Uterine leiomyomas (fibroids) are the most common benign neoplasms in premenopausal women, which confer significant morbidity during the reproductive years and represent a significant public health issue. The incidence of fibroids has been associated with African-American race, early onset of menarche, early parity, and environmental/dietary exposures. These sex steroid-responsive uterine tumors are characterized by de novo transformation of the myometrium into fibroids via excessive formation of the extracellular matrix (ECM). Cytogenic anomalies, mutations in mediator complex subunit 12 (MED 12), and aberrant DNA methylation/demethylation have been observed, but have not been reported as direct mediators of fibroid development. Recent advances in epigenetics have implied a functional role of G protein-coupled receptor 10 (GPR10) overexpression and irregular microRNA expression in the pathobiology of fibroids that require future investigation. Herein, the impact of epidemiologic and genetic factors on the incidence and development of fibroids is reviewed.
Highlights
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Race/ethnicity is the most consistent factor associated with fibroid development.
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Direct cause of genetics and the genesis of fibroids remain uncertain.
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Models are needed for determining functional contributions of epigenetic modifiers.
Introduction
Human leiomyomata (fibroids) are benign smooth muscle tumors of the uterus, which represent the most common neoplasms in women of reproductive age, and have a lifetime incidence of approximately 70% in the general population . Approximately 20–40% of women with fibroids report significant symptoms and seek gynecologic care . The most common clinical symptoms include abnormal uterine bleeding, dysmenorrhea, pelvic pain, infertility, and recurrent pregnancy loss; fibroids remain the leading indication for hysterectomy in the United States . This disorder constitutes a major public health concern resulting in a significant degree of morbidity in premenopausal women with an estimated annual societal cost of approximately $5.9–34.4 billion (USD) in the United States .
These estrogen- and progesterone-dependent uterine tumors are clonal in origin and are typically diagnosed following menarche . The most commonly accepted molecular mechanism of disease development is the transformation of myometrial smooth muscle (comprising the majority of uterine muscle mass) fibroblasts and the formation of dysfunctional extracellular matrix (ECM) . However, the specific functional role of genetic mediators in cellular transformation, proliferation, apoptosis, neovascularization, and cellular hypertrophy has been difficult to characterize with certainty . Most importantly, transforming growth factor beta (TGF-β) and its cognate receptor (TGF-βR) have been implicated by several investigators as critical mediators of cell signaling contributing to the genesis of uterine fibroids . The intrinsic biological functions of TGF-β, including cellular hypertrophy and ECM turnover, are central to various fibrotic disorders, potentially including uterine leiomyoma . Recently, investigators have provided additional insight into the possible roles (independent and synergistic) of several other molecules, including RE1-suppressing transcription factor (REST), G protein receptor 10 (GPR10), and matrix metalloproteinases (MMPs); alteration of several genes (e.g., MED12 , HMGA2, CYP1A1, and CYP1B1 ), proto-oncogenes (e.g., p27 and p53), and related signaling pathways (e.g., PI3K-AKT-MTOR); and epigenetic etiologies such as histone modification, DNA demethylation, and aberrant microRNA (miRNA) expression .
Despite the first formal description of fibroids in the 16th century, the influence of genetic and epigenetic mediators in the pathobiology of this disorder remains unclear. The interplay of population health and genomics, demographics, environmental exposure, and genetics with the development of uterine fibroids warrants comprehensive examination. In this review, we will discuss contemporary epidemiologic and genetic topics pertinent to the pathogenesis of uterine leiomyomata.
