1.2.2.1 Fibroid Growth Rates

The Fibroid Growth Study followed 262 fibroids in 38 black and 34 white premenopausal women over a 12-month period [9]. Black women 35 years of age or older had a 2.8-fold increased risk of rapid fibroid growth (>20% increase in volume over 6 months) when compared to similar white women [10]. Fibroids from women more than 45 years of age grew more rapidly in black women (increase in volume of 15% over 6 months) than in white women (increase in volume of 2% over 6 months) [9]. White women, but not black women, had a decrease in growth rate with age. Rapid growth was seen more frequently in young white women than in older white women. The frequency of fibroids with rapid growth did not vary by age in black women. Fibroid volume changes in a 6-month period ranged from −89% to +138%. Both black and white women had a median increase in volume of 9% over 6 months. About 34% of fibroids increased in volume by 20%, and 7% experienced a 20% decrease in volume over 6 months. Fibroid shrinkage was generally associated with loss of arterial blood supply as indicated by contrast enhancement. Women often had fibroids with varying growth and shrinkage [7].

Fibroid growth rates were faster in women with a single fibroid than in women with multiple fibroids [9]. Fibroid growth rates did not differ by patient BMI, parity, size, or location. About 62% of women undergoing surgical resections of fibroids without hysterectomy have been reported to have a recurrence of a fibroid at least 2 cm in diameter within 5 years, and 9% required surgery for this recurrence [11].

1.2.2.2 Age

Fibroids are often diagnosed in older premenopausal women. Most fibroids occur in women in their thirties or forties, associated with chronic exposure to oestrogen and progesterone throughout the reproductive life course [12]. The Seveso Women’s Health Study found fibroids in 21.4% of Italian women aged 30–60 who were screened by ultrasound [11]. Most fibroids diagnosed by fibroid screening are symptomatic. Ultrasound identified fibroids in 3.3% of Swedish women aged 25–32 years and 7.8% of women aged 33–40 years. A woman’s age at birth of the last child was inversely related to risk of fibroids [13]. Fibroids have not been described in prepubertal girls [12].

1.2.2.3 Race

Most studies evaluating race-related risk of developing fibroids were performed in the United States. The incidence of fibroids by age 50 was estimated as 70% for white women and 80% for African-American or black women [7]. Black women had a lower urinary 2-hydroxyoestrone/16α-hydroxyoestrone metabolite ratio than white women [14]. 2-hydroxyoestrone metabolites have less oestrogenic activity than 16α-hydroxyoestrone metabolites, possibly leading to greater oestrogen exposure in black women. Black women had a three times greater risk of clinically symptomatic fibroids, and were younger at first diagnosis, had more severe disease, and underwent hysterectomy more frequently than white women [12]. Fibroids were detected about 10 years earlier in black women than in white women [15, 16].

A random selection of adult women in an American health plan found that 35% of premenopausal women had a previous diagnosis of fibroids and that 51% of the premenopausal women with no clinical diagnosis had ultrasound-detectable fibroids [7]. Black women had fibroids more frequently than white women (cumulative incidence by age 50, >80% vs. 70%, OR = 2.9). There was little change in risk after adjustment for parity or body mass index (BMI). White women appeared to have an increasing risk with increasing age, while black women had a constant higher risk. Parity was not a risk factor in black women, and about two-thirds of white women were nulliparous. Black women were diagnosed at a younger age than white women (33 vs. 36 years). Black women were more likely to have multiple fibroid tumours than white women (73% vs. 45%). This difference was greatest in younger women (35–39 years, 74% vs. 31%). Clinically relevant premenopausal fibroids were present in about half of black women and 25% of white women [7]. A much lower incidence was reported in 334 Swedish women screened with ultrasound [17]. Only about 5% of all Swedish women were affected and only 8% of women 33–40 years of age. Pathologic study of 2-mm sectioned hysterectomy specimens obtained from adult American women demonstrated fibroids in 77% [18]; 84% of these women had multiple fibroids.

The Study of Environment, Lifestyle and Fibroids evaluated 1,696 black American women with ultrasound and found 22% had at least one fibroid 0.5 cm in diameter [15]. Prevalence increased with age: 10% for women 23–25 years of age and 32% for women 32–35 years of age.

