Letter to the Editors: Alcohol Exposure in Utero and Breast Cancer. Richard G. Stevens and Leena Hilakivi- Clarke Alcohol and Alcoholism Vol.36, No.3, pp.276-277, 2001

1. © 2001 Medical Council on Alcoholism
276
Since the pioneering work of Hiatt and Bawol (1984),
there has amassed a considerable amount of evidence that
moderate-to-heavy alcohol consumption increases risk of breast
cancer in women (Willett et al., 1987; Longnecker, 1999).
A plausible mechanism is by alcohol’s effects on circulating
hormone levels. Alcohol administration has been reported
to increase circulating oestradiol levels in pre-menopausal
women (Reichman et al., 1993); the evidence is mixed in post-
menopausal women (Purohit, 1998). In a cross-sectional study
of pre-menopausal women, Muti et al. (1998) determined an
association between reported alcohol consumption and serum
oestradiol levels during the luteal phase of the menstrual cycle,
and found an 18% elevation in drinkers, consuming an average
1 drink per day, compared to abstainers. It is not clear how
alcohol affects circulating oestradiol levels. Alcohol has been
reported to increase aromatase activity; i.e., the conversion of
testosterone to oestrogens, resulting in reduced testosterone
and increased oestrogen levels (Gavaler and Van Thiel, 1992).
Alcohol also might interact with luteinizing hormone produc-
tion from the pituitary (Rettori and McCann, 1997), resulting
in increased oestradiol release from the ovaries.
In addition to affecting oestrogen levels, alcohol appears to
influence melatonin. Alcohol administration has been reported
to reduce the nocturnal rise in serum melatonin in rats (Moss
et al., 1986), and in humans (Ekman et al., 1993; Rojmark
et al., 1993) under experimental conditions. In a large cross-
sectional study, Stevens et al. (2000) found a significant
inverse association of alcohol consumption and urinary
6-sulphatoxymelatonin, a good indicator of nocturnal blood
levels (Cook et al., 2000), in healthy women living under nor-
mal conditions in the Seattle area. Importantly, there was no
effect of one drink on melatonin level, but a 9% reduction with
2 drinks, 15% with 3 drinks, and 17% with 4 drinks or more.
It may be that an increase in circulating oestradiol levels
and a reduction in melatonin levels after alcohol exposure, are
not just simultaneous events, but causally related. Stevens and
Hiatt (1987) suggested that alcohol ingestion may result in
lowered melatonin levels which, in turn, may lead to elevated
circulating oestradiol concentration in blood (Cohen et al.,
1978). Specifically, decreased concentrations of melatonin might
increase release of gonadotrophins, leading to an increase in
ovarian oestrogen production (Kauppila et al., 1987; Penny
et al., 1987; Voordouw et al., 1992; Brzezinski, 1997).
Both high oestrogen levels and low melatonin levels have
been implicated in increasing the risk to develop breast cancer.
Findings in human breast cancer cells growing in culture
and in animal models (Clarke et al., 1992), as well as in
epidemiological studies, at least in post-menopausal women
(Key, 1999; Kabuto et al., 2000), link elevated circulating
oestrogen levels to increased breast cancer risk. In addition, in
vivo data indicate that reduced melatonin levels can increase
chemically induced mammary cancer in rats (Tamarkin et al.,
1981; Blask et al., 1991). The epidemiology is, however, quite
sparse (Tamarkin et al., 1982) due in part to the fact that there
has not, until recently, been a reliable technique for estimating
nocturnal circulating melatonin levels that is feasible to use in
large-scale epidemiological studies.
These observations can be considered in the context of the
hypothesis that an elevated exposure to oestrogens in utero
will increase the lifetime risk of breast cancer (Trichopoulos,
1990) by altering normal breast development. This hypothesis
was subsequently supported in a number of epidemiological
studies (Potischman and Troisi, 1999). Animal models also
support the hypothesis and show that elevated in utero
oestradiol levels lead to altered mammary gland develop-
ment (Hilakivi-Clarke et al., 1997); further, an exposure of
pregnant rats to oestradiol, or feeding them a diet high in n-6
polyunsaturated fatty acid (PUFA), which significantly
raises circulating oestradiol levels, results in increased
7,12-dimethylbenz[a]anthracene-induced mammary tumour
incidence in their female offspring.
For women who are pregnant, ingestion of alcohol, even in
moderation, may lead to elevated circulating oestradiol levels,
either through a reduction of melatonin or some other mechan-
ism. This may then affect the developing mammary tissue
such that the lifetime risk of breast cancer is raised in their
daughters.
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Alcohol & Alcoholism Vol. 36, No. 3, pp. 276–277, 2001
LETTER TO THE EDITORS
ALCOHOL EXPOSURE IN UTERO AND BREAST CANCER RISK LATER IN LIFE
RICHARD G. STEVENS* and LEENA HILAKIVI-CLARKE1
University of Connecticut Health Center, Farmington, CT 06030 and 1
Lombardi Cancer Center, Georgetown University Medical Center,
Washington, DC 20007, USA
(Received 24 October 2000; accepted 4 January 2001)
*Author to whom correspondence should be addressed.

2. LETTER TO THE EDITORS 277
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