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Vollenhoven B. Introduction:
the epidemiology of uterine
leiomyomas

ARTICLE in BAILLIRE S CLINICAL OBSTETRICS AND GYNAECOLOGY JULY


1998
DOI: 10.1016/S0950-3552(98)80059-X Source: PubMed

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Beverley Vollenhoven
Monash University (Australia)
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1

Introduction: the epidemiology of


uterine leiomyomas

BEVERLEY VOLLENHOVEN PhD, FRACOG, CREI


Senior Lecturer
Department of Obstetrics & Gynaecolog); Monash University, Level 5, Monash Medical Centre,
246 Clayton Road, Clayton, Victoria 3168, Australia

Uterine fibroids, or leiomyomas, are the most common tumours in women during the
reproductive years. In most countries, they are the most frequent indication for hyster-
ectomy in pre-menopausal women and therefore present a major public health issue. In this
chapter, the epidemiology of these common tumours will be discussed. Also discussed will
be the socio-economic impact on the community in terms of the overall cost of these
turnouts, as well as the social impact of uterine leiomyomas on the individual woman in
terms of symptoms and the effect and consequences of these on her life.

Key words: uterus; fibroid; leiomyoma; epidemiology; social impact.

Surgical pathology specimens


For m a n y years, uterine l e i o m y o m a s or fibroids have been quoted as being
the most c o m m o n tumours of w o m e n in the reproductive age group or,
alternatively, in w o m e n over the age of 30 years. The various figures that
have been reported for the presence of fibroids range f r o m 20% (Graves,
1933) to 77% (Cramer and Patel, 1990). Graves (1933) was the first to
report the frequency of uterine leiomyomas. He wrote that 20% of w o m e n
over the age of 35 years have fibroids, these figures being based on the
presence o f these tumours at autopsy. Wallach (1992) reported that 50% of
w o m e n at post m o r t e m examination have uterine leiomyomas.
Cramer and Patel (1990) investigated the frequency of these turnouts b y
performing gross serial sectioning at 2 m m intervals in 100 consecutive
total hysterectomy specimens after routine pathology testing had been
performed. The w o m e n undergoing hysterectomy were both pre- and post-
menopausal, and 33 had the pre-operative diagnosis of fibroids. This is the
only study to examine the incidence of these tumours in such a systematic
fashion. Examination of the hysterectomy specimens at 2 m m intervals
tripled the number of fibroids that were noted in the routine pathology
reports. These authors reported that the incidence of uterine fibroids was
Baillikre's Clinical Obstetrics and Gynaecology-- 169
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ISBN 0-7020-2452-X All rights of reproduction in any form reserved
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t70 B. V O L L E N H O V E N

77%. There was no difference in the incidence of fibroids whatever the pre-
operative diagnosis, and there was also no difference in the incidence
between pre- and post-menopausal specimens. This report provides us with
information on the true incidence of these tumours and tells us that if the
incidence of uterine leiomyomas is based on a clinical diagnosis or routine
pathology testing alone, the true incidence of fibroids will be vastly under-
estimated.

Family history
Vikhlyaeva et al (1995) have reported a familial predisposition to uterine
leiomyomas. They showed that fibroids were 2.2 times more frequent
(P < 0.001) in first-degree relatives within families where there were two or
more family members with fibroids. Lumbiganon et al (1995) also reported
a relative risk of 3.47 for the development of fibroids when there was a
family history of these tumours.

Race
Uterine leiomyomas are said to be more common in the black population
compared with the white population; why this is so has never been studied.
Witherspoon and Butler (1934) reported that the incidence in black women
was nine times that in white women and suggested that the higher incidence
in these women was associated with an increased number of pelvic
infections, which could cause myometrial irritation and abnormal muscle
growth. However, this has not been further investigated. Kjerulff et al
(1996) studied 409 black women undergoing hysterectomy for non-
cancerous conditions and compared the findings with those of 836 white
women also undergoing hysterectomy for similar indications. They
reported that 89% of the black women had fibroids compared with 59% of
the white women. They also discovered that the black women having
hysterectomies had significantly larger and a greater number of fibroids and
that the fibroids caused significantly greater pelvic pain and significantly
worse anaemia compared with the white women. Fibroids were also
diagnosed and operated on at a younger age in significantly more black
compared with white women. It has been estimated that black women have
a 2-3 times greater risk of undergoing a hysterectomy for fibroids than
white women (Cramer, 1992).

