Epidemiology and Risk Factors of Uterine Fibroids

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Epidemiology and Risk Factors of Uterine

Fibroids

Dora Pavone, Sara Clemenza, Flavia Sorbi,

Massimiliano Fambrini, Felice Petraglia

*

Department of Biomedical, Experimental and Clinical Sciences, Division of Obstetrics and Gynecology, University of Florence, Florence, Italy

Keywords: Uterineﬁbroids Risk factor Epidemiology Reproductive history Genetic factors Lifestyle

a b s t r a c t

Risk factors, both modifiable and non-modifiable, are associated with the development of fibroids. These include age, race, endogenous and exogenous hormonal factors, obesity, uterine infection, and lifestyle (diet, caffeine and alcohol consumption, physical activity, stress, and smoking). Some of the epidemiological data were conflicting; consequently, further studies are needed to better understand the factors that influence fibroid prevalence.

Introduction

Uterineﬁbroids are the most common pelvic tumor in women. Despite the high prevalence, the

pathogenesis, incidence, natural history, and risk factors are far from being completely understood.

Nevertheless,ﬁbroids are a signiﬁcant health care burden on women's health: among 15e54

year-old-women,ﬁbroids accounts for 29% of gynecologic hospitalizations[1]. Furthermore,ﬁbroids account for

40%e60% of all the hysterectomies performed and for 30% of hysterectomies among young women

18e44 years of age[2]. Nonetheless, there are several challenges in understanding the epidemiology of

fibroids. The first issue is that fibroids are often asymptomatic: about 30%e50% of the premenopausal

women who had no previous diagnosis have ultrasound evidence ofﬁbroid tumors[3]. The large

amount of undetectedﬁbroids creates a strong bias in epidemiological data and evidence on associated

risk factors. Another important source of confusion is that there is still no universally accepted system

of classification of fibroids. In recent years, the FIGO classification system for the classification of

* Corresponding author. Department of Biomedical, Experimental and Clinical Sciences, Division of Obstetrics and Gyne-cology, University of Florence, Largo Brambilla 3, 50134, Florence, Italy.

E-mail address:felice.petraglia@uniﬁ.it(F. Petraglia).

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abnormal uterine bleeding has been developed to facilitate research and clinical care[4]. In this system, a subclassification is specifically designed to describe the different types of fibroids. Hopefully, the FIGO

classiﬁcation will provide a guide for international epidemiological data collection and research. The

most relevant studies in progress are related to the risk factors (Fig. 1) and are summarized in the present study.

Risk factors Age

Age is a signiﬁcant risk factor for the development of ﬁbroids. The incidence of pathologically

diagnosed_{ﬁbroids increases with age and reaches a peak at 50 years. Myomas do not occur before}

puberty, and their frequency decreases with menopause[5]. The data on young (19e35 years old)

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women comes from early pregnancy screening of pregnant women[6]. Studies on pregnant women

demonstrated earlier onset ofﬁbroids in Black women than in White women. The incidence of uterine

ﬁbroids by age 35 was found to be 60% among African-American women, increasing to >80% by age 50,

whereas Caucasian women have an incidence of 40% by age 35 and almost 70% by age 50[3]. The rate of

hospitalization for uterine leiomyomas increases by age, with a peak at 62.7 per 10,000 among women who were 45e49 years old; hospitalization rate then declines to 31.8 per 10,000 among women who

were 50e54 years old[1]. Advancing age increases the incidence and the number ofﬁbroids many fold

and mirrors the natural history ofﬁbroids: most grow in time and are thus expected to be diagnosed in

greater numbers in older age[7].

