Review

International Journal of Obesity (1998) 22, 10351040

1998 Stockton Press All rights reserved 03070565/98 $12.00
http://www.stockton-press.co.uk/ijo

Teenage obesity in relation to breast cancer risk

BA Stoll*1
1

Oncology Department, St Thomas' Hospital, London, SE1 7EH, UK

While most studies show a higher body mass in Western women to be positively associated with an increased breast
cancer risk in postmenopausal women, they show a negative association in the case of premenopausal women. A
review of case-control and cohort studies suggest that such protection applies mainly to obesity in teenage girls,
whereas obesity appearing after the teenage years is more likely to be associated with a higher risk of postmenopausal breast cancer. The mechanisms are uncertain. There is evidence that obesity and the components of the
Western diet can independently provoke hyperinsulinaemic insulin resistance at puberty, and in adolescent girls this
has been related to evidence of abnormal ovarian steroidogenesis and anovulation. This may decrease promotion of
mammary carcinogenesis. If however, obesity continues after the teenage years, the higher concentration of insulinlike growth factor 1 (IGF1) associated with hyperinsulinaemia can interact with oestrogen receptors in mammary
epithelium to lead to increased proliferative activity.
This review postulates that the observed protective effect of early obesity against premenopausal breast cancer is
likely to be replaced by an increased risk of postmenopausal breast cancer if obesity continues after the teenage years.
The manifestation of breast cancer is merely postponed to an older age. Recent prospective and case-control studies
suggest that increased bioavailability of IGF1 is a marker of increased breast cancer risk in premenopausal women.
Nutritional intake in early life may programme later activity in the growth hormone IGF1 axis and inuence the
progression of transformed cells in mammary tissue. The question remains whether deliberate weight loss can
reverse the effects of weight gain.
Keywords: adolescence; breast cancer; insulin-like growth factor; insulin resistance; obesity; Western diet

Introduction
Studies on identical twins show that a tendency to
obesity may be determined genetically. Its mechanism
may involve genetic control of appetite drive or of
energy expenditure.1 However, most of the overweight which characterizes Western populations is
determined by social and cultural factors and is
subject to control. Considerable evidence shows that
in women living in industrialised Western countries,
the risk of pre- and postmenopausal breast cancer
differs in its association with body mass.2 The presence of a higher body mass is associated with an
increased risk of postmenopausal breast cancer, but a
modestly reduced risk of premenopausal breast
cancer. However, in Asian countries with a relatively
low incidence of breast cancer, a higher body mass is
associated with an increased risk of both pre- and
postmenopausal breast cancer.3
Studies on the timing of weight gain are more likely
to clarify the effect of obesity on breast cancer
promotion than do measurements of body mass.4,5 A
review of case-control and cohort studies shows that
*
Correspondence: Dr Basil A. Stoll, Oncology Department,
St Thomas' Hospital, London, SE1 7EH, UK.
Received 15 June 1998; revised 31 July 1998; accepted
4 August 1998

obesity manifesting in the teenage years (< 19 y) is

associated with a reduced risk of breast cancer before
the menopause, but less certainly after the menopause.6 11 However, if obesity appears after the teenage years, the risk of postmenopausal breast cancer is
increased.12 16 The strongest evidence of this is
provided by the USA Nurses Health Study involving
more than 95 000 women aged 30 55 y, followed for
16 y.17 Overweight before the age of 18 y was associated with a reduced breast cancer risk before, and
less so after, the menopause; overweight after 18 y
was related to a higher risk of postmenopausal,
although not of premenopausal, breast cancer.
A protective effect of adolescent obesity against
premenopausal breast cancer risk has been attributed
to an effect on ovarian hormone concentrations. Obesity in premenopausal women is frequently associated
with a reduced serum level of oestradiol18 and progesterone,19 and anovulation has been suggested to
explain the reduced risk of breast cancer. However,
we need to examine the tendency for overweight in
adolescent girls to persist in later life.
The widely quoted `breast-tissue age' model for
human mammary carcinogenesis20 postulates that
international differences in breast cancer rates
mainly reect different timing of major hormonalmetabolic events, such as puberty, pregnancy and
menopause. In this context, the presence of obesity
at puberty is critical, because it is often related to the

Teenage obesity and breast cancer risk

BA Stoll et al

1036

manifestation of insulin resistance.21,22 This review

examines evidence that rich nutrition in childhood
together with inadequate physical exercise are linked
to (a) earlier onset of menarche, (b) earlier triggering
of insulin resistance, (c) adolescent obesity and (d)
increased tendency to obesity throughout adult life.
The resulting increase in the risk of postmenopausal
breast cancer will probably more than compensate for
any protection from premenopausal breast cancer
which may be conferred by teenage obesity.