Radiation
Fibroids are more common in atomic bomb survivors (Kodama et al, 1996).
Kodama et al (1996) reported a dose-response relationship between the
incidence of fibroids and atomic bomb radiation exposure. This was
confirmed by Kawamura et al (1997). They examined 1190 Hiroshima
atomic bomb survivors using ultrasound and reported a significant dose-
response relationship for the prevalence of uterine leiomyomas. This is now
being further studied.
INTRODUCTION: EPIDEMIOLOGY 171

~SK FACTORS FOR THE GROWTH OF FIBROIDS

Nulliparity
There is a definite association between nulliparity and the incidence of
fibroids. The relative risk of fibroids has been shown to decrease with an
increasing number of term pregnancies. The risk is one-quarter in women
with five term pregnancies (live births and stillbirths) compared with
women with no term pregnancies (Ross et al, 1986). There was no
reduction in risk reported with incomplete pregnancies but in fact a small,
although not significant, increase in risk (Ross et al, 1986). Lumbiganon et
al (1995) also reported that fibroids were significantly less common in
parous women and more common in women who had undergone termi-
nation of pregnancy. Samadi et al (1996) and Parazzini et al (1996a) have
reported similar results with respect to parity and fibroid development. The
latter group showed that parous women had a relative risk of 0.5 of fibroid
development compared with nulliparous women and that the risk declined
with the number of births. However, as opposed to Ross et al (1986), who
reported that only term births were important in this risk reduction,
Parazzini et al (1996a) showed that the risk of fibroids was also reduced
with the number of induced abortions but not with the number of spon-
taneous abortions. They also showed that a history of infertility increased
the relative risk of fibroid development twofold in comparison with women
who did not report such a history.
The risk of fibroids does not appear to be related to the age at the first
term pregnancy. However, the later the age at the last term pregnancy, the
lower the risk of tumour development (Ross et al, 1986). Kjerulff et al
(1996) reported a significant positive correlation between increasing
uterine weight and time since birth of the last child in black women.
The underlying risk factor between parity and fibroid development is
most probably the continuous oestradiol (E2) secretion, uninterrupted by
pregnancy and lactation, or the increased number of menstrual cycles in a
reproductive life. It is an increased number of cycles rather than an increase
in serum E2 concentration per cycle that is the risk factor, as it has been
shown that women with fibroids have circulating E2 concentrations similar
to those of women who do not have fibroids (Spellacy et al, 1972).

Obesity
Weight is strongly related to the risk of developing uterine fibroids. Women
weighing 70kg or more have an almost threefold risk of developing
fibroids compared with women weighing less than 50 kg. Obesity increases
the risk of fibroid development by 21% with each 10 kg weight gain (Ross
et al, 1986). Shikora et al (1991) reported that 50% of women presenting to
a tertiary referral hospital in the USA with symptomatic fibroids were obese
(>120% desirable body weight) and 16% were severely obese (>150%
desirable body weight). This figure is in contrast to the 25% clinical obesity
and 7.2% severe obesity rate in the general female population in the USA.
172 B. VOLLENHOVEN

There may be two reasons for this weight-related risk. First, there is
increased peripheral conversion by fat aromatase of circulating androgens
to oestrogen (E) in obese women. Second, in such women, there is a
decrease in the hepatic production of sex hormone-binding globulin
(SHBG), a carrier for E. This lowered concentration of SHBG may result
in higher levels of 'free', physiologically active E (Shikora et al, 199t).
Therefore, obesity confers a relative hyperoestrogenic state, which may
predispose to fibroid growth.
Kjerulff et al (1996), in their hysterectomy study, reported that, for black
women only, increasing uterine weight was significantly correlated with
increasing body mass index.