Race and genetics

A 2e3-fold incidence of ﬁbroids has been found in black women, while the incidence of ﬁbroids

among Hispanic, Asian, and White women is similar[5]. The lifetime risk forﬁbroids (intended as the

cumulative risk of developing aﬁbroid by age 50) was found to be nearly 70% in white women and

>80% for black women. Considering only clinically-signiﬁcant ﬁbroids (9-week gestation uterus, at

least one>4 cm tumor or at least one submucosal leiomyoma), incidence reached up to 50% in Black

women and 25% in White women[3]. These results are in agreement with the Black Women's Health

Study (BWHS)[8], which is a prospective cohort study conducted on 60,000 black women aged 21e65

years and provided a solid base for further epidemiological analysis on the difference in risk factors

present in Black women[9,10]. Black women are diagnosed earlier in life;ﬁbroids in these women are

often multiple, larger, and cause more severe symptoms compared to other ethnic groups[11].

African-American women are 2.4 times more likely to undergo hysterectomy and have a 6.8-fold increase of

undergoing uterus-sparing myomectomy [12]. The racial disparity in the incidence and biological

behavior ofﬁbroids suggests that different races may imply differences in estrogen biosynthesis and/or

metabolism, probably in a genetically mediated way.

Genetic linkage studies in families with syndromes characterized byﬁbroids suggest that these

might be a genetic predisposition to leiomyomas[13]. The most important syndrome in this context

is the hereditary leiomyomatosis and renal cell carcinoma, an autosomal dominant disease char-acterized by cutaneous and uterine leiomyomata and papillary renal cell carcinoma. The gene involved in this syndrome is the fumarate hydratase, which alters a tumor suppressor mechanism for uterine leiomyomata. This enzyme may play a role in non-syndromic leiomyomata in White

women[14].

Alteration of several genes (e.g., MED12, HMGA2, CYP1A1, and CYP1B1), protooncogenes (e.g., p27 and p53), signaling pathways (e.g., PI3K-AKT-MTOR), and epigenetic mechanisms have been

associated with UL etiology[15]. Although leiomyomas are believed to be rather chromosomally

stable, approximately 40%e50% of leiomyomas have cytogenetic anomalies, such as trisomy 12; rearrangements of 12q, 6p, 10q, and 13q; and deletions of 7q, 3q, and 1p. The most common chromosomal translocations in leiomyoma t (12; 14) (q14dq15; q23dq24) are found upstream of the high-mobility group AT-hook (HMGA2) gene promoter, resulting in HMGA2 overexpression,

associated with tumor formation[16]. In addition to chromosomal changes, point mutations in key

regulatory gene appear to be a frequent initiating event in leiomyomas. Mediator complex subunit 12 (MED12), is the most frequently mutated gene in uterine leiomyomas, with a frequency of 50%e 85%[17]. The MED12 is a transcriptional regulator that bridges DNA regulatory sequences to the RNA polymerase II initiation complex. Inactivation of MED12 results in the upregulation of trans-forming growth factor b (TGF-b), which has an effect on the genes encoding proteins involved in

collagen formation and on the excessive extracellular matrix formation, characteristic of_ﬁbroids.

Finally, MiRNA, small (22e25 bp) non-coding RNAs that regulate gene expression through gene silencing with either inhibition of translation or degradation of target mRNA, are aberrantly

expressed in ﬁbroids. Evidence supports a functional role for miRNA, particularly miRNAs let-7,

200a, 200c, 93, 106b, and 21 involved in cellular proliferation, apoptosis, extracellular matrix

turnover, angiogenesis, and inﬂammation, as regulators of gene expression, which affects the

pathobiology of uterine ﬁbroids. Further studies may provide future applications of miRNAs in

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Reproductive factors

Several studies registered a protective effect of pregnancy on the development ofﬁbroids, with high

parity (three or more delivery) decreasing the risk ofﬁbroids up to 5-fold[19,20]. Pregnancy, with its

sharp elevations and declines in the production of estrogen and progesterone that are associated with

very early pregnancy and the postpartum period can cause a dramatic effect onﬁbroid growth. Almost

36% offibroids present in first trimester of pregnancy are not identified on an ultrasound screen

performed 3e6 months post partum[21]; ﬁbroids that remained were reduced in diameter by a

median of 0.5 cm. The relation between high parity and lowﬁbroid prevalence is considered to be

overestimated because the presence ofﬁbroids could lead to infertility or subfertility, thus reducing

parity itself. Time since last birth increased the risk of developingﬁbroids approximately 2e3-fold in

women who last gave birth 5 or more years ago compared with those who gave birth more recently, in

both Black[11]and White women[22]. Breastfeeding has been found to have little to no inﬂuence on

ﬁbroid incidence, particularly after controlling for parity[22].