Epidemiology
Prevalence
Prior to the mid-1990s, the majority of prevalence data for uterine fibroids were based on a small number of European case series that described findings from the histologic examination of surgical specimens . Unfortunately, these studies did not provide an accurate estimate of the true prevalence of disease as they did not account for women who were asymptomatic or symptomatic and did not undergo surgical treatment. In the late 1990s, the Nurses’ Health Study (NHS), a prospective cohort of >95,000 premenopausal women, reported that the annual rate of new annual fibroid diagnosis was approximately 12.8 per 1000 woman years . Subsequently, the National Institute of Environmental Health Sciences (NIEHS) Uterine Fibroid Study reported that >80% of African-American (AA) and 70% of Caucasian women developed fibroids by 50 years of age . Racial/ethnic disparity of uterine fibroids has been a consistent observation by several independent investigators and is one of the most consistent epidemiologic characteristic of uterine fibroids. Additional risk factors such as age of menarche, parity, environmental exposure, and dietary/lifestyle habits have been delineated over the past decade, and have prompted an analysis of the effect of “nature versus nurture” on the development of this gynecologic disorder.
Risk factors
Race/ethnicity
One of the most intriguing demographic associations with fibroids has been the disproportionate prevalence and severity of uterine fibroids in women of African descent. Although the disparity of disease and outcomes in AA women has been attributed to differences in socioeconomic status, health-care access, genetics, and environmental exposures, the underlying causes of racial/ethnic differences remain uncertain. Uterine fibroids are diagnosed in AA women thrice more frequently than in Caucasian women , and the NIEHS Fibroid Study revealed a significantly higher cumulative incidence in AA women during the reproductive years . Marsh et al. conducted an elegant prospective pilot study to assess the prevalence (via ultrasound) of fibroids in asymptomatic young Caucasian and AA women with 18–30 years of age . AA women also demonstrated a threefold higher prevalence of uterine fibroids (26% vs. 7%), a larger number of fibroids, and a larger uterine volume than Caucasian women . These findings supported the observations of earlier studies, which also reported a higher growth rate and disease burden in AA women and observed a 10–15-year earlier age of onset of symptoms in AA women .
Of particular interest has been the insight gained from the Black Women’s Health Study (BWHS). It is a prospective cohort study conducted in the United States since 1995, which enrolled 60,000 black women aged 21–65 years . Several published secondary analyses of this study reported an association of age, age of menarche, body mass index, interval since last live birth, and alcohol use (mainly beer) with the likelihood of having fibroids . The age of first live birth, first contraceptive use, use of progestin-only injectable contraception, smoking, and parity were inversely associated with the incidence of fibroids . Notably, dietary intake was associated with the likelihood of fibroids in AA women; in particular, individuals with an increased intake of citrus fruits and animal-derived sources of vitamin A demonstrated a significantly reduced risk of developing fibroids . A 30% reduction in the risk of developing fibroids was also observed in those who reported intake of four or more dairy products per day compared with who consumed one or fewer dairy products .
In addition to the ethnic disparity of the prevalence and severity of the disease, an important characteristic of fibroids is the difference in outcomes of surgical treatment. AA women have increased rates of hospitalization, myomectomy, and hysterectomy (relative risk 3.5, 6.8, and 2.4, respectively) compared with Caucasian women . Furthermore, a study by Wilcox et al. reported that uterine fibroids were more than twice likely to be the indicator of hysterectomy in AA women than their Caucasian counterparts (61% vs. 29%) . Following abdominal myomectomy, Roth et al. reported a higher rate of postoperative complications (odds ratio [OR] 2.5; 95% CI 1.5–4.8) and blood product transfusion (OR 2.3; 95% CI 1.1–5.0) .
Although racial ethnic differences in fibroids have been studied extensively, the underlying mechanisms for observed disparities remain speculative. Differences in severity of disease, rate of surgical procedures, and postoperative complications may be attributed, in part, to delay in diagnosis, more severe preoperative fibroid, larger uterine size, and higher technical difficulty of surgery (secondary to larger uterine size) in AA women than Caucasian women . Association of in utero/early childhood exposure, environmental exposures, socioeconomic characteristics, reproductive tract infections, stress, and dietary exposures with fibroid development has been inconsistent and remains contemporary areas of continued investigation and validation.
