Best Practice & Research Clinical Obstetrics and Gynaecology

Vol. 22, No. 4, pp. 571–588, 2008

doi:10.1016/j.bpobgyn.2008.04.002
available online at http://www.sciencedirect.com

Incidence, aetiology and epidemiology

of uterine fibroids

Stanley Okolo * MBBCH, PhD, FWACS, FRCOG

Medical Executive Director and Professor of Ob-Gyn
North Middlesex University Hospital, Sterling Way, London, UK

Uterine fibroids are the most common benign tumour of the female genital tract. However, their
true prevalence is probably under-estimated, as the incidence at histology is more than double
the clinical incidence. Recent longitudinal studies have estimated that the lifetime risk of fibroids
in a woman over the age of 45 years is more than 60%, with incidence higher in blacks than in
whites. The cause of fibroids remains unclear and their biology poorly understood. No single
candidate gene has been detected for commonly occurring uterine fibroids. However, the occur-
rence of rare uterine fibroid syndromes, such as multiple cutaneous and uterine leiomyomatosis,
has been traced to the gene that codes for the mitochondrial enzyme, fumarate hydratase. Cy-
togenetic abnormalities, particularly deletions of chromosome 7, which are found in up to 50%
of fibroid specimens, seem to be secondary rather than primary events, and investigations into
the role of tumour suppressor genes have yielded conflicting results. The key regulators of fi-
broid growth are ovarian steroids, both oestrogen and progestogen, growth factors and angio-
genesis, and the process of apoptosis. Black race, heredity, nulliparity, obesity, polycystic ovary
syndrome, diabetes and hypertension are associated with increased risk of fibroids, and there is
emerging evidence that familial predisposition to fibroids is associated with a distinct pattern of
clinical and molecular features compared with fibroids in families without this prevalence.

Key words: fibroids; familiality; growth factors; genes; lifetime risk.

First described in 1793 by Matthew Baillie of St George’s Hospital, London, uterine

fibroids are the most common benign tumour in women, being clinically apparent in
up to 25% of all women1 and up to 30–40% of women over 40 years of age. However,
a large proportion of fibroids remain undiagnosed since most are asymptomatic. The
aetiology of uterine fibroids and their biology are poorly understood. Several risk fac-
tors have been identified, such as ethnicity, nulliparity, genetics and hormonal factors,
yet little is known regarding the reasons for the heterogeneity in behaviour of fibroids
and the symptoms attributable to them. Why is it that fibroids are solitary, small and

* Tel.: þ44 (0) 20 8887 4117.

E-mail addresses: s.okolo@medsch.ucl.ac.uk, stanley.okolo@nmh.nhs.uk
1521-6934/$ - see front matter ª 2008 Elsevier Ltd. All rights reserved.
572 S. Okolo

slow growing in some women, and multiple, large and fast growing in other women?
Why is it that there is a prevalence of uterine fibroids in some families but not in
others? Traditional teaching is being updated, and molecular research is continually im-
proving our understanding of the epidemiology of this debilitating condition which has
significant morbidity and socio-economic impact.

INCIDENCE

The population incidence of uterine fibroids is not known because most studies have
evaluated the incidence in women seeking medical help. Reports based on clinical di-
agnosis or diagnostic tests underestimate the true incidence, since they only relate to
women with symptoms or those who come into contact with health professionals. On
the other hand, reports based on histology alone may overestimate the true incidence
as they relate to women with symptoms in whom non-surgical treatments have failed,
most of whom may therefore have fibroids. In one such study which included histolog-
ical assessment of hysterectomy specimens, the incidence of uterine fibroids was 33%
based on clinical assessment, 50% based on ultrasound and 77% based on histological
assessment.2 The reported incidence therefore ranges from 30% to 70% in premeno-
pausal women and increases with increasing age.3 A population-based study of mem-
bers of an urban health plan aged 35–49 years, selected at random, reported uterine
fibroids in 59% of Black women and 43% of White women with no previous diagnosis
of fibroids, with the incidence reaching over 75% and 65%, respectively, in those aged
45 years or more.4 This study estimated that most women have a lifetime risk of de-
veloping uterine fibroids of nearly 70%. However, many of these studies were cross-
sectional and whilst they confirm the incidence at any point in time, they do not offer
any insight into the trends of diagnosis with age, in contrast with longitudinal studies.
Studies with a cohort design also have the limitation that participants are not usually
screened at entry.
An alternative method of reporting incidence is to assess the rates of new diagno-
ses per year in women followed-up in longitudinal observational cohort studies such as
the Nurses Health Study or the Black Women’s Health Study in the USA, with re-
ported rates of 12.7 per 1000 woman-years and 29.7 per 1000 woman-years,
respectively.3,5