Teenage obesity and mammary

carcinogenesis
Both menarche before the age of 12 y and also a
delayed rst full-term pregnancy are markers of
increased breast cancer risk. Taken together, the
observations suggest that a longer interval between
the two events is important in the promotion of
mammary carcinogenesis.23 In addition, biological
evidence suggests that the rapidly proliferating terminal end buds in developing mammary tissue are
highly vulnerable to mutation in the experimental
mammary cancer model.24
Epidemiological observations conrm this window
of increased susceptibility. First, the risk of subsequent breast cancer among atomic bomb survivors
was reported to be highest in women who were
younger than 20 y at the time of exposure.25 Second,
the risk of subsequent breast cancer after repeated
chest x-ray examinations for tuberculosis was reported
to be highest among girls who were monitored
between the ages of 10 14 y.26 Finally, it is reported
that breast cancer risk among Japanese immigrants to
the USA does not rise in the rst generation of women
if they migrate after adolescence,27 although in subsequent generations the risk gradually rises to approximate that of Caucasian-American women.
The epidemiological evidence reviewed in the
Introduction suggests that teenage obesity may protect
Western women against the appearance of breast
cancer before the menopause. The protective effect
has been attributed to the inuence of obesity by
increasing anovulatory cycles, but the mechanism is
uncertain. The concomitants of insulin resistance may
be involved.28 Obese adolescent girls show evidence
of hyperinsulinaemia22 and also a higher androgen=
oestrogen ratio in the circulation.29 Higher concentrations of insulin can impair oocyte maturation in the
ovary30 and the resulting hormonal dysfunction has
been postulated to reduce breast cancer risk.28
Higher basal insulin concentrations are associated
with obesity not only in adolescent girls,22 but also in
preadolescent girls,31 the insulin concentration being
correlated with magnetic resonance imaging (MRI) of
visceral fat deposits. An increase in abdominal fat is
common in girls at the time of puberty and is thought

to be related to increasing levels of androgen and

insulin.21 Differences in the distribution of adipocyte
receptors may then lead to a more truncal or visceral
distribution of fat.32 It is also reported that circulating
concentrations of insulin-like growth factor 1 (IGF1)
are signicantly higher in obese adolescent and preadolescent girls.33,34
The prevalence of insulin resistance varies between
populations and there is strong evidence that in individuals with a genetic susceptibility its manifestation
is favoured by the presence of obesity.35 It is believed
to result from an effect on skeletal muscle by a large
release of non-esteried fatty acids from adipose
tissue.1 In Western industrialised countries, it is estimated to affect as many as 25% of the normal population and is associated with hyperinsulinaemia.35

Nutrition, obesity and insulin

resistance
What is the evidence that rich nutrition in childhood is
linked to earlier onset of menarche, earlier triggering
of insulin resistance, adolescent obesity and increased
tendency to obesity throughout adult life? Early onset
of menarche, associated with rich nutrition, is likely to
be triggered by a threshold weight-for-height index36
and a critical level of body fat.37 Although a prospective study in Europe has reported a higher energyadjusted fat intake between the ages of 8 15 y, to be
associated with earlier menarche,38 most evidence
suggests that the effect of diet is to promote accumulation of adipose tissue, rather than through the intake
of specic macronutrients.39,40
It is widely conrmed that the risk of both pre- and
postmenopausal breast cancer is increased in association with earlier onset of menarche (before the age of
12 y). Extreme leanness together with strenuous physical exercise are associated with delayed onset of
menarche in ballet dancers and gymnasts, and a
decreased breast cancer rate has been shown in
athletes.41 Nevertheless, no association has been
shown between body mass in childhood (9 14 y)
and subsequent breast cancer risk.7,8,10,42
Although menarche is likely to be triggered by a
threshold level of adiposity, the mechanism is uncertain. It has recently been suggested that a critical
blood leptin concentration may trigger menarche
through a hypothalamic mechanism.43 Serum leptin
concentrations, body-fat percentage and timing of
menarche were recorded in 343 pubertal females in
a four year study extending over the menarche. Serum
leptin concentrations were strongly related to total
body fat, and a rising leptin concentration was associated with a lowered age at menarche. However, a
causative relationship is unclear.
Both insulin and IGF1 are likely to have a role in
synchronising early sexual maturation with early
linear growth.44 Switching on of gonadotrophin-