Some studies found an inverse association with early age at menarche andﬁbroid incidence[23]. No

studies have speciﬁcally investigated the relation between late age at menopause and risk for ﬁbroids:

the later the menopause begins, the more the woman is prone to develop newﬁbroids[1,24].

Hormonal factors

Both estradiol and progesterone are critical for leiomyoma growth [25]; ovarian activity is

essential forﬁbroid growth, and most ﬁbroids shrink after menopause. Recent evidence shows that

estrogen acts primarily by increasing cell responsiveness to progesterone [26,27]. At theﬁbroid

level, the number of progesterone receptors is elevated[25,28]. It has been proved that the level of

PR-B expression (measured by PR-B mRNA) in leiomyoma tissue is directly associated with the number of tumors and inversely correlated with the intensity of intermenstrual bleeding and dysmenorrhea, suggesting that PR-B signaling favors leiomyoma growth while attenuating clinical

symptoms[29]. IGF-I, insulin, and diabetes are inversely associated withﬁbroid incidence, probably

because of the localized vascular dysfunction present in diabetic patients[30]. Interestingly,

poly-cystic ovary syndrome, despite its strong association with chronic hyperglycemic status, is

associ-ated with 65% higher incidence of_{ﬁbroids, even after adjustment for confounding factors}[31]; this

correlation is probably due to the hyperestrogenic status, which is typical in this condition. Because LH shares a receptor with human chorionic gonadotropin, the hormone that stimulates uterine growth during early pregnancy, it is hypothesized that during peri-menopausal status, an increase

in LH levels can stimulateﬁbroid growth[32]. The association between oral contraceptives (OC) and

ﬁbroids is not yet completely understood. Studies have demonstrated conﬂicting data, showing

higher, equal, or lower incidence ofﬁbroids among users and non-users of combined OC[33]. There

are several confounding factors in the association between OC andﬁbroids. Levonorgestrel

intra-uterine system (LNG-IUS) reduces menstrual blood loss and likely reduces menstrual pain. However,

the use of the LNG-IUS does not predictably reduce overall uterine or uterineﬁbroids size[34]. In

postmenopausal women receiving hormone replacement therapy, both in women receiving

estro-gens only and in those receiving combined therapy, a correlation with growth ofﬁbroids is shown

[35].

Endocrine disruptors

Endocrine-disrupting chemicals (EDCs) are present in pharmaceuticals, plasticizers, dioxins, poly-chlorinated biphenyls, organochlorines, phthalates, genistein, and diethylstilbestrol (DES). Uterine development may be a particularly sensitive point to EDC exposure. In particular, DES has shown to increase tumorigenesis in both rodent models and human epidemiologic studies. The mechanisms by which EDC exposures may increase tumorigenesis are still being elucidated, but direct association with estrogen receptor and epigenetic reprogramming of the developing uterus is an emerging hypothesis [36]. High serum levels of dioxin measured after a chemical explosion in Seveso, Italy, were associated

with reducedﬁbroid risk, with an OR of 0.58 (95% conﬁdence interval (CI): 0.41e0.81); however, the

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Obesity

Higher body mass index (BMI) is associated with a modest increase in risk ofﬁbroids[33]. A higher

incidence of surgically treatedﬁbroids has been found in women who gained >20 kg compared with

women who gained<10 kg, and a reduced risk has been found in those who lost weight[24]. Obesity

holds a role as risk factor for uterine ﬁbroids, acting either through hormonal and inﬂammatory

mechanisms. Obesity is responsible of an increase in the conversion of adrenal androgens to estrone and a reduced hepatic production of sex hormone binding globulin (SHBG), resulting in more unbound

active estrogen[33]. Ciavattini et al.[38]studied the association between the presence of uterine