AETIOLOGY

Although the aetiology of uterine fibroids is unknown, there have been some major
advances in understanding of the pathogenesis of this condition. As with all tumours,
there are two distinct stages in development: transformation from a normal to an ab-
normal cell; and growth and proliferation of the abnormal cells. Although fibroids may
be multiple or solitary in a woman’s uterus, studies have established that, irrespective
of size, each fibroid develops from one single cell (the monoclonal development of
fibroids concept). In hysterectomy specimens from women with multiple fibroids,
glucose-6-phosphate dehydrogenase iso-enzyme (A or B) activity was identical in
each cell of a particular fibroid tumour, exhibiting a single electrophoretic pattern
even when as many as eight samples from the same tumour were analysed.6 This
has been confirmed using polymerase chain reaction involving the differential inactiva-
tion of X-linked phosphoglycerol-kinase gene from fibroid specimens.7 All the cells
from each fibroid tumour were found to have a single type of active allele, again
 Incidence, aetiology and epidemiology of uterine fibroids 573

indicating that each tumour had a single cell origin. What determines the transforma-
tion from a normal myometrial cell to an abnormal myocyte which then multiplies and
grows into a fibroid tumour remains unclear. Whatever initiates this transformation
must be a frequent occurrence in those women with multiple fibroids and a rare event
in women with a single uterine fibroid.
The different phases in a cell cycle are well known; a phase of DNA replication and
synthesis (S-phase) and a phase of cell mitosis (M-phase), separated by gap or rest
phases (G0, G1 and G2 phases). This results in orderly and identical replication of cells
with the same phenotype. Transformation to a different cell phenotype appears to be
a stepwise process determined by genomic alterations. Transformation is independent
of cell proliferation, although unrestricted proliferation may be favoured with repeated
and progressing transformation. However, transformed cells often exhibit one of the
following features: immortalization; change in cell morphology; decreased contact in-
hibition; altered dependence on growth factors; and tumourigenicity.8 Initiation of
transformation may result from altered activity of any factor in the transformation sig-
nalling pathway9 or from reduced activity of transformation-inhibiting factors such as
tumour suppressor genes and anti-oncogens. However, their specific roles in the
transformation from a normal myocyte to a fibroid cell have not been fully established.
Candidate genes for rare uterine fibroid syndromes, such as hereditary leiomyoma-
tosis and renal cell cancer syndrome or multiple cutaneous and uterine leiomyoma
syndrome, also known as Reed syndrome, have been identified recently.10 These
have been localized to the gene that codes for the mitochondrial enzyme involved
in Kreb’s cycle, fumarate hydratase, but attempts at identifying such mitochondrial
genes in the common non-syndromic uterine fibroids suffered by most women have
failed.11–14 However, there is growing evidence that uterine fibroids are not a single
gene disorder.

Insight from cytogenetic and molecular studies

In the past decade, it has been reported that uterine fibroids occurred frequently in
atomic bomb survivors15, with an odds ratio of 1.61 (95% confidence interval 1.12–
2.31). There was a dose–response relationship between atomic bomb radiation expo-
sure and the incidence of fibroids.16 Similar findings were published in the Radiation
Effects Research Foundation Adult Health Report17 and confirmed in a recent up-
date.18 Although it is unclear how prior radiation leads to future development of fi-
broids, radiation typically causes cytogenetic abnormalities indicating that cellular
damage may be one of the initiators of the initial transformation from a normal to
an abnormal myocyte. However, this presumption has been questioned and it is
thought that the cytogenetic alterations are secondary, rather than primary, factors
in the development of a fibroid tumour.19
Studies of uterine fibroid specimens have shown that approximately 50% of these
tumours have cytogenetic chromosomal alterations.20–23 Chromosomal changes
such as translocations, duplications and deletions are common in uterine fibroids.
The most common cytogenetic abnormalities are deletions in chromosome 7 and
translocations involving chromosomes 7, 12 and 14. The critical region affected in
chromosome 7 appears to be on the long arm (7q21-22), where several known genes
such as cytochrome p450 gene, collagen type 1 alpha 2 and MET proto-oncogen are
coded.24 Recurrent balanced translocations in chromosomes 12 and 14 (q13-15,
q24) are also common in fibroids.21 There is a suggestion that cytogenetic
574 S. Okolo

abnormalities in fibroids are associated with a loss of oestrogen dependency, thereby

