world cancer report - iarc

PHYTO-ESTROGENS AND
CANCER PEVENTION
Plant foods contain phyto-estrogens, lignans
and isoflavones, which are structurally
similar to the mammalian estrogen,
estradiol-17β. The significance of the
structural similarity of the lignans and
isoflavones to mammalian estrogens and
possible cancer preventive effects were
first promulgated in the early 1980s
(Setchell KDR et al., Am J Clin Nutr,
40, 569, 1984; Adlercreutz H, Gastroenterology,
86, 761-6, 1984). The
isoflavones are diphenols and include
daidzein, equol and genistein, all of which
have been shown to bind to α- and especially
β-estrogen receptors (Kuiper GG et
al., Endocrinology, 138, 863-870, 1997).
In common with many other weak estrogens,
the isoflavones have been shown to
be anti-estrogens, competing for estradiol
at the receptor complex, yet failing to
stimulate a full estrogenic response after
binding to the nucleus. In animal models,
inclusion of soy in the feed, a rich source,
reduces mammary tumorigenicity. The
lignans enterolactone and enterodiol are
derived from microbial fermentation of
secoisolariciresinol and matairesinol in
foods, and excreted in urine. These have
to an exposure to estrogens alone (as in
postmenopausal women not using any
exogenous hormones), risk of breast cancer
is increased further in women who
have elevated plasma and tissue levels of
estrogens in combination with progestogens.
This theory is supported by observations
that postmenopausal women
using estrogen-plus-progestogen preparations
for hormone replacement therapy
have a greater increase in breast cancer
risk than women using estrogens alone
[10,11]. In premenopausal women, the
estrogen-plus-progestogen theory may
explain why obesity is associated with a
mild reduction in breast cancer risk [16],
because obesity may cause chronic
anovulation and decreases in lutealphase
progesterone levels.
78 The causes of cancer
also been shown to be weakly estrogenic
and anti-estrogenic, and supplements have
been shown to reduce tumorigenesis in a
rodent model of breast cancer. However,
proliferative effects of phytoestrogens on
the human breast have also been suggested
(reviewed in Bingham SA et al., Br J Nutr,
79, 393-406, 1998).
The cancers most closely linked to plant
estrogens are the hormone-related carcinomas
of breast and prostate, which
appear to be less common in soy-consuming
populations. However, in the most
recent and largest prospective study of
34,759 women in Hiroshima and Nagasaki,
there was no association between breast
cancer risk and soya foods (Key TJ et al., Br
J Cancer, 81, 1248-1256, 1999). Some
recent epidemiological studies include
biomarkers of intake, e.g. urine excretion
of plant estrogens. One recent case-control
study showed that tumour patients excreted
significantly less equol and enterolactone
in 72 hour urine collections than
matched controls, but genistein was not
measured (Ingram D et al., Lancet, 350,
990-992, 1997). A second study showed
that overnight urine total isoflavonoid
excretion, especially of glycetein, was significantly
lower in cancer cases compared
Endometrial cancer
Most observations relating endometrial
cancer risk to endogenous and exogenous
sex steroids, as well as to other risk factors
(obesity, ovarian hyperandrogenism
syndromes; see below) are explicable by
the “unopposed estrogen” hypothesis
[13,14]. This stipulates that risk is
increased among women who have high
plasma levels of bioavailable estrogens
and low plasma progesterone, so that the
effect of estrogens is insufficiently counterbalanced
by that of progesterone. The
hypothesis is supported by observations
that proliferation of endometrial cells, a
necessary condition for cells to accumulate
genetic mutations and to expand clonally
with selective growth advantage,
occurs at greater rates during the follicu-
Fig. 2.72 A Nigerian woman boiling milk from
strained soya beans to make soy curd. This is
becoming a substitute for a cheese traditionally
made from more expensive cows’ milk.
with controls (Zheng W et al., Cancer
Epidemiol Biomarkers Prev, 8 35-40,
1999). Messina MJ et al. (Nutr Cancer 21,
113-131, 1994) reviewed the evidence
relating to the impact of soy on cancers
at sites other than the breast.
lar phase of the menstrual cycle (when the
ovary produces estrogens but very little
progesterone), than during the luteal
phase (when the ovaries produce both
estrogens and progesterone). Furthermore,
there are frequent case reports of
ovarian hyperandrogenism (polycystic
ovary syndrome) in women developing
endometrial cancer before the age of 40
and other studies showing an increased
risk of endometrial cancer in polycystic
ovary syndrome patients [13]. Polycystic
ovary syndrome is a relatively frequent
endocrine disorder, with an estimated
prevalence of 4-8%, and in premenopausal
women is associated with frequent anovulatory
menstrual cycles and hence with
impaired luteal-phase progesterone synthesis.
Finally, the theory explains why