Risk Factors

Age-Related Risk

The prevalence of leiomyomas increases with age during the reproductive years. Women are most likely to be diagnosed with leiomyomas in their fifth decade of life. The hormonal fluctuations that occur throughout a woman's reproductive lifespan contribute to the growth and development of these tumors.

Ethnicity and Racial Disparities

The prevalence of leiomyomas displays notable disparities across racial lines, with Black women experiencing a higher incidence compared to their white counterparts. By the age of 50, the estimated cumulative prevalence reaches nearly 70% for white women, while exceeding 80% for Black women. 

This disparity extends further. Black women not only experience leiomyomas more often but also encounter them earlier in life, emphasizing the importance of early interventions (Laughlin, 2010) Figure 1.

Paradoxically, despite their younger diagnosis age, Black women tend to experience more severe symptoms, leading to earlier hysterectomy than their white counterparts with similar socioeconomic backgrounds. Black women, in comparison to white women, exhibit a greater propensity for having seven or more leiomyomas. Furthermore, they are predisposed to experiencing symptoms like anemia and severe pelvic pain at higher rates. Unraveling the causes of these disparities remains challenging. Even when factoring in established risk factors like marital status, body mass index, and reproductive history, the root causes remain elusive. Genetic factors might contribute, hinted by variations in the estrogen-metabolizing enzyme COMT between Black and white women. Yet, the precise mechanisms driving these racial differences remain to be untangling Interestingly, when comparing leiomyoma rates among different ethnic groups like white, Hispanic, and Asian women, the patterns tend to converge. This implies that factors beyond ethnicity, such as genetics and environment, collaboratively shape the intricate epidemiological landscape of leiomyomas.

Association with Early and Late Menarche

Early onset of menstruation has been associated with an increased risk of developing leiomyomas. Conversely, late menarche appears to confer a protective effect. These associations underline the role of hormonal changes in leiomyoma development. Research findings illuminate this association, showcasing a relative risk of 1.24 for women with a history of early menarche (before the age of 10). In contrast, women who experience late menarche (after the age of 16), demonstrate a significantly lower relative risk of 0.68 for developing leiomyomas (Marshall, 1998). 

Parity and Pregnancy-Related Factors

The number of pregnancies and age at first birth play a role in leiomyoma risk. Parity (having one or more pregnancies) decreases the chance of fibroid formation. Additionally, the interval since the last birth influences the incidence of leiomyomas. Nulliparous women face a doubled risk of leiomyoma occurrence compared to women who have had one or more pregnancies extending beyond 20 weeks of gestation. The inverse correlation between the number of pregnancies and leiomyoma risk is evident, with additional pregnancies further diminishing the likelihood of fibroid formation. Additionally, the age at which the first pregnancy occurs impacts the risk, with older age at first birth linked to decreased susceptibility. Conversely, longer intervals since the last birth correlate with an increased incidence of leiomyomas, highlighting the intricate interplay between reproductive experiences and uterine health.

Familial and Genetic Predisposition

Familial and genetic factors play a significant role in the development of uterine leiomyomas. The existence of familial clusters suggests heritability, with having more than two first-degree relatives increasing the risk by 2.2-fold. Twin studies reinforce this link, showing an elevated risk when a sibling is diagnosed with the condition. Rare autosomal dominant hereditary syndromes, like multiple cutaneous and uterine leiomyomatosis (Reed syndrome), have also been identified.

Uterine leiomyomas present with diverse genotypes, underlying their common phenotype. Several genetic pathways contribute to the development of these tumors. Most fibroids arise from somatic mutations, primarily involving genes such as mediator complex subunit 12 (MED12), high mobility group AT-hook (HMGA1 and HMGA2), and collagen type IV (COL4A5 and COL4A6). Inherited mutations in the fumarate hydratase gene (FH) constitute a significant subgroup, associated with hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC), a rare autosomal dominant syndrome linked to aggressive forms of cancer. Notably, genotype-phenotype relationships exist, with factors like MED12 mutations being linked to smaller fibroids. Although certain mutations seem to be mutually exclusive, the complex clonal nature of fibroids can result in multiple genotypes within the same uterus, suggesting redundant downstream signaling pathways for most groups, except for the FH group.

Influence of Lifestyle and Environmental Factors

Obesity, associated with heightened estrogen levels, escalates both risk and growth of these tumors. Remarkably, diets rich in green vegetables mitigate risk, while smoking reduces it. Conversely, vitamin D deficiency elevates chances of leiomyomas, with serum levels inversely correlated to tumor size. Prenatal diethylstilbestrol (DES) exposure augments susceptibility, leading to larger tumors in comparison to unexposed individuals.

The intricate relationship between fibroids and body mass index (BMI) is influenced by factors like parity and changes in body composition. Dietary choices, including increased red meat consumption and reduced green vegetable and fruit intake, correspond to heightened fibroid risk. Marine omega-3 fatty acids may elevate risk in some cases, while dietary vitamin A from animal sources could lower it. Vitamin D deficiency, particularly among Black patients, is linked to increased fibroid risk, offering a potential avenue for prevention trials. Alcohol, particularly beer, amplifies fibroid risk. There is mixed evidence correlated smoking to a reduction in the risk of developing leiomyomata, possibly through the inhibition of aromatase.

Hormonal Contraception

While some studies suggest reduced risks associated with oral contraceptives (OCs), others find no such association. Standard or lower dose OCs (≤35 mcg ethinyl estradiol/day) are generally not linked to fibroid growth, making them suitable for patients with fibroids. However, exceptions exist, as the Nurses' Health Study hinted at increased leiomyoma risk in patients with early OC exposure. Long-acting progestin-only contraceptives, like depot medroxyprogesterone, may offer protection against leiomyoma development and volume. Notably, their effects on postpartum fibroid regression and symptomatic control of bleeding through progestin intrauterine devices are nuanced, showing limited decreases in fibroid or uterine size.