ﬁ-broids and fat tissue distribution: only the ultrasound measurement of preperitoneal fat thickness,

expression of visceral fat, was associated with the presence ofﬁbroids, while subcutaneous fat

thick-ness was not signiﬁcantly associated with the disease. A proinﬂammatory effect is more pronounced in

visceral than in subcutaneous fat compartments. Central obesity may promote insulin resistance and

hyperinsulinemia. Hyperinsulinemia may directly or indirectly inﬂuence the development of ﬁbroids

by promoting myometrial smooth muscle cell proliferation and increasing circulating levels of ovarian hormones. Central obesity, insulin resistance, elevated blood pressure, and hyperlipidemia are

com-ponents of metabolic syndrome and all factors associated with higherﬁbroid risk[39,40].

Lifestyle and diet

Physical activity, stress, diet, smoke, alcohol, and caffeine consumption seem to modulate signaling

pathways and molecular mechanisms involved inﬁbroids development and growth.

Exercise may be protective forﬁbroids, although few studies have examined this relation. Physical

activity can reduce circulating sex hormones, insulin levels, and the bioavailability of circulating

es-trogen increasing SHBG levels. In women who perform regular exercise, the risk ofﬁbroid seems to be

lower than in women who do not exercise[33]. Baird et al.[41], in a logistic regression with adjustment

for BMI and other risk factors, showed an inverse association between physical activity andﬁbroids in

both African-American and White women. The study has also found a dose-response pattern: women in the highest category of physical activity were signiﬁcantly less likely to have ﬁbroids (OR ¼ 0.6, 95% CI¼ 0.4e0.9) for the highest vs. the lowest category (equivalent to approximately, 7 h/week vs. <2 h/ week).

Stress is a potentialﬁbroid risk factor. Childhood exposure to physical, sexual, and emotional abuse,

for example, seems to increase leiomyoma risk, although an emotionally supportive relationship might

mitigate this effect[42]. Stressful experiences have been associated with high BMI, obesity, alcohol

consumption, and elevated blood pressure, all factors that increase the risk of myoma. In addition,

stress hormones can upregulate various growth factors, cytokines, and matrix metalloproteinases[33].

Stress also inﬂuences hypothalamic-pituitary-adrenal and gonadal axes, thus affecting the

bioavail-ability of estrogen and increasing risk forﬁbroid development[43]. Diet might play a role on uterine

fibroids risk. In fact, some dietary components seem to modify endogenous hormone metabolism, particularly estrogen effects. As a result, the eating habits of the different countries could partly explain the different prevalence of myomas. For example, the predominant contribution of fatty acids of animal origin rather than of dairy origin in Black women's diet might contribute to the greatest prevalence of fibroids in this population. Nevertheless, diet is a difficult variable to study because of the many confounding factors.

In an Italian case-control study, a signiﬁcant consumption of beef and other red meats (1.7-fold) or

ham (1.3-fold) was associated with an increased risk of ﬁbroids and consumption of ﬁsh with a

decreased risk[44]. In another retrospective study[45], the consumption ofﬁsh was positively

asso-ciated with incidence of leiomyomas, while Wise et al.[46]did notﬁnd an association between ﬁbroid

risk and totalﬁsh and seafood consumption. However, they found a positive relationship with

dark-meat ﬁsh, which are an important source of long-chain omega-3 PUFAs. Moreover, mechanisms

involved in this association may not be related solely to marine fatty acids: according to the study

conducted in the Great Lakes area[45], these divergent results may be related to the larger or smaller

presence of environmental pollutants inﬁsh from different countries. In Chiaffarino et al.'s case-control

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vegetables (OR 0.5) and fruit (OR 0.8). Several studies support an inverse association between

leio-myoma and a great intake of fruits and vegetables, particularly for citrus fruit[46], cruciferous

vege-tables (broccoli, cabbage, and Chinese cabbage), tomatoes, and apples [46]. Fruit and vegetables

contain various nutrients that may decreaseﬁbroid risk through inhibition of proliferation, apoptosis,

or hormone-dependent pathways[47].

Several studies suggest that vitamin D deﬁciency is a risk factor for uterine ﬁbroids [48e50].