Age of menarche
Several studies over the past decade have demonstrated an association of early age of menarche with the risk of developing fibroids . However, the results of the first studies are difficult to interpret, as age of menarche was not considered as a continuous variable and the reference groups of early menarche were inconsistent. In a multicenter prospective cohort study conducted from 2001 to 2011, which screened and followed women for fibroids during very early pregnancy, investigators observed an association of age of menarche and the presence of leiomyoma. In particular, a 1-year increase in age of menarche was inversely associated with the presence of fibroids (adjusted risk ratio: 0.87, 95% CI: 0.82–0.91) . This has been the most comprehensive study to date and the first to demonstrate an inverse relationship between the age of menarche and the number of fibroids. It is important to note that women with the earliest age of menarche had the highest risk of having multiple fibroids (adjusted risk ratio: 2.31, 95% CI: 1.50–3.59) . Similar to previous studies, this study did not observe an association between race and the age of menarche. Menarche at age ≤11 years was associated with the highest risk of developing fibroids, whereas that at >13 years of age was associated a reduced risk. Similar to the NIEHS Fibroid Study, an association between age of menarche and all three fibroid types (subserosal, intramural, and submucosal) was observed .
Investigators have speculated that the association of menarche age and fibroids may be based on the duration and degree of exposure to endogenous sex steroid hormones . The two prevailing hypotheses include a longer duration of exposure to estradiol and progesterone with an earlier age of menarche and a unique hormonal milieu (associated with an early menarche), which may increase the risk of fibroid development . However, the mechanisms of these hypotheses have not been confirmed in animal or human studies to date.
Parity
In several studies, including the NHS and BWHS , increasing parity appeared to reduce the likelihood of developing fibroids. The potential protective effect of pregnancy was described in the observational study by Laughlin et al., in which women were systematically screened for fibroids in early pregnancy and again in the postpartum period. Within the cohort of 171 women with a single fibroid observed in early pregnancy, 36% did not have any fibroids within 3–6 months after delivery . Furthermore, fibroids that were not eliminated demonstrated a reduction in volume after pregnancy . Suggested mechanisms for this association include apoptosis induced by postpartum remodeling and fibroid ischemia during parturition .
Baird et al. proposed that the inverse association between parity and fibroid development may be an artifact of reverse causation. In this case, where fibroids may cause infertility and reduced parity, nulliparous women will appear to be more at risk of developing fibroids , and parity will appear protective . Interestingly, this inverse association persists when authors control for infertility in epidemiological studies, and has been observed in the Eker rat murine fibroid model . Unfortunately, this association is difficult to interpret because of intrinsic selection biases in prospective studies . This complicates studies that include a considerable proportion of patients undergoing hysterectomy. Compared with women who still desire pregnancy and uterine preservation, women with symptomatic fibroids who have completed childbearing will be more likely to opt for definitive surgery (hysterectomy) , and will be excluded from most observational studies. An additional bias to consider when examining the association of parity and fibroids is the exclusion of parous women with fibroids from observational studies . Typically, parous patients would have had ultrasounds during their prior pregnancy(ies) and would be more likely to have observed asymptomatic fibroids (i.e., prior screening for fibroids). As a result, parous patients without fibroid diagnosis are included in cohort studies. As many patients with fibroids are asymptomatic and may have fibroids that are not detected during baseline ultrasound for study enrollment, only a subset of them will be excluded . As a result, there may be an underestimation of fibroids in parous women in previous studies, and additional prospective incidence studies are warranted to delineate the putative protective effect of parity further.