altering the growth potential of the tumour.25
Recent molecular studies have also increased understanding of the pathogenesis of
fibroids and provided clues to their aetiology. Some known genes have been investi-
gated as candidate genes in the aetiology of fibroids, with comparative studies of
gene expression between fibroid tissue and adjacent normal tissue.24,26,27 However,
the results are not consistent. One study found significantly reduced expression of
a tumour suppressor gene, cut-like homeobox gene, in fibroids indicating that this is
of significance in the aetiology of fibroids.27 A comparative study of fibroid specimens
and leiomyosarcoma tissue investigated the loss of p53 function which has been impli-
cated in the pathogenesis of many human tumours. Although the study determined
that alterations in exons 5–8 of p53 are the mutation hot spots for this gene in leio-
myosarcoma, there were no such changes in any of the fibroid specimens.26
Investigations of the role of tumour suppressor genes and oncogenes in the aetiol-
ogy of uterine fibroids have yielded conflicting results. The expression of secreted tu-
mour suppressor gene mac25 mRNA is significantly reduced in small and large
untreated fibroids compared with adjacent myometrium28, while monocyte chemotac-
tic protein, a chemokine with antitumour effects, is increased in fibroids relative to
myometrium.29
The aetiology of uterine fibroids therefore remains obscure, and there is increasing
evidence that this is not a single gene disorder. However, several factors play a role in
regulating the growth and development of fibroids once the initial transformation has
occurred.

Regulation of the growth of uterine fibroids

Several factors appear to influence the growth of uterine fibroids. These include not
only ovarian steroids, growth factors and angiogenesis, but also the process of
apoptosis.

Role of ovarian steroids

Uterine fibroids are oestrogen and progesterone dependent by a yet undetermined
cellular and molecular mechanism. It has long been known that fibroid growth only
occurs in women of reproductive age, and growth is diminished under hypo-oestro-
genic states such as the menopause or during treatment with gonadotrophin-releasing
hormone agonist (GnRHa)30,31, with a reversible reduction in fibroid size with GnRHa
therapy.32
Although there is no evidence of abnormal levels of circulating oestrogen or pro-
gesterone in women with fibroids, there is some indication that tissue receptor ex-
pression for these hormones may play a part. Mitotic activity in uterine fibroids
varies in response to the menstrual cycle, being highest in the luteal phase and during
pregnancy.33 Whilst these may initially be regarded as physiological states of progester-
one dominance, the presence of other endogenous sex steroids means that the fibroid
activity observed is in response to a mixture of endogenous hormones, rather than
due to one sex steroid or the other. In-vitro studies often provide excellent models
for studying the role of individual ovarian steroids in the growth of fibroids.
There is experimental evidence of increased oestrogen receptor gene expression in
uterine fibroids compared with normal myometrium34, and an enhanced response to
oestrogen stimulation by fibroid cells compared with normal myometrial cells.34–36
 Incidence, aetiology and epidemiology of uterine fibroids 575

Animal models have been used to investigate the growth characteristics and tumour-
igenicity of cell lines from uterine fibroids obtained from Eker rats.37–42 Sixty-five per-
cent of female Eker rats would normally develop spontaneous uterine fibroid tumours
by the age of 16 months, with high expression of oestrogen and progesterone recep-
tors in these fibroid cell lines. These Eker rat leiomyoma tumour-derived cell lines
(ELT 3) proliferate in culture in a dose–response manner to 17b-oestradiol stimula-
tion, and when injected into nude mice, the resulting xenografts also proliferate in
vivo in response to 17b-oestradiol administration. At sexual maturity, sex hormones
are diminished and there are significantly lower levels of apoptosis in these animals, yet
the fibroid cell lines continue to proliferate in vivo in response to oestrogen stimula-
tion, unlike normal myometrial cells, indicating that fibroid cells exhibit enhanced sen-
sitivity to steroid hormone stimulation.
The response of ELT 3 cells to several doses of representative oestrogenic stimula-
tion is complex. Some of the experiments involved exogenous oestrogen receptor li-
gands (ion, molecule or molecular group that binds to another chemical entity to
form a larger complex) which bind to oestrogen receptors with varying affinities similar
to that of oestradiol. Eker rats treated with diethylstilbestrol showed dramatic enlarge-
ment of their myometrium, whereas those treated with tamoxifen, a selective oestro-
gen receptor modulator, did not.40 Treatment with genisten, a plant-derived oestrogen,
stimulated fibroid tumour cell line growth in vitro at moderate concentrations, but was
inhibitory at high concentrations even in oestrogen-receptor-negative cell lines.43
The role of progesterone in stimulating uterine fibroid growth is becoming clearer.
Uterine fibroids exhibit increased mitosis in the progesterone-dominant luteal phase of
the menstrual cycle, and progesterone receptors have been shown to be increased in fi-
broids relative to normal myometrium.33 Expression of the cell-proliferation-associated
antigen Ki-67 (also known as cycling cells) in fibroids is reduced in the follicular phase
of the menstrual cycle but increased in the luteal phase and during pregnancy44, both
of which are high progesterone physiological states. Increased mitotic activity has been
demonstrated in fibroid specimens from women treated with a progestogen.44,45 Proges-
terone has been shown to upregulate, in fibroid cell culture, the level of some proteins
that influence cell proliferation, such as anti-apoptotic protein Bcl-246 and proliferating
cellular nuclear antigen.47 Finally, the maintenance of a differentiated cellular state in fi-
broids appears to be regulated negatively by progesterone but positively by oestrogen.48
Ovarian steroids therefore appear to stimulate fibroid growth but in a non-uniform
manner, with both oestrogen and progesterone stimulating growth.