Other factors
Samadi et al (1996) have reported that frequent PAP smears, combined oral
contraceptive pill (OCP) use and higher education, which are all markers of
access to health care, are associated with fibroid presence and detection.
Lumbiganon et al (1995) have also reported that higher education (relative
risk 3.46 if over 12 years of education; P < 0 . 0 0 1 ) and tubal ligation
(relative risk 1.6) impact positively on fibroid presence. This is the first
study to describe a positive association between tubal ligation and the risk
of fibroid development. However, the risk is only slightly increased
(although statistically significant) and may not be of clinical importance
given the advantages of tubal ligation (Lumbiganon et al, 1995).

F A C T O R S P R O T E C T I N G AGAINST T H E G R O W T H OF
FIBROIDS

Cigarette smoking
Smoking cigarettes is associated with a decreased risk of fibroid develop-
ment in a dose-dependent manner. Women who smoke 10 cigarettes per day
have an 18% lowered risk of fibroid development compared with non-
smokers (Ross et al, 1986). Similar findings have also been reported by
Lumbiganon et al (1995) and Parazzini et al (1996b). The latter group
showed, in a case-control study, that women with fibroids were less
frequently current smokers (22%) than were controls (32%). They reported
that the relative risk for fibroid development in smokers was 0.5 compared
with never-smokers. Surprisingly, they did not report a clear association
between duration of smoking and the risk of fibroid development, and ex-
smokers were not at a lower risk of tumour development (Parazzini et al,
1996b). There is a need for further studies in order to understand
completely the relationship between smoking and the risk of fibroid
development.
Smoking is regarded as anti-oestrogenic, and smokers have lower
concentrations of endogenous E (MacMahon et al, 1982). Smokers also
INTRODUCTION: EPIDEMIOLOGY 173

undergo menopause on average 3 years earlier than non-smokers (Daniell,


1978; Parazzini et al, 1992a). In effect, female smokers behave as though
they were E deficient (Baron et al, 1990). Women who smoke are also at
lower risk for the development of other 'E-dependent diseases' such as
endometriosis (Cramer et al, 1986) and endometrial carcinoma (Baron,
t984).

Combined oral contraceptive pill


Increasing duration of use of the OCP decreases the risk of developing
fibroids. The risk is decreased by 31% in women who have used the OCP
for 10 years. The risk may also be expressed as decreasing by approxi-
mately 17% with each 5 years of OCP usage. The mechanism of protection
of the OCP against fibroid development may be related to the progestogenic
component as the higher the dose of the progestogen, the more protection
is afforded (Ross et al, 1986). However, this was only shown to be so for
formulations that did not contain ethynodiol diacetate as the progestogen.
This progestogen is known to be more 'oestrogenic' than others.
Lumbiganon et al (1995) have reported similar findings. In complete
contrast to the findings of Ross et al (1986) and Lumbiganon et al (1995),
Parazzini et al (1992b) reported no :interaction between the risk of fibroid
development and OCP usage.
In the short term (1 year), women with fibroids may benefit from the use
of the OCP because it causes a decrease in the duration of menstrual flow
with a resultant improvement in haematocrit levels (Friedman and Thomas,
1995).

Depot-medroxyprogesterone acetate
Depot-medroxyprogesterone acetate (DMPA) has been associated with
protection against fibroid growth. Women who had used DMPA have been
reported to have a relative risk of fibroid development of 0.44 compared
with never-users of DMPA. There also appears to be a duration-response
relationship between DMPA and fibroid growth, with a continuing
protection against fibroid development that may last for more than 10 years
after the last dose of DMPA, regardless of the initial duration of use
(Lumbiganon et al, 1995).