Environmental exposure and dietary/lifestyle habits
As observed in the areas of autoimmune disorders and cancer biology, data regarding the association of environmental exposures and incidence of fibroids continue to emerge. In utero exposure of the synthetic estrogen, diethylstilbestrol (DES) and the endocrine disruptor, bisphenol A (BPA) has been associated with the development of fibroids in animal models . Several investigators have found associations between exposures of DES and phthalates (estrogenic effect in cell models) and the development of fibroids in human observational studies . The third National Health and Nutritional Examination Survey (NHANES) reported a positive correlation of fibroids with urinary levels of monbutyl phthalate and a negative association of urinary levels of mono (2-ethylhexyl) phthalates with the likelihood of developing fibroids . A similar association of urinary monoethylhexyl phthalate was also observed in an analysis of gene polymorphisms associated with adenomyosis, endometriosis, and leiomyoma . Notably, an increased risk of developing fibroids has also been observed in hair relaxer (containing phthalates) users, and was correlated with the frequency and duration of its use .
Associations of the incidence of fibroids and other lifetime habits and exposures, such as smoking, hormonal contraceptives, alcohol and caffeine, and dietary factors, have been inconsistent . Emerging evidence suggested a possible association of vitamin D deficiency with the development of fibroids. An insightful work by Al-Hendy et al. has demonstrated in vivo inhibitory effect of 1,25 hydroxyvitamin D3 in the Eker rat model . Vitamin D treatment have also been shown to inhibit in vitro EM formation, proliferation, and reduce the rate of apoptosis in immortalized leiomyoma cell culture . Interestingly, investigators have observed an association between lower vitamin D levels and prevalence and size of fibroids in observational studies . Although an intriguing target for fibroids, further investigation is warranted to confirm whether vitamin D deficiency is a true risk factor for fibroid development or feasible dietary therapeutic targets for fibroids.
As highlighted by Buck Louis et al., if there is an association of environmental exposure with the risk of developing fibroids, it is likely due to cumulative exposures (“exposome”) over an extended period of time . Although relevant to epidemiologic exposure studies, further investigation of the biologic relevance of the “exposome” will require more comprehensive study.
Epidemiology
Prevalence
Prior to the mid-1990s, the majority of prevalence data for uterine fibroids were based on a small number of European case series that described findings from the histologic examination of surgical specimens . Unfortunately, these studies did not provide an accurate estimate of the true prevalence of disease as they did not account for women who were asymptomatic or symptomatic and did not undergo surgical treatment. In the late 1990s, the Nurses’ Health Study (NHS), a prospective cohort of >95,000 premenopausal women, reported that the annual rate of new annual fibroid diagnosis was approximately 12.8 per 1000 woman years . Subsequently, the National Institute of Environmental Health Sciences (NIEHS) Uterine Fibroid Study reported that >80% of African-American (AA) and 70% of Caucasian women developed fibroids by 50 years of age . Racial/ethnic disparity of uterine fibroids has been a consistent observation by several independent investigators and is one of the most consistent epidemiologic characteristic of uterine fibroids. Additional risk factors such as age of menarche, parity, environmental exposure, and dietary/lifestyle habits have been delineated over the past decade, and have prompted an analysis of the effect of “nature versus nurture” on the development of this gynecologic disorder.
Risk factors
Race/ethnicity
One of the most intriguing demographic associations with fibroids has been the disproportionate prevalence and severity of uterine fibroids in women of African descent. Although the disparity of disease and outcomes in AA women has been attributed to differences in socioeconomic status, health-care access, genetics, and environmental exposures, the underlying causes of racial/ethnic differences remain uncertain. Uterine fibroids are diagnosed in AA women thrice more frequently than in Caucasian women , and the NIEHS Fibroid Study revealed a significantly higher cumulative incidence in AA women during the reproductive years . Marsh et al. conducted an elegant prospective pilot study to assess the prevalence (via ultrasound) of fibroids in asymptomatic young Caucasian and AA women with 18–30 years of age . AA women also demonstrated a threefold higher prevalence of uterine fibroids (26% vs. 7%), a larger number of fibroids, and a larger uterine volume than Caucasian women . These findings supported the observations of earlier studies, which also reported a higher growth rate and disease burden in AA women and observed a 10–15-year earlier age of onset of symptoms in AA women .
