world cancer report - iarc

REPRODUCTIVE FACTORS AND HORMONES
SUMMARY
>Female sex steroid hormone metabolism,
reproductive factors and menopausal
status affect the development of
endometrial, ovarian and breast cancer.
>Use of combined oral contraceptives
accounts for a slight increase in risk of
breast cancer, but is protective against
ovarian and endometrial cancers.
> Hormone replacement therapy is associated
with increases in risk of breast and
endometrial cancers, but may relieve
other health problems associated with
menopause.
> Energy imbalance due to a Western
lifestyle causes increased serum levels
of insulin-like growth factor I (IGF-I)
which is predictive of an elevated risk
for prostate cancer.
There is overwhelming evidence that sex
steroids (androgens, estrogens, progestogens)
can have an important role in the
development of human tumours, especially
of the female reproductive organs
(endometrium, ovary) and breast.
Cancers of the breast, endometrium
and ovary
For breast cancer, incidence rates rise
more steeply with age before menopause
than after, when ovarian synthesis of
estrogens and progesterone ceases and
ovarian androgen production gradually
diminishes. Furthermore, breast cancer
risk is increased in women who have early
menarche, or who have late menopause,
whereas an early age at first full-term
pregnancy and high parity are associated
with reduced risk of the three forms of
cancer [1]. The rise in incidence rates of
endometrial cancer also appears to flatten
off at older age, but this change is related
76 The causes of cancer
less markedly to the menopausal transition
than is the case with breast cancer.
Ovarian cancer risk does not show strong
relationships with menstrual history, but is
clearly and inversely related to parity [2].
Obesity (related to various alterations in
plasma levels of total and bioavailable sex
steroids) is a strong risk factor for
endometrial cancer, as well as for breast
cancer in postmenopausal women.
Circulating levels of sex steroids are regulated
by a range of factors, including
insulin and insulin-like growth factors
(IGFs), which thus provide a possible link
between many observations regarding
excessive energy intake and increased
risk of cancer (Box: IGF-1 and cancer,
p79). Together, these observations suggest
that alterations in endogenous sex
steroid metabolism, and notably the ovarian
synthesis of sex steroids, can be an
important determinant of risk for each of
the three forms of cancer in women.
Breast cancer risk is increased in postmenopausal
women with a hyperandrogenic
(excess of androgens) plasma hormone
profile, characterized by increased
plasma levels of testosterone and ∆-4
androstenedione, reduced levels of sex
hormone-binding globulin and increased
levels of total estradiol, and bioavailable
estradiol not bound to sex hormone-binding
globulin [e.g. 3-5]. Similarly, postmenopausal
women are at increased risk
from endometrial cancer. The situation for
breast cancer in premenopausal women is
less clear [6,7].
Oral contraceptives
Oral contraceptives, in the form of estrogen-progestogen
combinations, were
introduced in the early 1960s, and rapidly
found very widespread use in most developed
countries. Over 200 million women
are estimated to have used oral contraceptives
since their introduction and
about 60 million women are currently
using them [8].
Preparations of oral contraceptives have
undergone substantial changes over time,
including reductions in the potency and
dosage of the estrogens, addition of different
progestogens (progesterone analogues),
and introduction (in 1983) of
biphasic and triphasic pills that vary in
the amounts of estrogen and progestogen
throughout the month. A progestogenonly
pill (“minipill”) was first marketed in
the USA in 1973, but has never been used
widely. Sequential pills, with two weeks of
estrogen alone followed by a combination
of estrogen and progestogen for five days,
were removed from the consumer market
in the 1970s after concern about a possible
association with endometrial cancer.
There is a small increase in the risk of
breast cancer in current and recent users
of combined oral contraceptives containing
both estrogen and progestogen [8].
This association, however, is unrelated to
duration of use or type and dose of
preparation and, 10 years after cessation
of use, is no longer present (Fig. 2.71).
The association of breast cancer with oral
contraceptive use may be a result of
detection bias, due to increased attention
to the occurrence of breast tumours in
women regularly visiting a physician for
contraceptive prescriptions.
Risk of endometrial cancer is approximately
halved in women using combination-type
oral contraceptives, the reduction
in risk being stronger the longer the
contraceptives are used [8]. The reduction
in risk persists for at least ten years
Fig. 2.70 Varieties of oral contraceptives. Use of
the contraceptive pill reduces the risk of cancers
of the ovary and endometrium, but is associated
with a slightly increased risk of breast cancer.