Role of growth factors and angiogenesis

The role of growth factors in stimulating fibroid growth has been receiving significant
attention in the past few years, but their full role has still not been established, given
the complex interactions of growth factors, ovarian steroids and cellular processes
such as apoptosis. For example, ovarian steroids, to which fibroids are responsive, in-
fluence the secretion of growth factor peptides and the expression of their recep-
tors49, with both oestrogens and progestogens inducing expression of vascular
endothelial growth factor (VEGF) mRNA in the rodent uterus. The effects of insu-
lin-like growth factor (IGF), platelet-derived growth factor (PDGF), epidermal growth
factor (EGF) and VEGF on uterine fibroids have been studied.50–54
IGF-1 and IGF-2 are polypeptide growth factors which play an important role in tis-
sue growth.55 It has been shown that IGF-1 expression in human uterine fibroids may
be up to three times greater than that found in adjacent myometrium, and up to seven
576 S. Okolo

times greater than that found in Eker rat uterine tumours.56,57 It appears that auto-
crine stimulation of IGF-1 receptor plays a role in the maintenance of normal myome-
trial growth, and that disordered IGF-1 signalling may contribute to uterine fibroid
growth.53,56 The role of IGF-2 in uterine fibroids appears to be very limited.
Fibroblast growth factor (FGF-2) increases the proliferation, migration and differen-
tiation of endothelial cells, smooth muscle cells and fibroblasts, all of which express
FGF receptors (FGF-R).57,58 FGF-2 acts synergistically with VEGF59 and has been re-
ported to stimulate the synthesis of VEGF in a number of tumour cell lines.60 Com-
parative studies of the expression of FGF-2 in fibroid specimens and normal
myometrium have yielded conflicting results: no difference in the immuno-expression
of FGF-2 or FGF-R in these tissues50; elevated FGF-2 mRNA transcripts in uterine fi-
broids, particularly in the extracellular matrix (ECM)61; and elevated FGF-R immuno-
reactivity in normal myometrium.62 FGF has also been shown to be mitogenic on
cultured fibroid cells in vitro, but less so on normal myometrium.63
The role of PDGF, a potent mitogen for smooth muscle and fibroblast cells, has also
been investigated in uterine fibroids. The results of comparative quantification of
PDGF mRNA expression between fibroids and myometrium are conflicting61,64–66,
but it appears that PDGF stimulates fibroid growth through DNA synthesis and cell
proliferation67,68 in an oestrogen-dependent manner.69
EGF is expressed in uterine fibroids, but whilst some studies have demonstrated
cyclic changes in the expression of EGF mRNA in response to the menstrual cycle70,
others have not.71 The results regarding differences in expression between fibroids
and adjacent myometrium are inconsistent, varying from no difference50,71,72 to higher
expression in fibroids68,70, or higher expression in normal myometrium.73
Equally intriguing are results of investigation of the role of transforming growth fac-
tors (TGF-a and TGF-b) in uterine fibroids. TGF-a has not been immunolocalized in
any significant amount in uterine fibroids or normal myometrium50, despite being
abundant in leiomyosarcoma cells from mice74 and being implicated in the transforma-
tion of normal fibroblasts into the malignant phenotype.75 On the other hand, disor-
dered TGF-b has been shown to play an important role in the ECM formation
characteristic of uterine fibroids76, being higher in fibroids than in normal myome-
trium.77–79 The ECM of fibroids is not only excessive in amount but is also disordered
in orientation and structure. It appears that increased TGF-b signalling leads to in-
creased ECM formation in fibroids, probably through interference with the normal
steps in wound healing and fibrosis formation leading to dysfunctional remodelling ap-
optosis and excessive fibrosis.76,80 TGF-b therefore appears to play a complex role in
conjunction with ECM coding genes in the growth of uterine fibroids.
Vascular endothelial growth factor-A (VEGF-A) has received the most attention in
the investigation of the role of growth factors in uterine fibroids. VEGF is a heparin-
binding glycoprotein originally identified as a protein produced by tumour cells81, but
subsequently discovered to be mitogenic for vascular endothelial cells and to stimulate
angiogenesis.82 Although many factors are now known to regulate angiogenesis, VEGF
remains the most selective angiogenic factor and appears to regulate angiogenesis in
many normal tissues and tumours. It is therefore arguably the most potent angioge-
netic growth factor that has been identified in fibroids to date. VEGF-A expression
has been reported in the uteri of various species49,83, and has been found to be higher
in uterine fibroids compared with adjacent myometrium52,70,84,85, indicating that it
plays a role in the growth of fibroids.
The biological actions of VEGF-A include proliferation and migration of endothelial
cells, and vasodilatation by influencing endothelial release of vasoactive substances such
 Incidence, aetiology and epidemiology of uterine fibroids 577