Of particular interest has been the insight gained from the Black Women’s Health Study (BWHS). It is a prospective cohort study conducted in the United States since 1995, which enrolled 60,000 black women aged 21–65 years . Several published secondary analyses of this study reported an association of age, age of menarche, body mass index, interval since last live birth, and alcohol use (mainly beer) with the likelihood of having fibroids . The age of first live birth, first contraceptive use, use of progestin-only injectable contraception, smoking, and parity were inversely associated with the incidence of fibroids . Notably, dietary intake was associated with the likelihood of fibroids in AA women; in particular, individuals with an increased intake of citrus fruits and animal-derived sources of vitamin A demonstrated a significantly reduced risk of developing fibroids . A 30% reduction in the risk of developing fibroids was also observed in those who reported intake of four or more dairy products per day compared with who consumed one or fewer dairy products .
In addition to the ethnic disparity of the prevalence and severity of the disease, an important characteristic of fibroids is the difference in outcomes of surgical treatment. AA women have increased rates of hospitalization, myomectomy, and hysterectomy (relative risk 3.5, 6.8, and 2.4, respectively) compared with Caucasian women . Furthermore, a study by Wilcox et al. reported that uterine fibroids were more than twice likely to be the indicator of hysterectomy in AA women than their Caucasian counterparts (61% vs. 29%) . Following abdominal myomectomy, Roth et al. reported a higher rate of postoperative complications (odds ratio [OR] 2.5; 95% CI 1.5–4.8) and blood product transfusion (OR 2.3; 95% CI 1.1–5.0) .
Although racial ethnic differences in fibroids have been studied extensively, the underlying mechanisms for observed disparities remain speculative. Differences in severity of disease, rate of surgical procedures, and postoperative complications may be attributed, in part, to delay in diagnosis, more severe preoperative fibroid, larger uterine size, and higher technical difficulty of surgery (secondary to larger uterine size) in AA women than Caucasian women . Association of in utero/early childhood exposure, environmental exposures, socioeconomic characteristics, reproductive tract infections, stress, and dietary exposures with fibroid development has been inconsistent and remains contemporary areas of continued investigation and validation.
Age of menarche
Several studies over the past decade have demonstrated an association of early age of menarche with the risk of developing fibroids . However, the results of the first studies are difficult to interpret, as age of menarche was not considered as a continuous variable and the reference groups of early menarche were inconsistent. In a multicenter prospective cohort study conducted from 2001 to 2011, which screened and followed women for fibroids during very early pregnancy, investigators observed an association of age of menarche and the presence of leiomyoma. In particular, a 1-year increase in age of menarche was inversely associated with the presence of fibroids (adjusted risk ratio: 0.87, 95% CI: 0.82–0.91) . This has been the most comprehensive study to date and the first to demonstrate an inverse relationship between the age of menarche and the number of fibroids. It is important to note that women with the earliest age of menarche had the highest risk of having multiple fibroids (adjusted risk ratio: 2.31, 95% CI: 1.50–3.59) . Similar to previous studies, this study did not observe an association between race and the age of menarche. Menarche at age ≤11 years was associated with the highest risk of developing fibroids, whereas that at >13 years of age was associated a reduced risk. Similar to the NIEHS Fibroid Study, an association between age of menarche and all three fibroid types (subserosal, intramural, and submucosal) was observed .
Investigators have speculated that the association of menarche age and fibroids may be based on the duration and degree of exposure to endogenous sex steroid hormones . The two prevailing hypotheses include a longer duration of exposure to estradiol and progesterone with an earlier age of menarche and a unique hormonal milieu (associated with an early menarche), which may increase the risk of fibroid development . However, the mechanisms of these hypotheses have not been confirmed in animal or human studies to date.
