world cancer report - iarc

after cessation of use. Interestingly, however,
use of sequential oral contraceptives,
containing progestogens only in the
first five days of a cycle, is associated
with an increased risk of endometrial cancer.
For ovarian cancer, risk is reduced in
women using combined oral contraceptives,
the reduction being about 50% for
women who have used the preparations
for at least five years (Table 2.22). Again,
this reduction in risk persists for at least
10-15 years after cessation of use. It has
also been suggested that long-term use of
oral contraceptives (more than five years)
could be a cofactor that increases risk of
cervical carcinoma in women who are
infected with human papillomavirus [9].
Postmenopausal hormone replacement
therapy
Clinical use of estrogen to treat the symptoms
of menopause (estrogen replacement
therapy or hormone replacement therapy)
began in the 1930s, and became widespread
in the 1960s. Nowadays, up to 35%
of menopausal women in the USA and
many European countries have used
replacement therapy at least for some period.
The doses of oral estrogen prescribed
decreased over the period 1975-83 and the
use of injectable estrogens for estrogen
replacement therapy has also diminished.
On the other hand, the use of transdermally
administered estrogens has increased
progressively to about 15% of all estrogen
replacement therapy prescriptions in some
countries. In the 1960s, some clinicians,
especially in Europe, started prescribing
combined estrogen-progestogen therapy,
primarily for better control of uterine bleeding.
The tendency to prescribe combined
estrogen-progestogen hormonal replacement
therapy was strengthened when first
epidemiological studies showed an
increase in endometrial cancer risk in
women using estrogens alone.
A small increase in breast cancer risk is
correlated with longer duration of estrogen
replacement therapy use (five years
or more) in current and recent users [8].
The increase seems to cease several years
after use has stopped. There appears to
be no material difference in breast cancer
risk between long-term users of all hor-
Fig. 2.71 Estimated risk of breast cancer by time since last use of combined oral contraceptives, relative
to never-users. Data adjusted by age at diagnosis, parity, age at first birth and age at which risk of conception
ceased. Vertical bars indicate 95% confidence interval.
mone replacement therapy and users of
estrogens alone. Nevertheless, one large
cohort study and a large case-control
study have provided strong evidence for a
greater increase in breast cancer risk in
women using hormone replacement therapy
than in women using estrogens alone
[10,11].
For endometrial cancer, there is an
increase in risk among women using estrogen
replacement therapy, the risk increasing
further with longer duration of use [8].
In contrast, women using hormone
replacement therapy have only a mild
increase in risk compared to women who
have never used any postmenopausal hormone
replacement and this increase is
much smaller than that of women who
used estrogens alone. There seems to be
no relationship between risk of ovarian
cancer and postmenopausal estrogen use,
while data on ovarian cancer risk in relation
to hormone replacement therapy use
are too scarce to evaluate.
Prostate cancer
Normal growth and functioning of prostatic
tissue is under the control of testosterone
through conversion to dihydroxytestosterone
[12]. Dihydroxytestosterone
is bound to the androgen receptor, which
translocates the hormone to the nucleus.
There have been conflicting findings as to
whether patients with prostate cancer
have higher levels of serum testosterone
than disease-free controls. Diminution of
testosterone production, either through
estrogen administration, orchidectomy or
treatment with luteinizing hormonereleasing
hormone agonists, is used to
manage disseminated prostate cancer.
Mechanisms of tumorigenesis
Breast cancer
The role of endogenous hormones in
breast cancer development suggests the
“estrogen excess” hypothesis, which stipulates
that risk depends directly on
breast tissue exposure to estrogens.
Estrogens increase breast cell proliferation
and inhibit apoptosis in vitro, and in
experimental animals cause increased
rates of tumour development when estrogens
are administered. Furthermore, this
theory is consistent with epidemiological
studies [4,15] showing an increase in
breast cancer risk in postmenopausal
women who have low circulating sex hormone-binding
globulin and elevated total
and bioavailable estradiol.
The “estrogen-plus-progestogen” hypothesis
[15,16] postulates that, compared
Reproductive factors and hormones
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