The incidence of newly diagnosed fibroids has been reported to be about 3% per year in reproductive-age black women [11]. It has been reported that 73% of black women and 45% of white women have multiple fibroids [7]. Hispanic women have been reported to have a similar incidence of fibroids as white women [4].

1.2.2.4 Obesity

BMI is inversely associated with sex hormone-binding globulin level and these levels are higher in obese patients [19]. Thus women with increased BMI may have more bioavailable circulating oestrogens and androgens. Obesity has been associated with a modest increased risk of fibroids in several, but not all, international studies [13, 19]. Each 10 kg increase in weight in adults was associated with an 18% increase in the development of fibroids [11]. BMI during adolescence has not to date been associated with an increased risk of fibroids.

1.2.2.5 Diet and Exercise

Several studies have suggested an association between diet and the development of fibroids. Increased consumption of red meat (RR = 1.7) and decreased consumption of green vegetables (RR = 2.0) have been associated with an increased risk of fibroids [11, 12]. A double-blinded randomized study showed that intake of green tea extract was associated with a reduction in uterine fibroid size and clinical severity, and an improvement in quality of life, compared to placebo control [20].

The dietary habits of 22,583 premenopausal black women were evaluated for their association with the development of fibroids [21]. Fruit and vegetable intake were each inversely associated with the risk of fibroids (2 servings/day vs. 2 servings/week). Citrus fruit had the highest inverse association (3 servings/week vs. 1 serving/month). Increasing fruit and vegetable consumption was observed with increasing patient age and multivitamin use. Risk was not associated with intake of vitamins C or E, folate, or carotenoids.

The National Institute of Environmental Health Sciences Uterine Fibroid Study correlated plasma vitamin D levels with the ultrasound diagnosis of fibroids in randomly selected 35- to 49-year-old women [22]. Moreover, 50% of white women and 10% of black women had normal plasma levels of 25-hydroxy vitamin D (>20 ng/mL). Women with normal levels of 25-hydroxy vitamin D had a 32% lower risk of having fibroids. Sun exposure for more than 1 hour per day was also associated with reduction in risk of having fibroids (adjusted OR = 0.6). Vitamin D deficiency is more common among black women, as their pigment inhibits sunlight-related stimulation of vitamin D production in the skin [23].

Premenopausal vegetarian women excreted three times more faecal oestrogen, had less urinary oestrogen excretion, and had 15–20% lower plasma oestrogen levels than non-vegetarian women [14]. Increased faecal excretion of oestrogen was linked to decreased deconjugation of faecal oestrogen that is needed for its reabsorption. Postmenopausal women placed on a low-fat diet experienced a 17% decrease in plasma oestradiol concentrations.

The effect of exercise on fibroid pathophysiology is not clear. While former college athletes were less likely than non-athletes (RR = 0.72) to develop fibroids, other differences such as diet and weight were not accounted for [14].

1.2.2.6 Caffeine

The Black Women’s Health Study found an increased risk of fibroids in the subgroup of women less than 35 years of age who drank over three cups of coffee a day or consumed more than 500 mg caffeine a day [19]. This association was not found when women of all ages were included in the evaluation.

1.2.2.7 Alcohol

Alcohol intake has been associated with the development of fibroids in most studies [19]. A report on Japanese women found fibroids, diagnosed by ultrasound, more frequently in those in the highest third of alcohol intake, compared to those in the lowest third (OR = 2.8, about 1 drink/day vs. non-drinkers). Current drinkers in the Black Women’s Health Study also had a higher risk than non-drinkers. The highest risk, a 60% increase, was with women drinking beer (7+ drinks/week vs. non-drinkers).

1.2.2.8 Smoking

Smoking is historically associated with a decreased risk of fibroid formation [12]. Smoking two packs of cigarettes a day was associated with an 18% increase in the development of fibroids [11]. More recent studies, including the National Institute of Environmental Health Sciences Uterine Fibroid Study, showed no association between risk of fibroids and smoking [19]. Protective effects found in earlier studies have been attributed to bias introduced by improper selection of the control groups.