Parity
In several studies, including the NHS and BWHS , increasing parity appeared to reduce the likelihood of developing fibroids. The potential protective effect of pregnancy was described in the observational study by Laughlin et al., in which women were systematically screened for fibroids in early pregnancy and again in the postpartum period. Within the cohort of 171 women with a single fibroid observed in early pregnancy, 36% did not have any fibroids within 3–6 months after delivery . Furthermore, fibroids that were not eliminated demonstrated a reduction in volume after pregnancy . Suggested mechanisms for this association include apoptosis induced by postpartum remodeling and fibroid ischemia during parturition .
Baird et al. proposed that the inverse association between parity and fibroid development may be an artifact of reverse causation. In this case, where fibroids may cause infertility and reduced parity, nulliparous women will appear to be more at risk of developing fibroids , and parity will appear protective . Interestingly, this inverse association persists when authors control for infertility in epidemiological studies, and has been observed in the Eker rat murine fibroid model . Unfortunately, this association is difficult to interpret because of intrinsic selection biases in prospective studies . This complicates studies that include a considerable proportion of patients undergoing hysterectomy. Compared with women who still desire pregnancy and uterine preservation, women with symptomatic fibroids who have completed childbearing will be more likely to opt for definitive surgery (hysterectomy) , and will be excluded from most observational studies. An additional bias to consider when examining the association of parity and fibroids is the exclusion of parous women with fibroids from observational studies . Typically, parous patients would have had ultrasounds during their prior pregnancy(ies) and would be more likely to have observed asymptomatic fibroids (i.e., prior screening for fibroids). As a result, parous patients without fibroid diagnosis are included in cohort studies. As many patients with fibroids are asymptomatic and may have fibroids that are not detected during baseline ultrasound for study enrollment, only a subset of them will be excluded . As a result, there may be an underestimation of fibroids in parous women in previous studies, and additional prospective incidence studies are warranted to delineate the putative protective effect of parity further.
Environmental exposure and dietary/lifestyle habits
As observed in the areas of autoimmune disorders and cancer biology, data regarding the association of environmental exposures and incidence of fibroids continue to emerge. In utero exposure of the synthetic estrogen, diethylstilbestrol (DES) and the endocrine disruptor, bisphenol A (BPA) has been associated with the development of fibroids in animal models . Several investigators have found associations between exposures of DES and phthalates (estrogenic effect in cell models) and the development of fibroids in human observational studies . The third National Health and Nutritional Examination Survey (NHANES) reported a positive correlation of fibroids with urinary levels of monbutyl phthalate and a negative association of urinary levels of mono (2-ethylhexyl) phthalates with the likelihood of developing fibroids . A similar association of urinary monoethylhexyl phthalate was also observed in an analysis of gene polymorphisms associated with adenomyosis, endometriosis, and leiomyoma . Notably, an increased risk of developing fibroids has also been observed in hair relaxer (containing phthalates) users, and was correlated with the frequency and duration of its use .
Associations of the incidence of fibroids and other lifetime habits and exposures, such as smoking, hormonal contraceptives, alcohol and caffeine, and dietary factors, have been inconsistent . Emerging evidence suggested a possible association of vitamin D deficiency with the development of fibroids. An insightful work by Al-Hendy et al. has demonstrated in vivo inhibitory effect of 1,25 hydroxyvitamin D3 in the Eker rat model . Vitamin D treatment have also been shown to inhibit in vitro EM formation, proliferation, and reduce the rate of apoptosis in immortalized leiomyoma cell culture . Interestingly, investigators have observed an association between lower vitamin D levels and prevalence and size of fibroids in observational studies . Although an intriguing target for fibroids, further investigation is warranted to confirm whether vitamin D deficiency is a true risk factor for fibroid development or feasible dietary therapeutic targets for fibroids.
As highlighted by Buck Louis et al., if there is an association of environmental exposure with the risk of developing fibroids, it is likely due to cumulative exposures (“exposome”) over an extended period of time . Although relevant to epidemiologic exposure studies, further investigation of the biologic relevance of the “exposome” will require more comprehensive study.
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