Alcohol association with ethanol: possible mechanisms
ALCOHOL ASSOCIATION WITH BREAST CANCER: POSSIBLE
TABULATED DATA ON PLASMA AND URINARY SEX HORMONE LEVELS
This brief report is a summary and tabulation of data on the effects of alcohol on plasma
and urinary sex hormone concentrations. It quantifies information already provided in
the report “Alcohol Association with Breast Cancer: Possible Mechanisms” (CC/99/8).
The data are presented in tabular form in Appendix 1.
Endogenous hormone levels
Most breast cancer has a hormonal aetiology (see Key and Pike, 1988), and any effects
of alcohol on the endogenous hormonal milieu in women could provide a potential
mechanism for carcinogenesis. Alcohol increases endogenous oestrogen levels in pre-
and postmenopausal women (Reichman et al.
, 1993; Ginsburg et al.
, 1995), and elevated
levels of oestrone sulphate, a long-term indicator of oestrogen levels, have been
demonstrated in women who regularly consume alcohol (Hankinson et al
Several studies have examined the relationship between alcohol intake and serum
oestrogens and other hormones. Such studies have generally been carried out in
postmenopausal women. Women are also frequently exposed to exogenous oestrogens
in the form of oral contraceptives (OCs) and hormone replacement therapy (HRT), and
the effects of alcohol ingestion in these women are discussed in subsequent sections.
Four studies on the relationship between alcohol intake and serum sex hormone levels
are described in Appendix 1. Three of the four studies demonstrated a positive
relationship between alcohol consumption and serum oestradiol levels, while one found
no relationship with plasma oestrogens, but a positive correlation with plasma
Reichman et al.
(1993) undertook a controlled-diet study lasting for six
consecutive menstrual cycles. Participants were randomly assigned to two groups and a
crossover design was used. During the last three menstrual cycles, alcohol consumption
of the two groups was reversed. In all, 34 premenopausal women, aged 21-40 years,
with a history of regular menstrual cycles, consumed 30 g ethanol (approximately two
average drinks) per day for three menstrual cycles and no alcohol for the other three.
Alcohol consumption was associated with statistically significant increases in
plasma DHEA sulphate (DHEAS), oestrone, oestradiol and urinary oestradiol. No
changes were found in the percentage of bioavailable oestradiol, but increased total
oestradiol levels in the peri-ovulatory phase suggested elevated absolute amounts of
Dorgan et al.
(1994) undertook a cross-sectional study in 107 premenopausal
women in the USA of alcohol intake and hormonal status. Oestrone, oestrone sulphate,
oestradiol, androstenedione, DHEAS and sex hormone binding globulin (SHBG) were
measured in plasma. After adjusting for age, weight and total energy intake, alcohol
ingestion was found not to be associated with plasma oestrogens in the follicular,
midcycle or luteal phases of the menstrual cycle, nor with the levels of SHBG or
DHEAS in plasma averaged from the three phases of the cycle. However, alcohol was
significantly positively associated with the average level of plasma androstenedione. The
authors concluded that the increased risk of breast cancer related to alcohol ingestion did
not appear to be mediated by increased plasma oestrogen levels in this population, but
that the alcohol/breast cancer association could be mediated via androstenedione.
Alcohol is more often unpleasant and causes tissue damage more rapidly in
women than in men. Eriksson and co-workers (1996)
studied the effect of acetaldehyde,
the first metabolite of alcohol, on plasma hormone levels in male and non-pregnant
female volunteers, aged 19-33 years. A proportion of the female subjects were taking
oral contraceptives. In the overall population of women, acetaldehyde correlated
= 0.406, P
= 0.026) with plasma oestradiol levels. Acetaldehyde levels did
not correlate with any of the other hormones measured (progesterone, testosterone or
cortisol). The authors admit that acetaldehyde estimations were not entirely reliable;
nevertheless, all samples were subjected to the same assay procedures and should
therefore be comparable. However, the authors state that the involvement of
acetaldehyde, rather than the parent compound, ethanol, in the aetiology of breast cancer
is still only a tentative possibility.
In a study by Muti et al.