1.2.2.9 Menarche

Early age of menarche increases a woman’s overall lifetime exposure to oestrogen and is associated with a higher risk for fibroids [13]. Women who are ≤10 years at menarche have a higher risk of fibroids than women who were 12 years of age or more at menarche (RR = 1.24) [14].

1.2.2.10 Menopause

Uteri evaluated pathologically using 2 mm sections were found to have similar numbers of fibroids whether they were obtained from pre- or post-menopausal women. However, the fibroids were smaller in postmenopausal women. Postmenopausal women have a decrease in circulating oestrogen and progesterone levels, and this has been attributed to fibroid shrinkage [14]. These findings could however be affected by selection bias, as postmenopausal women were often treated more conservatively and did not undergo hysterectomy.

1.2.2.11 Parity

High concentrations of oestrogen and progesterone are found in pregnancy and with oral contraceptive (OC) use, two conditions associated with a decreased risk of fibroids [12]. Pregnancy longer than 20 weeks in duration has been associated with decreased risk of fibroid formation. Women undergoing childbirth had a lower risk of fibroids than women who never had children (RR = 0.5) [14]. A progressive decrease in risk was seen with increasing number of births. Pregnancy has been associated with a five-fold reduction in the incidence of fibroids [11]. This number may be biased, as women with fibroids are less likely to become pregnant or deliver at term.

1.2.2.12 Oral Contraceptives (OCs)

The use of OCs in adult women is associated with a decrease in clinically evident fibroids [12, 24]. Women taking oral contraceptives for more than 12 years had 50% fewer fibroids than similarly aged women who did not take oral contraceptives [11]. This study may have been biased because women with fibroids tend to have more trouble with conception and take oral contraceptives for shorter periods than women without fibroids. Nevertheless, the relative risk of developing fibroids was shown to decrease in a dose-dependent fashion with the duration of oral contraceptive use. The Nurses’ Health Study II, a study of 95,061 American women, found that oral contraceptive use between the ages of 13 and 16 years was associated with an increased risk of clinically symptomatic fibroids [24].

1.2.2.13 Hormone Replacement Therapy

Symptoms related to fibroid growth often decrease after menopause, when circulating oestrogen and progesterone levels decline. It has been reported in several studies that women who take hormones after menopause may experience renewal of these symptoms [12].

Postmenopausal women with small asymptomatic uterine fibroids were randomly treated with either transdermal oestradiol (E2) plus medroxyprogesterone acetate (MPA) or conjugated equine oestrogen (CEE) plus MPA [25]. Women treated with transdermal E2 plus MPA had larger fibroids after 1 year, while women treated with conjugated equine oestrogen plus MPA had no change in fibroid size. In a separate study, 70 postmenopausal women with fibroids were treated with either transdermal 17β-oestradiol patches plus MPA or calcium carbonate for about 11 months [26]. No change in fibroid size was observed in either treatment group. Post-menopausal women with solitary uterine fibroids that were taking CEE and MPA for 3 years were evaluated for fibroid growth [27]. This hormone replacement combination increased fibroid size, although the main effect was observed during the first 2 years.

1.2.2.14 Tamoxifen

Animal studies have shown that tamoxifen inhibits the growth of fibroids [28]. These findings have not been reproduced in women, where results have been mixed. A randomized trial evaluating the effect of tamoxifen on fibroid growth is not available.

1.2.2.15 Xeno-oestrogens

Xeno-oestrogens have been hypothesized to antagonize fibroid growth. Xeno-oestrogens are synthetic or natural chemicals with oestrogenic activity. Synthetic xeno-oestrogens include polychlorinated biphenyls, bisphenol A, the pesticide DDT, and phthalates. Natural xeno-oestrogens are generally plant-derived chemicals called phyto-oestrogens. Phyto-oestrogens are converted into oestrogenic substances by bacterial degradation during digestion and absorbed [14]. Soy and flax contain the greatest quantities of these compounds. The anti-oestrogenic effects sometimes reported with phyto-oestrogens may be due to their ability to compete with natural oestrogens such as oestradiol at the oestrogen receptor (ER).