as nitric oxide and prostacyclin. It causes rapid coagulation and fibrinolysis of blood clots
within spiral arterioles. VEGF stimulates endothelial cell synthesis of tissue plasminogen
activator, and increases vascular permeability, thereby resulting in activation of the extra-
vascular coagulation cascade with consumption of fibrin. This may, in part, explain its role
in the menstrual disorders of uterine fibroids, particularly as higher levels of tissue plasmin-
ogen activator are found in the endometrium of women with heavy periods.86
Both oestrogen and progestogen can induce VEGF expression in human cells. In an-
imal studies, oestrogen has been shown to increase the expression of VEGF mRNA in
the uterus through a primarily oestrogen-receptor mediated effect.85,87–89 Both oes-
trogen receptors a and b are involved in this regulation of VEGF mRNA. Progestogens
have also been shown to induce VEGF expression in human and animal stromal
cells83,90,91, as well as in immature rat uterus83,89, but the effects of progestogens
have not been studied as extensively as those of oestrogen. Finally, VEGF expression
may also be dependent on a number of signalling pathways such as those involving ac-
tivation of protein kinases. However, it is unclear whether there is interaction be-
tween steroid regulation and signalling pathways in the regulation of VEGF.
VEGF is of particular interest in the growth of tumours such as uterine fibroids be-
cause of its pre-eminence in angiogenesis. Tumour proliferation is severely limited by nu-
trient supply to, and waste removal from, the tumour.92 The progressive growth of solid
tumours such as uterine fibroids is therefore dependent on their ability to stimulate for-
mation of new blood vessels (angiogenesis) that will supply tumour cells with oxygen and
essential nutrients.93 Factors that influence angiogenesis include positive facilitators
such as nitrous oxide and VEGF, as well as negative regulators or inhibitors such as an-
giostatin and thrombospondin.94,95 VEGF-A is an endothelial-specific growth factor and
induces angiogenesis through sprouting of capillaries from pre-existing vessels in vivo. Its
strong expression in uterine fibroids compared with adjacent myometrium may there-
fore reflect a role in promoting blood supply that feeds tumour growth.

Role of apoptosis
Apoptosis, or programmed cell death, is a physiological and highly regulated form of
cell death that occurs in many normal and pathological tissues. Cells die in response
to a variety of stimuli, and during apoptosis, they do so in a controlled, regulated fash-
ion. This distinguishes apoptosis from necrosis; another form of cell death that is un-
controlled and associated with morbidity. Apoptosis occurs during the sloughing off of
the endometrium at the beginning of menstruation and during the formation of synap-
ses between neurons in the brain. It is also needed for destroying cells that have be-
come infected by viruses or sustained DNA damage as a result of oxidant activity or
other insult. Cells respond to DNA damage by increased production of p53, a tumour
suppressor gene and a potent inducer of apoptosis. Tumour necrosis factor-a (TNF-a)
is also a pro-apoptotic cytokine produced by activated macrophages and many cell
types in the female genital tract. Conversely, apoptosis may be inhibited by activation
of the apoptosis-blocking oncogen bcl-2 protein in response to genomic alterations.8
A balance in favour of anti-apoptotic activity will lead to prolonged cell survival, and
may conceivably contribute to growth of fibroids or other tumours.
There are conflicting reports on the role of apoptosis in the regulation of fibroids.
Although some reports have indicated a lack of difference in bcl-2 expression in uter-
ine fibroids cells compared with myometrium96, other evidence indicates greater ex-
pression in uterine fibroids97,98 and that sex steroids, specifically progesterone,
upregulate bcl-2 expression in fibroids.97 TNF-a expression is higher in fibroid cells
578 S. Okolo

