The Critical Role of Alcohol Consumption in Determining the Risk of Breast Cancer with Postmenopausal Estrogen Administration
Barnett Zumoff
Beth Israel Medical Center
New York, New York 10003
Address correspondence and requests for reprints to: Barnett Zumoff, Division of Endocrinology and Metabolism, Beth Israel Medical Center, 1st Avenue at 16th Street, New York, New York 10003.
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Introduction
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Discussing with a postmenopausal woman whether she
should take hormone replacement is one of the most important tasks of
the clinical endocrinologist. Because of the reported major health
benefits to a postmenopausal woman from taking estrogens, including
decreased osteoporosis (1, 2, 3), decreased coronary disease (4, 5, 6),
possibly decreased Alzheimers disease (7), and decreased overall
mortality (8, 9), the endocrinologist can probably do such a woman more
good by prescribing estrogens and encouraging their continued use than
by any other treatment. However, many women resist taking estrogens
because they are afraid it might cause breast cancer. Convincing them
that there is little or no danger of that is what an endocrinologist
has to do to secure compliance with his or her advice. Telling a
patient that the benefits of estrogen administration outweigh the
danger doesnt work in many cases; the patient is looking for
assurances, not sophisticated explanations of benefit/risk ratios.
To give such assurances, the endocrinologist must be convinced that
there is indeed little or no danger from estrogen administration.
Unfortunately, the literature has not reached a consensus about
estrogens dangers. Since 1941, there have been 70 epidemiological
studies dealing with estrogen administration and the risk for breast
cancer, 7 meta-analyses of this problem, and uncounted reviews, and
though I believe that both the weight of opinion and the weight of
evidence indicate that the risk is exceedingly small or nonexistent
(10, 11, 12, 13, 14, 15), there are respected voices that still say there is indeed a
risk, though probably only with prolonged administration (16, 17, 18). This
difference of opinion persists despite the fact that new
epidemiological studies continue to appear in the literature at a
steady pace, in the hope, so far unrealized, that better experimental
design will produce the "definitive" study that will resolve the
controversy once and for all.
A solution to the dilemma may be at hand. Because the literature had
arrived at a consensus that alcohol consumption is a risk factor for
breast cancer (19), the large Nurses Health Study, which sought to
evaluate the role of estrogen administration as a risk for breast
cancer, was designed to stratify for alcohol consumption as a possible
associated risk. Analysis of the data, as reported by Colditz et
al. (20), yielded a startling finding: only women who consumed
alcohol manifested an increased risk of breast cancer with estrogen
administration; those who did not consume alcohol showed no increase in
risk. To quote the authors: "Among women who did not consume alcohol,
the risk of breast cancer was not increased by current use of
menopausal hormones ... among alcohol consumers, current hormone
users were at increased risk of breast cancer." This is at odds with
the statement made by Susan Love in The New York Times (21)
that "taking hormones for more than 10 years could increase a
womans risk of developing breast cancer. The Nurses Health Study, a
definitive 14-year study of 122,000 nurses issued in 1995, estimated
that women between ages 60 and 64 who took hormones for at least five
years increased their risk of getting breast cancer by 71 percent. They
increase their risk of dying of breast cancer by 45 percent." This is
a misstatement in two regards: 1) The Nurses Health Study showed an
overall increase in breast cancer incidence of 41%, not 71%, and said
nothing at all about the risk of dying of the cancerother workers
have reported that the death rate from breast cancer discovered during
estrogen use is substantially lower than with other breast
cancers, as Colditz et al. mention; 2) The Nurses Health
Study showed that women who did not consume alcohol had no
increased risk of developing breast cancer at all. Colditz
et al. noted the finding about the role of alcohol
consumption in their discussion, but did not place great emphasis on it
despite its potentially profound implications; they merely commented
that "the apparent difference in risk due to estrogens according to
level of alcohol intake is unexpected and intriguing. Further study is
needed ..."