(1998), alcohol intake was compared with serum
oestradiol levels in 60 premenopausal women. Two blood samples were taken, 1 year
apart. A significant association between alcohol intake and oestradiol levels was found
when oestradiol was averaged across the two visits (Spearman’s r
= 0.29, P
When intraindividual variability of oestradiol was controlled over time, women showing
consistently high oestradiol levels at both visits were characterised by a significantly
higher alcohol intake (92.8 g/week) in comparison with those showing consistently low
oestradiol levels at both visits (31.6 g/week). In addition, the prevalence of drinkers in
the group with consistently high oestradiol was significantly higher than in the group
with consistently low oestradiol. The authors concluded that alcohol intake seems to be
associated with consistently higher oestradiol levels appear than in non-drinkers.
A much larger number of studies on the effects of alcohol on hormone levels have been
carried out in postmenopausal women. Three studies (Trichopoulos et al.
, 1987, Cauley
, 1989, London et al
., 1991) found no association between plasma oestrogen levels
and alcohol intake, but the majority found significant increases in plasma levels of
oestrogens in women taking alcohol regularly, even after controlling for confounding
In a study of 220 postmenopausal women aged 54-66 years, from Greece (n
= 99) and
the USA (n
= 121), Trichopoulos et al.
(1987) found no consistent association of urinary
oestrogen levels (oestrone, oestradiol, oestriol or total oestrogens) with alcohol
A study by Cauley et al.
(1989), carried out in 176 healthy postmenopausal
women (mean age 58 years), examined several lifestyle factors in relation to serum sex
hormone levels. They found that both oestrone and oestradiol levels tended to decline
with increasing alcohol consumption, although this decline was not significant.
London et al.
(1991), in a study of 325 healthy women in the USA aged 50-60
years who were at climacteric, investigated serum levels of oestrone, oestradiol, percent
free oestradiol and SHBG in relation to alcohol and other dietary factors. Alcohol intake
was not associated with concentrations of oestrogens in their study.
Gavaler and coworkers (1991) reported an international study of the relationship
between alcohol intake and oestradiol levels in postmenopausal women. The major
source of postmenopausal oestrogens is from the aromatisation of androgens, and
alcohol has been reported to increase the rate of aromatisation. In a study of 128
postmenopausal women in the USA, a direct association was found between moderate
alcohol consumption and serum oestradiol levels. Three comparable study populations
were then recruited in Europe: 62 in Copenhagen, 34 in Lisbon and 20 in Madrid. No
association was detected in the Madrid subjects, but in both the Copenhagen and Lisbon
study populations, not only were oestradiol levels increased in alcohol users compared
to abstainers, they were also significantly correlated with the amount of alcohol
consumed. It was concluded that the increase in oestradiol levels seen with moderate
alcohol consumption is not an isolated finding. In a further analysis of the US cohort,
Gaveler and Van Thiel (1992) found that among abstainers, serum oestradiol levels were
101 ± 12 pmol/l, compared with 163 ± 12 pmol/l in alcohol users, a 62% increase.
Using the same cohort of 128 US women, Gaveler and Love (1992), however,
found that a relationship between alcohol intake and oestrogen levels could be
demonstrated only when alcohol consumption based on the food record data was
analysed; self-report data were found to be less reliable. The authors therefore advised
that data based on self-reporting of alcohol consumption should be treated with caution.
Katsouyanni et al.
(1991) determined levels of oestrone, oestradiol and oestriol
in 88 postmenopausal women in relation to diet, including alcohol consumption.
Alcohol intake was positively associated with of urinary oestrogens (specifically
oestrone and oestradiol), after controlling for energy intake, obesity and reproductive
Gaveler et al.
(1993) were able to estimate the level of alcohol consumption
associated with increases in oestrogen levels. In a comparison of alcohol-abstaining
postmenopausal women with postmenopausal women with moderate alcohol intake,
they showed that alcoholic beverage consumption in the range of 0.1-28 total weekly
drinks produced detectable changes in oestradiol and testosterone levels.
Newcomb et al.
(1995) examined the relationship between endogenous sex
hormones and alcohol intake in a study of dietary and lifestyle factors. Oestrone,
DHEAS, SHBG and free and total testosterone were measured in the serum of 253
postmenopausal women not using HRT. They found only a weak association with
alcohol intake in these women. However, almost 50% of the women in this study were
considered obese, and a positive association between adiposity and plasma oestrogen
levels in postmenopausal women has been consistently reported (see Hankinson et al.
1995, for discussion). This may have masked any effects of ethanol intake per se
In the study of Hankinson et al.
