fibroids in the same uterus can have different molecular characteristics 1
• The histology remains virtually indistinguishable from normal myometrium, consisting of smooth muscle and fibroblast components with variable cellularity 1

Genetic Mechanisms

Approximately one-third of myomas harbor clonal chromosomal aberrations, though these are inconsistent even between different fibroids in the same woman 1, 3:

• Specific cytogenetic abnormalities include the 12:14 chromosomal translocation resulting in abnormal expression of the high-mobility group IC gene 3
• Loss of the tuberous sclerosis 2 gene has been demonstrated to result in leiomyoma development 3
• Myomas with abnormal karyotypes tend to be larger than those with normal karyotypes, suggesting distinct genetic subgroups with different clinical behaviors 1, 3
• The inheritance pattern is non-Mendelian with up to 50% recurrence rate after surgical removal, indicating strong genetic predisposition 1, 3

Hormonal Influences

Sex steroid hormones (estrogen and progesterone) are essential for myoma growth, though they do not cause the initial transformation 1:

• Myomas do not appear before puberty and typically regress after menopause when hormone levels decline 1
• These tumors possess both estrogen and progesterone receptors and respond to hormonal stimulation 1
• Myomas often enlarge dramatically during pregnancy when hormone levels are elevated 1
• Medically-induced hypogonadism causes myoma shrinkage, confirming hormone-dependence 1

Critical caveat: There is no evidence that women with myomas have higher or aberrant patterns of ovarian hormone secretion—the problem lies in the tumor cells' hypersensitivity and inappropriate response to normal hormone levels 1

Proposed Pathophysiologic Model

Myomas exhibit characteristics of differentiated myometrial cells similar to pregnant myometrium, but with defective signaling pathways 1:

• Tumor cells mimic the differentiated state of myometrium during pregnancy and show hypersensitivity to sex steroids 1
• Unlike normal postpartum myometrium, myoma cells lack the ability to produce or respond to prostaglandins, which normally trigger apoptosis or dedifferentiation 1
• This defect prevents myoma cells from responding to normal apoptotic signals and returning to a non-proliferative state 1
• The result is accumulation of differentiated, proliferating cells that continue to expand as benign tumors 1

Demographic and Environmental Risk Factors

Race represents the strongest non-modifiable risk factor 1, 3:

• African American women have greater than 80% incidence by age 50 compared to approximately 70% in White women 1, 4
• Black women develop clinically significant disease at earlier ages 4

Additional contributing factors include 1, 5:

• Age: Prevalence increases throughout reproductive years, affecting 70-80% of women by age 50 3
• Obesity: Obese women show increased predisposition 5
• Parity: Reproductive patterns influence risk 1
• Body mass index: Higher BMI correlates with increased risk 1

Clinical Implications of Etiology

Understanding the multifactorial etiology explains key clinical observations:

• The benign nature of these tumors reflects their origin as differentiated smooth muscle cells rather than malignant transformation 1
• High recurrence rates (27% at 10 years after myomectomy, higher with multiple fibroids) result from the underlying genetic predisposition affecting multiple myometrial cells 3
• Leiomyosarcomas (occurring in less than 1 in 1000 cases) likely represent de novo malignancies rather than transformation from benign fibroids 6
• The extremely low malignancy risk (2.94 per 1,000) in perimenopausal women reflects the distinct pathways of benign versus malignant smooth muscle tumors 7

Future Research Directions

Molecular epidemiologic studies incorporating biomarkers of somatic changes and inherited genetic factors offer the greatest potential for clarifying etiology and identifying therapeutic targets 1, 3:

• Stratifying patients by ultrasonographic, histopathologic, or molecular tumor characteristics may reveal distinct etiologic subgroups 1
• Identifying the specific factors that prevent myoma cells from responding to normal apoptotic signals could enable novel non-surgical interventions 1
• Understanding the genetic basis may allow development of prevention strategies for genetically predisposed individuals 1