Teenage obesity and breast cancer risk

BA Stoll et al

releasing hormone is associated with increased growth

hormone secretion and also with evidence of hyperinsulinaemic insulin resistance.45 Thus, earlier onset
of puberty involves not only an earlier menarche, but
also an earlier growth spurt. While catch-up may
occur in adolescence, a subset of girls may proceed
to greater adult height and there is considerable
evidence from case-control and prospective studies,
that taller women have an increased breast cancer
risk.46 Not only tallness, but also earlier completion of
bone growth, is associated with a higher breast cancer
risk. Comparison of 747 premenopausal breast cancer
cases with controls showed a 30% reduction in breast
cancer risk for women who reached their maximum
height at 18 y compared to those who reached it at
13 y.47
Girls who are fat in childhood usually attain
menarche at a younger age37,48,49 and girls who had
an earlier menarche tend to greater obesity as young
adults.50,51 A Dutch study has reported that in girls
with an early onset of menarche, a higher body mass
persisted until the age of 27 y.52 The association has
been reported to persist even into postmenopausal age
both in Caucasian-Americans50 and in African-American women.53
Teenage obesity in Western girls is associated with
an increased prevalence of menstrual irregularity, both
long and short cycles, and a tendency to anovulation.54 Teenage obesity is also associated with an
increased likelihood of irregular menstrual cycles
continuing into adult life.55,56 It is reported that in
Western women regular ovulatory cycle are established relatively late and that about 50% of cycles in
teenagers are anovulatory, the proportion only falling
to 15 20% after the age of 20 y.54
Obesity in teenagers often continues into adult
life57 and about one third of obese adult women
report obesity in adolescence.21 In contrast, most
Asian populations have a lower prevalence of obesity
at all ages and do not show a reduced risk of
premenopausal breast cancer to be associated with a
higher body mass.3 Obesity appearing after the teenage years is associated with increased risk of postmenopausal breast cancer in all populations and the
overall incidence is about ve times greater in Western, than in Asian, populations.
Adolescent adiposity in girls is of two types58 and
even at the time of early puberty in girls, fat distribution can be distinguished as either predominantly
gluteal (gynoid) or predominantly abdominal
(android). Girls with the highest measures of abdominal fat show the greatest degree of obesity. While
there is no evidence that body mass or body-fat
distribution can trigger puberty in healthy girls,
early sexual maturation is reported to be associated
with increased deposits of abdominal fat.58,59 Western
children, at the time of puberty, frequently show
evidence of insulin resistance, which is compensated
for by hyperinsulinaemia, and this is increased in the
presence of obesity, particularly abdominal obesity.60

Although they occur at the same time, early

menarche and pubertal hyperinsulinaemia may exert
opposing effects on ovarian steroid concentrations in
teenagers. Onset of menarche before the age of 12 y is
reported to be associated with earlier establishment of
regular ovulatory cycles and an increased serum oestradiol level, which may still persist in women aged
20 30 y,61,62 although another study has failed to
conrm the latter observation.19 As noted in the previous section, pubertal hyperinsulinaemia is associated
with a higher androgen=oestrogen ratio in the circulation and an increased tendency to anovulatory cycles.
There is no evidence that higher energy intake
during adolescence may inuence subsequent breast
cancer risk. A recent large case-control study of dietary fat intake in adolescence by women with premenopausal breast cancer showed no association,63 and
previous studies showed a similar result.7,8,64
Although it is widely believed that the percentage of
energy from body fat is an important determinant of
obesity, there is no conclusive evidence that it is any
more important than other macronutrients.65,66
Both obesity and insulin resistance are likely to be
genetically determined, but there is so far no evidence
of a genetic link between them.67 The manifestation of
insulin resistance in individuals who are genetically
susceptible is inuenced by obesity, but also independently by the fatty acid prole of the Western diet.68
Considerable research in rats and in humans has
shown that the incorporation of more unsaturated
fatty acids into the phospholipids of muscle cell
membranes is associated with improved insulin
actin, while a higher proportion of saturated fats is
linked to insulin resistance. There is also evidence that
a high ratio of n-6 to n-3 polyunsaturated fatty acids
may favour insulin resistance.68 Studies on obese
children, around the age of puberty, have shown that
insulin concentrations correlated positively with
plasma lipid concentrations of n-6 polyunsaturated
fatty acids,69 but negatively with plasma lipid levels
of n-3 polyunsaturated fatty acids.70
It has been suggested that in some cases, the early
manifestation of insulin resistance may be favoured
by poor nutrition in fetal life (reected by a low
birthweight) interacting with abundant nutrition in
later life. A series of studies has related low birthweight to evidence of impaired glucose tolerance and
hyperinsulinaemia in children,71 young adults72 and
older adults.73 This may account for a report of
reduced breast cancer risk in a group of mainly
premenopausal women with a history of a birthweight < 4000 g.74

