Fibroids, also known as leiomyoma of the uterus, are benign tumours (they do not spread to other parts of the body like malignant tumours) of the muscle layer of the uterus (womb). The prevalence of fibroids in studies varies from 4.5% to 68.6% of women. The reason for this wide variation is that prevalence varies according to age, race, lifestyle factors and that many women have no symptoms from fibroids, which may only be found incidentally during other gynaecological examinations or imaging.
Fibroids are the most common type of gynaecological tumour and can give rise to a wide variety of problems. These include: pelvic pain, abnormal uterine bleeding, constipation and urinary problems. Fertility problems may also occur, such as failure of the fertilised egg to implant in the uterus, premature labour, recurrent miscarriage, physical obstruction of labour and urinary incontinence after delivery.
Fibroids can occur anytime after puberty and regress after menopause, with symptoms occurring most commonly in the 4th and 5th decades of life, although only 20-40% of women exhibit symptoms. The cause of fibroids is a genetic mutation in the normal cells of the uterine smooth muscle layer, which leads to an expansion of abnormal smooth muscle cells and the supporting tissues around the muscle cells (extracellular matrix). These mutations are believed to be caused by a variety of factors, including age, genetic predisposition, lifestyle factors, medical factors and race.1
Fibroids are most common in older women before menopause. A Swedish study shows the prevalence of fibroids in women aged 25-40 years, 3.3% in the 25-32 age group compared with 7.8% in the 33-40 age group. This is thought to be due to the cumulative effect of female sex hormones (oestrodiol and progesterone) on the muscle layer (myometrium). Fibroids regress after menopause.2
Most studies of fibroid incidence and ethnic origin have been performed in the USA, where the lifetime incidence of fibroids at age 50 is 80% in afro-carribeans compared to 70% in caucasians. Additionally, black women have 3 times the risk of symptomatic fibroids, develop fibroids younger and have more severe disease compared with caucasians.3
A proinflammatory diet (i.e. rich in red meat and low in green vegetables) is associated with an increased risk of fibroids. The National Institute of Environmental Health Sciences Uterine Fibroid Study also correlated vitamin D levels to fibroid incidence and showed that a normal vitamin D level was associated with a 32% decrease in the risk of developing fibroids. Afro-Caribbean women tend to have lower vitamin D levels because the dark pigmentation of their skin interferes with the production of vitamin D from sunlight exposure. Additionally, lower incidences of fibroids were found in vegetarian women.4
Data from the Black Women’s Health Study suggested that an intake of more than 3 cups of coffee per day was associated with an increased risk of fibroids, but only in women under the age of 35.5
In women who do regular exercise, the risk of fibroids is lower, thought to be due to the effects of exercise on hormonal regulation and reducing insulin sensitivity.6
Increased alcohol intake has been associated with the development of fibroids. A Japanese study found that the risk of developing fibroids was 2.8 times higher in heavy drinkers compared to those who consumed lower amounts of alcohol. Data from the Black Women’s Health study also supports this.7,5
Traditionally, smoking was thought to be a protective factor in the development of fibroids, however, data from the National Institute of Environmental Health’s Uterine Fibroid study may refute this.4
Developing menstrual periods earlier than the age of 10 was associated with an increased risk of fibroids. After the menopause, the levels of the female sex hormones, estrogen and progesterone, decrease. As estrogen and progesterone promote the growth of fibroids, fibroids decrease in size after menopause, although the overall number remains the same.1
In both pregnancy and the use of the combined oral contraceptive pill, very high doses of estrogen and progesterone circulate, which leads to downregulation of the receptors of these hormones in the uterus. Multiple pregnancies and use of the oral contraceptive pill therefore reduce the risk of fibroids; however, during pregnancy, fibroids which are already present tend to increase in size due to high levels of estrogen and progesterone.
The Xeno-oestrogens are synthetic chemicals which stimulate estrogen receptors, they include polychlorinated biphenyls and the pesticide DDT. Soybean and flax seeds contain substances which are converted to chemicals with estrogenic activity by gut bacteria, called phyto-estrogens. Both can theoretically increase the growth of fibroids.1
A family history of fibroids is associated with approximately a 3 times greater risk of developing fibroids. Also, fibroids are seen to run in families across generations.8
The female hormone estrogen, which promotes the growth of fibroids, is produced in the body’s fatty tissue. A 2021 meta-analysis (a type of study that pools the results of many smaller studies) revealed a link between obesity and increased prevalence of fibroids.9
A 2022 meta-analysis revealed an association between fibroids and high blood pressure, with a risk of developing fibroids being nearly 1 ½ times greater in women with hypertension.10
The disease process in fibroid development is complex. Like all tumours, there are 4 phases: initiation of the tumour, a genetic mutation causing abnormal growth, promotion and progression (factors promoting growth of the tumour and leading to progression) and malignant transformation (which is very rare in fibroids).
The exact cause of the initiation of fibroids is unclear. The first theory is that long-term exposure to high levels of circulating female sex hormones (estrogen and progesterone) leads to more rapid cell division, leading to mutations in DNA during cell division. Another is that rapid cell division occurs in response to injury to the muscle layer of the uterus caused by factors that constrict blood vessels during menstruation. Finally, inherited genes are thought to play a role.1
Promotion and progression of fibroids involve the growth of both uterine muscle cells and an increase in the extracellular supporting matrix holding the muscle layer together. In fibroids, estrogen and progesterone receptors are found in higher concentrations. Many growth factors, such as epidermal growth factor, basic fibroblast growth factor and tumour growth factor-B3, are found in higher quantities in both leiomyoma cells and the surrounding extracellular matrix, leading to increased growth and reducing the natural cell death or apoptosis. Estrogen and progesterone activate growth factor pathways either directly or by causing errors in DNA copying in cell division due to more rapid cell growth.1
Aromatase is an enzyme that converts circulating androgens (male sex hormones, also found in women) into estrogen. High estrogen levels are considered the driver in fibroid development. The levels of the enzyme aromatase P450 are found to be expressed between 1.5-25 times more in fibroid cells compared to normal uterine muscle cells. Afro-Caribbean women have higher levels of aromatase activity. Levels of growth factors are also higher in fibroid cells and the extracellular matrix surrounding them. Furthermore, in fibroids, there is increased expression of estrogen and progesterone receptors.1
There is evidence for heritability in fibroids, with women with a strong family history being increasingly at risk. Additionally, certain inherited diseases, such as Reed’s syndrome and Alport’s syndrome, present with fibroids amongst other abnormalities. Two main genetic abnormalities have been identified; 69% of fibroids had a mutation in the gene coding for transcription factor MED12. This factor binds to estrogen receptors, and increases the cell replication and response to circulating progesterone. The other, less common abnormality is the so-called high mobility group at HOOK2 (HMGA-2), a mutation associated with large, solitary fibroids.11
Fibroids (uterine leiomyomas) are benign tumours of the smooth muscle layer of the uterus. A number of lifestyle and genetic/inherited factors are implicated in a causal link to fibroid development. These include age, race, weight, smoking and alcohol intake. The female sex hormones estrogen and progesterone drive the growth of fibroids via complex mechanisms that lead to an increase in cellular growth factors. Specific genetic mutations are found in many cases of fibroids, and a strong family history is a known risk factor. Rapid cell growth, triggered by estrogen and progesterone, may initiate mutations. Alternatively, this could be a result of rapid cell growth due to the healing of damage caused by the constriction of blood vessels during menstruation. The combination of lifestyle factors and genetic mutations leads to fibroid development.