1.2.3.1 Initiation

While many genetic events have been described in fibroids, the initiating events are not clear [14]. Hypothesized initiating events include chronic exposure to high levels of oestrogen and progesterone, leading to increased cellular proliferation and an associated introduction of genetic mutations through errors during gene copying. Increased levels of ERs are found in fibroids and may be a contributing factor. Genetic findings in fibroids similar to those found in scars have led to the ‘injury’ hypothesis [31]. Here, vasoconstrictive factors secreted during menses are thought to lead to ischaemia and local uterine muscle injury [14]. Another potential initiating factor may be activation of genes associated with the familial or inherited occurrence of fibroids [14, 32, 33].

1.2.3.2 Promotion and Progression

Oestrogen is more generally accepted as the principal promoter of fibroid growth [14]. Several observations suggest oestrogens contribute to fibroid development and growth. Oestradiol binds to oestrogen receptor α (ERα), activating transcription of multiple genes, including the progesterone receptor (PR) [28]. Fibroids have been observed to increase in size after exposure to exogenous oestrogen, the increased levels of oestrogen found in pregnancy, or hormone replacement therapy. They have been observed to decrease in size after menopause or gonadotrophin-releasing hormone (GnRH) agonist treatment [8]. Leiomyoma (fibroid) cells transfected with an inactive ERα mutant suppressed both ERα- and PR-related gene expression [28]. Expression of IGF-I, a growth factor related to cellular proliferation, is not found in leiomyoma samples obtained from women with decreased oestrogen levels [34].

Fibroids have been observed to have a greater number of PRs (both A and B forms) than normal uterine muscle [8]. Animal studies have shown that PR-A is linked to ovulation and the anti-proliferative effects of progesterone in the uterus, and that PR-B is associated with mammary gland development [28].

Progesterone is also thought to contribute to tumour promotion [14]. Progesterone binds to the PR, activating genes related to suppression of apoptosis, cellular proliferation, and extracellular matrix formation [28]. Anti-progestins will block these effects. The mitotic index of fibroids increases during the progesterone-rich luteal phase of the menstrual cycle. Leiomyoma proliferative activity in post-menopausal women has been shown to increase after administration of oestrogen plus progestin, but not with oestrogen alone [28]. The administration of progestins with GnRH antagonists is associated with an inhibition of the GnRH antagonist effect on uterine shrinkage [8].

Progesterone has been shown to increase the expression of the growth factor, epidermal growth factor (EGF), and the anti-apoptotic protein bcl-2 by binding to progesterone response elements found on these genes. EGF activates c-Myc, a transcription factor that increases cellular proliferation and decreases apoptosis by down-regulating Bcl-2 expression [28].

IGF-I, IGF-II, and IGF-II receptor, but not IGF-I receptor type, are more highly expressed in fibroid tissues than in normal uterine muscle cells [34]. In vitro studies have shown that IGF-I stimulates the proliferation of leiomyoma cells. In vitro treatment with the selective progesterone receptor modulator (SPRM) asoprisnil decreases the expression of IGF-I in fibroids, but not in normal uterine smooth muscle cells [34].

The SPRMs mifepristone, asoprisnil, ulipristal acetate, and telapristone acetate have been reported in clinical trials to suppress uterine bleeding and decrease leiomyoma size [28, 34]. Ulipristal acetate (UPA) is an SPRM that has been shown to initiate apoptosis in uterine fibroids and to decrease fibroid size [35]. Treatment with UPA did not alter GnRH blood levels and maintained oestradiol levels above 1.05 × 10⁻³ pm/L [35]. Use of Depo-MPA, an injectable progestin contraceptive, has been associated with a reduced risk of fibroid development [19]. Both progestins and anti-progestins may diminish ER signalling and leiomyoma cell growth, suggesting cross-talk occurs between ER and PR signalling [13]. Risk factors for fibroid formation that frequently affect the expression of cellular factors are listed in Table 1.2.

1.2.3.3 Effectors

Oestrogen and progesterone mediate their effects through transcriptional activation or suppression of growth factors and their receptors, and by direct activation or suppression of growth factor pathways.

1.2.3.4 Genetic Findings

Stay updated, free articles. Join our Telegram channel

Join