SOCIAL IMPACT OF UTERINE FIBROIDS

Fibroids have traditionally been treated surgically, and they are the major
reason for hysterectomy. In Australia, 21.7% of hysterectomies are reported
to be performed because of fibroids, the prevalence of hysterectomy in
Australia being 3.97 per 1000 women. Hysterectomy is one of the most
common surgical procedures performed in this country (Renwick and
Sadhowsky, 1991). In the USA, over 650 000 women undergo a hyster-
ectomy every year, and 27% of these procedures are for the diagnosis of
174 t3. VOLLENHOVEN

fibroids (Pokras and Hufnagel, 1988; Bachmann, 1990). In Finland, the


annual incidence of hysterectomy is 3.9 per 1000 women, and 50% of these
hysterectomies are performed because of fibroids (Luoto et al, 1994). The
number of women requiring hysterectomy for fibroids varies between age
groups such that women in the 45-54-year-old age group have the highest
incidence of hysterectomy for uterine leiomyomas. The majority of these
procedures are carried out via the abdominal route (Greenberg and
Kazamel, 1995). It has been estimated that 10-15% of women between the
ages of 25 and 64 years will require a hysterectomy for fibroids (Cramer,
1992).
Hysterectomy carries considerable morbidity but low mortality. In
Australia, the crude mortality rate at hospital discharge is 8 per 10 000 non-
neoplastic hysterectomy procedures (Opit and Gadiel, 1982). In the USA,
the mortality is estimated to be 5 per 10 000 cases, and the risk of dying
within 30 days of a hysterectomy is estimated to be six times greater than
for the rest of the population (Greenberg and Kazamel, 1995). The
combined major and minor morbidity associated with hysterectomy has
been variously reported to be between 18% and 47% (Opit and Gadiel,
1982; Dicker et al, 1982; Brunello, 1990). The short-term complications of
hysterectomy include post-operative haemorrhage (2%), incidental injury
to adjacent organs (0.5%), fever (15-38%), infection and urinary retention.
The long-term effects include urinary or bowel dysfunction, longstanding
abdominal pain and sexual (15-30%) and psychological problems (6-8%)
(Dicker et al, 1982; Opit and Gadiel, 1982; Schofield et al, 1991; Greenberg
and Kazamel, 1995). The increasing use of minimally invasive surgery,
with or without the use of pre-operative medical treatment, with more effort
at uterine conservation may prevent some of the common complications
associated with hysterectomy for fibroids.
As well as the attendant morbidity and loss of income for the woman
associated with hysterectomy--the average hospital stay being 6-7 days
with a 6-week recovery period--fibroids also constitute a major public
health cost. In Australia, this community outlay has been estimated to be
$100 million per year in direct hospital charges, outpatient attendances,
general practitioner consultations and other support services (Opit and
Gadiel, 1982). In the USA, this annual cost is estimated to be $3 billion
(Pokras and Hufnagel, 1988; Bachmann, 1990).
Thirty per cent of women with fibroids have been reported to have
menstrual abnormalities, most often menorrhagia (Buttram and Reiter,
1981). Menorrhagia in a woman with fibroids can be torrential, causing a
rapid fall in haemoglobin (Hb). When this occurs on a monthly basis, not
only are the medical consequences severe, but also the social effects may
be of great concern. Women who suffer from menorrhagia are often
concerned about failure of their sanitary napkins. These women will often
be housebound on their heaviest days of menstruation, preferring loss of
income to social embarrassment. This causes considerable disruption to
their lifestyles.
The major medical consequence of menorrhagia is anaemia
(Hb< 100g/l). Menorrhagia is the most common cause of anaemia in
INTRODUCTION: EPIDEMIOLOG Y 175

developed countries. Fraser et al (1986) reported that anaemia is more


common in women with fibroid-associated menorrhagia than in menor-
rhagia due to other causes.

CONCLUSION

Fibroids are a major medical problem for a woman and also constitute an
important public health cost to the community. Despite the fact that these
tumours are so common, their epidemiology has not been investigated in a
systematic fashion. It is hoped that, in the near future, more studies will
address this important issue, particularly in relation to the risk and
protective factors for fibroid growth.

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