Fibroids are non-cancerous growths that develop in or on the muscular wall of the uterus. They are also known as uterine myomas or leiomyomas. Fibroids are extremely common, with estimates stating that 70-80% of women will develop fibroids by the age of 50. Most fibroids do not cause any symptoms and often go undetected. However, for some women, fibroids can cause significant problems including heavy menstrual bleeding, pelvic pain and pressure, frequent urination, and reproductive issues. Understanding what causes fibroids to develop can help guide treatment options.
What are the risk factors for developing fibroids?
While the exact cause of uterine fibroids is unknown, certain factors are believed to increase a woman’s risk:
– Genetics – Women with a family history of fibroids appear to be at higher risk. Fibroids contain genetic changes (mutations) that seem to predispose them to abnormal growth. Having a first-degree relative with fibroids increases your risk.
– Ethnicity – African American women are 2-3 times more likely to develop fibroids compared to Caucasian women. Hispanic women also have an increased risk.
– Age – Fibroids become more common as women age, with incidence increasing during the 30s and 40s. Postmenopausal women tend to develop less symptomatic fibroids.
– Obesity – Women who are overweight or obese have a higher risk of fibroids. This may be due to increased estrogen levels in those with excess fat.
– Early menstruation – Women who start their periods at an early age (before age 10) are at higher risk.
– Pregnancy – Pregnancy appears to protect against fibroids. Women who’ve had a pregnancy have a lower rate of fibroids.
Estrogen and progesterone’s role in the growth of fibroids
Estrogen and progesterone are key drivers of fibroid growth. These are the two main female reproductive hormones that stimulate endometrial growth and regulate the menstrual cycle.
– Estrogen – Estrogen promotes growth of the uterine lining (endometrium) during the menstrual cycle. Similarly, it stimulates growth of fibroid cells. Fibroids contain more estrogen and progesterone receptors than normal uterine muscle cells. High estrogen levels, especially during the reproductive years, appear to fuel fibroid growth. Use of exogenous estrogen after menopause can cause new fibroid development.
– Progesterone – Progesterone counterbalances estrogen’s proliferative effects on the uterus. However, progesterone also appears to promote fibroid growth by increasing production of extracellular matrix proteins like collagen and fibronectin. These proteins provide structural support for growing fibroids. Progesterone may also increase cell proliferation in fibroids.
Estrogen dominance
An estrogen dominant state, where estrogen levels are high relative to progesterone levels, creates optimal conditions for fibroid growth. Estrogen dominance may arise due to:
– Overweight or obesity – Fat cells increase estrogen levels through conversion of adrenal androgens to estrogen via the enzyme aromatase.
– Early menstruation/late menopause – More years of menstrual cycles means higher cumulative estrogen exposure.
– Chronic stress – Elevated cortisol reduces progesterone production in the corpus luteum after ovulation.
– Environmental estrogens – Compounds like BPA and phthalates mimic estrogen in the body.
Low progesterone
Low progesterone relative to estrogen enhances the effects of estrogen on fibroid growth. Causes of progesterone deficiency include:
– Luteal phase defect – Impaired progesterone production after ovulation.
– Chronic stress – Hinders progesterone synthesis.
– Perimenopause – Progesterone levels start to decline as menopause approaches.
– Polycystic ovary syndrome (PCOS) – Anovulatory cycles prevent corpus luteum formation, lowering progesterone secretion.
Other proposed contributors to fibroid development
While estrogen and progesterone play pivotal roles, researchers are investigating other factors that may promote fibroid pathogenesis:
Genetic mutations
Specific mutations affecting genes involved in cellular proliferation, apoptosis, and extracellular matrix production may contribute to fibroid formation. Potential mutations include:
– MED12 – This gene regulates cell growth and division. About 70% of fibroids contain MED12 mutations.
– HMGA2 – This gene regulates growth and cell proliferation. Overexpression is linked to tumor growth.
– FH – Mutations in this Krebs cycle enzyme are seen in hereditary leiomyomatosis and renal cell cancer syndrome, associated with massive uterine and cutaneous leiomyomata.
Growth factors
– IGF-1 – Insulin-like growth factor-1 enhances cellular proliferation and inhibits apoptosis in fibroids. IGF-1 levels are higher in African American women, who have an increased risk of fibroids.
– TGF-β3 – Transforming growth factor beta 3 increases extracellular matrix production in fibroid cells.
– VEGF – Vascular endothelial growth factor promotes angiogenesis to support fibroid growth. Expression is increased in fibroids.
Inflammation
Inflammation may promote fibroid growth and symptoms. Markers of inflammation including IL-6, TNFα, TGF-β1 and macrophage chemoattractant protein-1 are elevated in women with symptomatic fibroids compared to asymptomatic fibroids.
Oxidative stress
Imbalance between pro-oxidants and antioxidants leads to oxidative cell damage, which may encourage fibroid growth. Women with fibroids have lower antioxidant levels and increased indicators of oxidative stress.
The key trigger: Hormonal modulation during the reproductive years
While various genetic, growth factor, and other influences are likely involved, the central factor permitting growth of fibroids appears to be estrogen and progesterone activity during the reproductive years.
Cyclic variation and stimulation of estrogen and progesterone release:
– Starts at puberty
– Stimulates rapid fibroid tumor growth
– Reaches a peak during a woman’s reproductive prime in her 30s and 40s
– Declines with menopause, slowing fibroid growth
The central role of estrogen and progesterone is evidenced by the fact that fibroids rarely form before menarche, regress after menopause, and rapidly degenerate during GnRH agonist medication treatment, which dramatically reduces estrogen and progesterone levels.
Conclusion
In summary, the predominant factor leading to uterine fibroid development is hormonal stimulation by estrogen and progesterone during the reproductive years. This leads to proliferation of fibroid cells, deposition of extracellular matrix, formation of new blood vessels to supply the tumors, and inhibition of apoptosis.
Underlying genetic mutations and growth promoting factors like IGF-1 and TGF-β3 likely complement the tumor-forming effects of estrogen and progesterone. However, the cyclic changes and peak levels of these hormones provide the key trigger initiating and driving fibroid growth in most women as they age from their 20s through 40s. Understanding the hormonal basis of fibroids can help guide medical and lifestyle approaches to manage symptoms or potentially prevent their occurrence.