Adult obesity increases mammary

carcinogenesis
The mechanism by which weight gain after the teenage years increases breast cancer risk in Western

1037

Teenage obesity and breast cancer risk

BA Stoll et al

1038

women is unclear, but considerable evidence conrms

that insulin resistance and hyperinsulinaemia increase
with advancing age. Case-control studies have shown
hyperinsulinaemia to be a marker of increased breast
cancer risk both in pre- and postmenopausal women,
independently of obesity.75 79 Hyperinsulinaemia is
associated with increased levels of IGF1 and experimental evidence suggests that the type 1 IGF receptor
plays an important role in breast cancer development.80 The IGF1 receptor is expressed in human
breast cancer specimens and in cell lines derived
from them. Its concentration is higher in cancer cells
than in normal breast tissue or benign tumours, and
the IGF1 receptor interacts with the oestrogen receptor in stimulating proliferative activity both in cancer
cells81 and in explants of normal mammary epithelium.82
IGF bioactivity in mammary tissue is inuenced by
autocrine and paracrine secretion of IGF1 and IGF11,
by circulating IGF1 levels and by the levels of IGFbinding proteins (IGFBPs) and IGFBP proteases.83
IGF1 circulates as a complex, bound to IGFBPs, of
which six appear to have a major role in maintaining
the pool of bound IGF1 which responds to metabolic
demands.30 Proteolysis of IGFBP3 is regulated by
insulin concentrations and is increased in the presence
of insulin resistance suggesting a probable long-term
regulating effect. On the other hand, IGFBP1 appears
to regulate IGF availability, in response to acute
changes in insulin concentrations.30
Case-control studies have reported that mainly in
premenopausal women the relationship between the
circulating concentration of IGF1 and the bioactive
concentration of IGFBP3 may be a marker of breast
cancer risk.79,84 88 One study has failed to conrm
this nding.89 Recent research shows that IGFBP3
acts not only by preventing IGF1 from binding to its
receptor, but also has independent effects including
the ability to induce programmed cell death (apoptosis) in human breast cancer cell lines.90 A similar
effect has been shown on human prostate cancer cell
lines.91
In the case of postmenopausal women, higher
circulating oestrogen concentrations may also have a
major role in the increased breast cancer risk associated with obesity. Several studies, including a large
prospective study,92 have shown a positive association
between endogenous oestrogen concentrations and
breast cancer risk. Obesity increases bioavailable
oestrogen concentrations, partly as a result of
increased conversion of adrenal androstenedione to
oestrogen in fat, and partly as a result of decreased
levels of sex hormone-binding globulin.93

Conclusion
Case control and cohort studies suggest that in industrialised Western populations, obesity in teenagers is

associated with a modestly reduced risk of premenopausal breast cancer, while obesity appearing after the
teenage years, is more likely to be associated with a
higher risk of postmenopausal breast cancer. This
review postulates that in Western girls, obesity and
the fatty acid prole of the diet may independently
provoke the onset of hyperinsulinaemic insulin resistance at puberty. Higher levels of insulin may impair
ovarian steroidogenesis in teenage girls and thus
decrease promotion of mammary carcinogenesis.
After the teenage years, the higher levels of IGF1
associated with hyperinsulinaemia in obese women
may interact with oestrogen receptors in mammary
epithelium, leading to increased proliferative activity.
The overall incidence of breast cancer in Western
industrialised populations is ve times greater than in
Asian populations, which do not show a protective
effect for teenage obesity. It is postulated that possible
protection derived from teenage obesity in Western
girls is temporary and small, compared to the risk of
increased promotion of carcinogenesis when obesity
continue after the teenage years. Teenage obesity may
merely postpone breast cancer risk to an older age.
Moreover, any perceived advantage from postponing
breast cancer risk must be weighed against the
increased risk of coronary heart disease (CHD) and
atherosclerosis in later life, which is likely for obese
adolescents aged between 13 18 y.94
Mechanisms may be claried and the hypothesis
tested following recent reports from case control
studies that mainly in premenopausal women, the
relationship between the circulating concentration of
IGF1 and the bioactive concentration of IGFBP3 may
be a marker of breast cancer risk. The important
question is whether deliberate weight loss can reverse
the effects of weight gain.

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