African-American women have lower levels of serum vitamin D3 than White women because of ge-netic factors, diet habits, and black pigmentation. Vitamin D3 is a potent antitumor agent that inhibits leiomyoma cell proliferation in vitro and decreases the size of uterine leiomyomas in in vivo animal

models. Uterineﬁbroids express reduced levels of vitamin D receptor (VDR) when compared with

adjacent myometrium; therefore, the loss of vitamin D functions, due to reduced levels of serum vitamin D3 and/or reduced expression of VDR, might be a pivotal step for the development of uterine

ﬁbroids[51]. Wise et al.[52]identiﬁed single-nucleotide polymorphisms in genes involved in vitamin

D metabolism, which are signiﬁcantly associated with uterine leiomyoma. Al-Hendy et al. [53]

observed that vitamin D3 could be a potent antiestrogenic agent, reducing the expression of sex ste-roid receptors, suggesting that vitamin D supplementation may have utility as a novel therapeutic

option for UF. Wise et al.[46]found an inverse relation between vitamin A andﬁbroid risk but only for

the intake derived from animal products. In fact, the study suggests that other components of the foods from which vitamin A is derived (i.e., dairy products), rather than vitamin A itself, could explain the reduction in risk. However, vitamin A intake might play an etiologic role through the retinoic acid pathway. Once absorbed, vitamin A is converted to more active compounds such as retinoic acid that

have shown efﬁcacy in inhibiting the growth of leiomyoma in vitro and in animal models. No

asso-ciation has been reported between dietary intake of vitamin C, E, and folates and risk ofﬁbroids[54].

Early studies suggested that phytoestrogens, contained for example in soy, would reduce UL risk and

could partly explain the lower incidence ofﬁbroids in the Asian population, but several studies did not

ﬁnd any association between soy and ﬁbroids[55,56].

Epidemiological studies investigating the relation between cigarette smoking and risk of uterine

ﬁbroids are conﬂicting[57]. Early studies suggested a protective effect of smoking[24,58]. Conversely,

subsequent studies showed an increased risk of myoma[19,59], while others have not documented a

relationship[60]. Smoking seems to reduce levels of circulating estrogens, for example, inhibiting the

aromatase, which is responsible for the conversion of androgens to estrone and shifting E2metabolism

toward 2-hydroxylation pathways, thereby decreasing estrogen bioavailability[61]. However, smoking

may also exert estrogen-related effects on the uterus, which could promote cell proliferation[62e64].

Several studies have shown associations between alcohol consumption and higher risk ofﬁbroids

[5,56]. The BWHS[11]has examined this risk in relation to the type of alcoholic beverage,ﬁnding a stronger association with beer (high in phytoestrogen) consumption than with wine or liquor con-sumption. The possible explanatory mechanism is the increase in total estrogen levels and bioavailable estrogens caused by alcohol.

Caffeine consumption increases levels of early follicular phase estradiol[65]and may enhance sex

steroids production, inhibiting phosphodiesterase [66]. Despite this biological evidence, caffeine

consumption has not be proven to be a risk factor forﬁbroids among women of all ages[44], while an

increased risk was found in younger women with high consumption of coffee or caffeine intake. Conclusion

Future research on risk factors affecting uterineﬁbroids will elucidate the epidemiology and the

natural history ofﬁbroids. Controlled, prospective studies are needed to further understand the biology

and the epidemiological associations, both to have a better understand of modiﬁable risk factors and to

shed light on the etiopathogenesis of this disease.

Conﬂicts of interest

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94(7):2703e7. Practice points

Fibroids occur mainly in women of reproductive age. Risk factors include age and black race.

Incidence may also be influenced by menstrual history, endogenous and exogenous hor-mone levels, and reproductive history.

Lifestyle aspects such as physical activity, diet, smoke, and caffeine consumption have an influence on fibroid incidence.

Research agenda

Asymptomatic/small fibroid prevalence in young women.

Investigation on exogenous hormones influence on fibroid natural history. The role of obesity epidemic in fibroids development.

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