compared with myometrium99, but little is known of its role in regulating fibroid
growth. However, because bcl-2 protein inhibits TNF-a-induced apoptosis in some
cells100, it is believed that bcl-2 protein also has a role in fibroid growth by controlling
TNF-a-induced apoptosis in fibroids. Expression of the p53 gene appears to be similar
in fibroids compared with normal myometrium, but with a higher expression in
GnRHa-treated leiomyoma101, indicating that p53 gene signalling may contribute to in-
creased fibroid cell death under hypo-oestrogenic conditions. In addition, oestrogen
treatment downregulates p53 protein content in fibroid cell cultures, whereas treat-
ment with progesterone alone or in combination with oestrogen has no effect. The
role of p53 gene expression in fibroid cell apoptosis under normal conditions is there-
fore unclear. However, dysregulation of cyclin G1, a protein which is a p53 gene tran-
scriptional target, may play an independent role in the proliferation and growth of
fibroids since it is highly expressed in uterine fibroids compared with normal myome-
trium, even in the absence of p53 gene mutations.102

EPIDEMIOLOGY

Epidemiological factors that have been linked to uterine fibroids are race, heredity, re-
productive factors, sex steroids and lifestyle/environmental factors. However, the
available information must be interpreted with caution. Most of the studies were
cross-sectional and cohort studies conducted in predominantly mono-ethnic popula-
tions. Population-based screening to determine risk factors is very difficult to achieve
due to the problem of defining a control group. To the purist, all other conditions need
to be identical in order to conclude that a specific factor predisposes an index group
to developing fibroids compared with the controls. Using multiple regression statistics
or Bayesian modelling statistics to accommodate for confounding factors has inherent
limitations. Finally, risk factors should ideally antedate the development of fibroids in
order to be regarded as true risk factors. It is therefore important to consider the
range of risk factors for uterine fibroids as an evolving science, rather than settled
knowledge, particularly since the aetiology and biology of fibroids remain unclear.

Race

Uterine fibroids are more common in Black women than Asians, with the incidence in
White women somewhere in between.3,103,104 Estimates of the racial variance in inci-
dence often depend on the study design, the health access behaviour of the population
and the method of diagnosis or verification of self-reported diagnosis. Several studies
have reported that, in comparison with White women, fibroids are between three and
five times more common in Black women, that Black women with fibroids are often
more symptomatic and have larger and multiple fibroids, and that Black women are
of a much younger age at diagnosis and at hysterectomy.3–5,72,103
It has been reported that fibroids from Black women have a higher prevalence of
oestrogen receptor a gene polymorphism than those from White women or His-
panics (35%, 13% and 16%, respectively), and that this genotype constitutes a genetic
risk factor for fibroids.105 However, genomic and proteomic profiling of fibroid spec-
imens has not confirmed ethnic differences in candidate genes or proteins.106 It is also
controversial whether there are any ethnic differences in steroid receptor expression
within fibroids.105,107,108 The reasons for the racial variation in fibroid occurrence are
therefore unknown.
 Incidence, aetiology and epidemiology of uterine fibroids 579

Heredity

Although no specific gene has been identified as the cause of non-syndromic fibroids,
there appears to be some epidemiological evidence for heritability of this condition.
Familial clustering of fibroids has been reported109, and cross-sectional studies in
mainly Caucasian populations have reported odds ratios of 2.2–4 for female relatives
of women with fibroids to develop the condition.110–112 Evidence from twin pair stud-
ies also indicates increased risk of fibroids in monozygotic compared with dizygotic
twins.113–116 In a study of over 300 multi-ethnic families with uterine fibroids, a consis-
tent pattern of clinical symptoms, operative findings and tissue molecular features was
found in families with a prevalence of uterine fibroids compared with families without
this prevalence.104 Families were regarded as having a familial prevalence when three
first-degree female relatives had confirmed uterine fibroids in contrast to control fam-
ilies with sporadic occurrence where only one of three first-degree female relatives
had fibroids. Women with fibroids in the familial group were significantly more likely
than those in the sporadic group to report menorrhagia (85% vs 52%), dysmenorrhoea
(64% vs 46%), dyspareunia (43% vs 28%) and a family history of cancer (52% vs 32%).
At operation, the mean number of fibroids was more than double in the familial group
(seven vs three), and strong VEGF-A expression was observed more frequently in the
fibroid specimens removed from the familial group (64% vs 28%).
There is therefore convincing evidence of the role of heredity as a risk factor for
uterine fibroids, and it appears that fibroids with familial prevalence behave differently
from those that occur sporadically in families, lending weight to the argument that fi-
broids are not a uniform pathological condition.