One might think that other epidemiologists would hasten to redesign
their studies and reanalyze their data in the light of this important
observation, but I have found only one study that has done so, the
almost equally large Iowa Womens Health Study, reported by Gapstur
et al. (22). The data from that study are quite unequivocal
about the critical role of alcohol consumption in determining the risk
of breast cancer with estrogen administration: only women who consumed
5 grams of alcohol or more per day manifested an increased risk of
breast cancer with estrogen administration; those who consumed less
alcohol than that or none at all showed no increase in risk (Fig. 1
).

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Figure 1. Data from Gapstur et al. (22).
The relative risk (RR) of breast cancer in women who do not consume
alcohol and have never used estrogens is set at 1.0. Increasing amounts
of alcohol consumption have no significant effect on RR in these
never-users of estrogens. Women who have used estrogen but consume
little or no alcohol show no significant increase in breast-cancer
riskRRs do not differ significantly from 1.0; in contrast, women who
have used estrogen and consume 5 grams of alcohol per day or more (5
grams corresponds to 2/3 ounce of whiskey or 3 ounces of wine) show a
highly significant increase in risk (RR of slightly over 1.8).
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It should be emphasized that no one has published data that disagree
with the findings of these two studies concerning the role of alcohol
consumption.
Gapstur et al. were also hesitant about placing great
emphasis on their finding about the role of alcohol because they were
concerned that there was no "biologically plausible" mechanism by
which alcohol could exert the observed effect; but recently a
biologically plausible mechanism has been reported: Ginsburg et
al. (23) have found that when a postmenopausal woman receiving
estrogens consumes alcohol her blood level of estradiol rises acutely,
by about 300% (Fig. 2
).

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Figure 2. Data from Ginsburg et al. (23).
Postmenopausal women who are not using estrogen replacement show
castrate levels of serum estradiol, and alcohol consumption does not
increase these levels. This corresponds to the absence of any effect of
alcohol on increasing breast-cancer risk in women who have never used
estrogens (see Fig. 1 ). Postmenopausal women who are on estrogens have
basal serum estradiol levels corresponding to those of the follicular
phase of the menstrual cycle; consumption of alcohol results in a rise
of serum estradiol to values corresponding to those of the
periovulatory peak in the menstrual cycle; the effect lasts for more
than 6 h.
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In light of the studies of Colditz et al., Gapstur et
al., and Ginsburg et al., I propose the following
hypothesis to account for the great variability of the results of even
well-designed studies intended to assess whether estrogen
administration is a risk for breast cancer and the apparently critical
role of alcohol consumption:
1) The elevation of blood estradiol by administration of postmenopausal
estrogen replacement therapy is only modest, i.e. from
castrate levels to values characteristic of the follicular phase of the
menstrual cycle (23); these values may be near a threshold value for
breast cancer-promoting effects, so that some women will manifest
increased risk and some will not, depending on their varying genetic
susceptibility factors, including family history of breast cancer;
abnormal BRCA1, BRCA2, or p53 genes; and elevated capacity to
16
-hydroxylate estradiol (24) [increased 16
-hydroxylation may be
a risk factor for breast cancer (25, 26)].
2) When alcohol is consumed by a postmenopausal woman receiving
estrogens, the blood estradiol is raised to values characteristic of
the periovulatory peak in the menstrual cycle (23), which may be above
the threshold of breast-cancer-promoting effects for all women
regardless of genetic background, resulting in a clearly demonstrable
increase in risk in whole populations.
The question of whether estrogen administration favors the development
of breast cancer has been the Gordian Knot of endocrinology. Hundreds
of workers have attempted to unravel it by epidemiological studies,
meta-analyses, and literature reviews, but without success. Alexander
the Great opened his Gordian Knot by slashing it apart with his sword;
it now seems that we may be able to dissolve our Gordian Knot in
alcohol. If we can assure our patients that consuming less than 5 grams
of alcohol daily will eliminate any breast-cancer-promoting risk of
estrogen administration, we will have made a very important therapeutic
advance.
Received March 26, 1997.
Accepted March 27, 1997.
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