Reproductive factors

Uterine fibroids are more common in nulliparous women, with the relative risk de-
creasing with increasing number of term pregnancies. The risk of being diagnosed
with uterine fibroids is higher with an earlier age at menarche, older age at first
term pregnancy, and the longer the interval from a woman’s last term preg-
nancy.117–124 In predominantly White populations, it has been estimated that the
risk of fibroids is up to four times higher in nulliparous women than in grand mul-
tips.123 This dose–response reduction of risk with parity appears to occur mainly in
White but not Black women.5 Pregnancies that end before viability do not appear
to alter the risk of fibroids.122,125 It has been postulated that the correlation between
nulliparity and fibroids is most probably due to the continuous oestrogen secretion in
nulliparity uninterrupted by pregnancy and lactation, for a relatively high number of
menstrual cycles in a woman’s reproductive life. Since there is no difference in serum
oestrogen concentration per cycle126, it appears that the likely risk factor is the rela-
tively increased number of cycles in nulliparous women compared with parous
women. However, this explanation ignores the role of other endogenous hormones
in the biology of fibroids. For example, there is some preliminary evidence that high
leuteinizing hormone (LH), independent of ovarian function, may influence the risk
of developing fibroids.127–130 An association has also been shown between uterine fi-
broids and polycystic ovary syndrome (PCOS), particularly in lean women with PCOS,
with the suggestion that LH hypersecretion, insulin resistance and increased IGF-1
levels may account for this association.28,131
580 S. Okolo

In pregnancy, contrary to popular belief, there is evidence that fibroids initially in-
crease in size in the first trimester, and then shrink in size over the next two trimes-
ters132, with the overall result of a relative decrease in uterine fibroid volume during
the course of pregnancy133 or no change in size.134 Therefore, it seems that the inter-
actions of endogenous hormones during pregnancy act to inhibit fibroid growth, irre-
spective of the reversible pregnancy-associated cellular hypertrophy in the uterus. The
pregnancy-induced changes in fibroid growth have been attributed to several factors
including long-term changes in reproductive hormones and growth factors, reduced
oestrogen receptor activity, decreased fibroid responsiveness to oestrogens, and in-
creased tissue remodelling with enhanced apoptosis.44,135–140

Exogenous sex steroids

The effect of the oral contraceptive pill (OCP) on the risk of fibroids is controversial,
with some studies showing a positive association and other studies showing a reduced
risk of fibroids in women who used OCPs or no association at all.117,141 Whatever the
trend, these reports indicate that the risk is dependent on duration of OCP use142 and
dose of the sex steroids123, with a direct association in some studies and an inverse as-
sociation in others. In one study, the risk of developing fibroids decreased by 17% and
31% at 5 and 10 years of OCP use, respectively.142 Some of these studies may be criti-
cized for design limitations or selection bias. Several are case–control or retrospective
studies, and there was a perceived reluctance in earlier years to prescribe OCPs to
women considered to be at risk of developing fibroids. What is important, however,
is that the OCP is an effective treatment for the menstrual disorders associated with
fibroids, and should continue to be offered to women who merit it since the majority
of studies indicate no association or a reduced risk of developing fibroids with OCP use.
Women who have used progestogen injections such as depot medroxy progester-
one acetate for contraception have been reported to have a reduced risk of uterine
fibroids, with a relative risk of 0.44 compared with non-users. The longer the duration
of use, the lower the risk of uterine fibroids, with some residual protection being ap-
parent up to 10 years after cessation of use.119
The effect of the levonorgestrel bearing intra-uterine device (LNG-IUS) on the risk
of fibroids is unknown. The LNG-IUS has been shown to be effective in the treatment
of menorrhagia associated with fibroids, and a recent small comparative study143 found
that it reduces uterine volume in women with fibroids by an as yet undetermined
mechanism, thereby indicating that the LNG-IUS may inhibit the growth of pre-existing
fibroids. It is important to evaluate the longer-term effect on fibroid growth of this
highly effective therapy for dysfunctional uterine bleeding that has revolutionized mod-
ern gynaecological practice and reduced the need for hysterectomies.

Lifestyle and some medical conditions

Obesity has been linked to the development of uterine fibroids.144–146 Body weight of
70 kg or more is reportedly associated with almost three times the risk of developing
fibroids compared with body weight less than 50 kg. Women presenting with uterine
fibroids were more likely to be obese (50% vs 25%) or severely obese (16% vs 7.2%)
than the general population. Weight reduction consistently results in a reduced risk of
developing fibroids. Obesity confers a relative hyper-oestrogenic state, which may pre-
dispose to fibroid growth, probably through increased peripheral conversion of
 Incidence, aetiology and epidemiology of uterine fibroids 581

circulating androgens to oestrogen and decreased hepatic production of sex hormone

binding globulin which results in higher levels of free physiologically active oestrogen.
Diabetes mellitus and hypertension have also been reportedly associated with in-
creased risk of uterine fibroids.145,147 A common metabolic factor in obesity, diabetes mel-
litus and hypertension is insulin resistance, and it is possible that insulin resistance,
increased IGF-1 activity and elevated androgen levels mediate the increased risk of uterine
fibroids observed in all three conditions. Smoking, on the other hand, reduces the risk of
developing uterine fibroids in a dose-dependent manner.118,121,123,148–150 However, it is
unclear whether this is due to the anti-oestrogenic effect of smoking or the effects of
the relatively high level of tissue free radicals associated with smoking. In one study,
women who smoked 10 cigarettes per day had an 18% lower risk of developing fibroids
compared with non-smokers, but there was no residual protection on giving up smok-
ing.151 It appears that the protective effect of smoking does not extend to Black women.5
Finally, there is very limited information on the influence of diet on the risk of de-
veloping uterine fibroids, and the few studies available are inconsistent on whether
a diet rich in red meat increases the risk of fibroids as opposed to a diet rich in white
meat, vegetables or lycopene (found in tomatoes).152,153

CONCLUSION

Uterine fibroids are very common in women, but knowledge of aetiology, epidemiol-
ogy and tumour biology is very limited. There is increasing evidence that multiple ge-
nomic alterations may play a role in the initiation of fibroid growth, and that molecular
and cellular mechanisms, rather than hormonal factors alone, play a major role in their
subsequent growth. Genetic codes that have been discovered in uterine fibroid syn-
dromes have not been found in non-syndromic fibroids. Epidemiological studies
have demonstrated differences in patterns of symptoms attributable to fibroids with
a familial prevalence compared with those that occur sporadically in families. It would
therefore seem that this enigmatic disorder with heterogenous symptomatology and
behaviour may not be a single disease entity. This should be reflected in future re-
search strategies and treatment modalities.

Practice points

 the lifetime risk for a woman over the age of 45 years of having fibroids is more
than 60%
 it is highly likely that the prevalence of fibroids is underestimated; the incidence
of histological analysis is more than double the clinical incidence, and the inci-
dence increases with increasing age
 while there is a clear-cut difference in the prevalence rates of fibroids between
Black and White women, this is not reflected in hormonal levels or oestrogen
receptor expression. In other words, the basis of the racial disparity is not
known
 all the cells within a given fibroid originate from a single cell (the monoclonal
origin of fibroids concept). However, candidate genes for common uterine fi-
broids have not yet been identified
582 S. Okolo

 fibroids are associated with PCOS, hypertension and obesity, while smoking in
White women (but not Black women) appears to be protective against the de-
velopment of fibroids. No diets have been proven to increase or decrease the
risk of developing fibroids
 familial predisposition to fibroids is illustrated by a number of observations: fe-
male relatives of women with fibroids have a significantly increased risk of de-
veloping fibroids; twin pair studies indicate increased risk of fibroids in
monozygotic compared with dizygotic twins; and there is a consistent pattern
of clinical symptoms, operative findings and tissue molecular features in families
with a prevalence of uterine fibroids compared with families without this
prevalence
 uterine fibroids are more common in nulliparous women, with the relative risk
decreasing with increasing number of term pregnancies. Contrary to popular
belief, in pregnancy, fibroids initially increase in size in the first trimester, and
then shrink in size over the next two trimesters. There is therefore an overall
relative decrease in uterine fibroid volume during the course of pregnancy
 the effect of the OCP on the risk of fibroids remains controversial, with some
studies showing an increased risk, others showing a decreased risk and others
showing no association at all

Research agenda

 as the human genome has been mapped successfully, genetic studies can better
focus on the genetics of fibroid disease development
 potential differences in response to treatment between fibroids occurring in
families (familial prevalence) and those occurring sporadically
 teasing out the molecular and hormonal interactions that culminate in fibroid
disease

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