(1995), involving a cohort of 217
postmenopausal participants in the Nurses’ Health Study (61.5 ± 5.0 years of age, mean
± SD), alcohol consumption was positively associated with plasma oestrone sulphate
= 0.17, P
= 0.02), after controlling for age, height, smoking status and
BMI. There appeared to be a direct relationship between the amount of alcohol
consumed per day and oestrone sulphate levels in plasma. No association was found
between alcohol consumption and plasma levels of oestradiol, oestrone or prolactin. The
authors concluded that the association of alcohol consumption with subsequent breast
cancer risk could be mediated, at least in part, through an effect on postmenopausal
plasma oestrogen levels, but that further studies would be necessary to elucidate the
physiological basis for this association.
Nagata et al.
(1997), in a study of the association of alcohol consumption with
serum hormone concentrations in 61 postmenopausal Japanese women (60.5 ± 6.3 years
of age, mean ± SD), found that serum oestradiol levels showed a strong positive
correlation with alcohol consumption after controlling for age (P
= 0.01), the
significance of which increased after also controlling for height and BMI (P
There was also a trend for increasing serum DHEAS levels with alcohol consumption (P
= 0.01) (see Table). There was no effect on progesterone levels, and a slight but non-
significant decrease in SHBG levels. The authors concluded that, since DHEAS is an
intermediate in the synthesis of oestrogens, alcohol could affect the risk of breast cancer
through effects on either or both oestradiol and DHEAS.
Madigan et al.
(1998) have related serum hormone and SHBG levels to various
lifestyle factors, including alcohol intake, in 125 postmenopausal women in the USA.
Oestrogens were associated positively, while SHBG was associated negatively with
alcohol intake. However, these findings were significant only for plasma oestrone levels
Elevated circulating prolactin levels have been suggested to be associated with breast
cancer (Ginsburg et al.
, 1995). Hankinson et al.
(1995) found no effect of alcohol
consumption on plasma prolactin levels and in postmenopausal women.
Ginsburg et al.
(1995) reported two randomised, crossover studies to examine
the effects of ethanol on prolactin levels in menopausal women using transdermal
oestradiol for hormonal replacement. In study 1, transdermal oestradiol patches (0.15
mg) were administered to seven menopausal women (59.3 ± 1.7 years) on the day before
ethanol administration. Prolactin levels were measured for up to 6.3 hours after alcohol
intake. Serum prolactin levels were significantly higher after ethanol ingestion than after
ingestion of an isocaloric carbohydrate drink (P
< 0.03). In study 2 (n
= 8, 58.6 ± 1.9
years), the transdermal oestradiol patches were removed after completion of ethanol or
carbohydrate ingestion. Serum prolactin was again greater after ethanol ingestion than
after carbohydrate ingestion (P
< 0.001). The authors concluded that in these women,
therefore, acute alcohol ingestion was associated with an increase in serum prolactin.
Only one study (Eriksson et al.
, 1996) has been found where the relationship between
alcohol intake and serum sex hormone levels was specifically reported in women on
OCs. No overall correlations were found between acetaldehyde concentrations and those
of ethinyloestradiol or other sex hormones. However, when OC users were divided into
those in the use and non-use phases of the menstrual cycle, differences emerged, with
significant levels appearing only during the use phase. Oestradiol and ethinyloestradiol
levels were 73 ± 94 and <100 pM (OC-) and 13 ± 33 and 457 ± 319 pM (OC+),
Hormone replacement therapy
Ginsburg et al.
(1996) sought to determine if moderate alcohol drinking increased
circulating oestradiol levels in 12 postmenopausal women on HRT (54.5 ± 4.0 years of
age). This group was compared with 12 postmenopausal women who were not using
HRT (61.7 ± 6.4 years). Each group drank 0.7 g/kg alcohol or an isocaloric placebo on
consecutive days. Alcohol ingestion led to a three-fold increase in circulating oestradiol
in women on HRT, but did not change oestradiol levels significantly in control women,
who were not on HRT. Blood alcohol levels did not differ significantly in women who
used HRT and those who did not (21 mmol/l in both groups). The authors concluded that
acute alcohol ingestion could lead to significant and sustained elevations in circulating
oestradiol to levels 300% higher than those achieved in clinical use of HRT.
The tabulated data suggest that ingestion of alcohol is in general associated with an
increase in sex hormone levels, particularly oestradiol and oestrone sulphate. This seems
to hold even when data are corrected for BMI, obesity being recognised as a
confounding factor in this analysis (Hankinson et al.
, 1995; Nagata et al.
However, out of 13 studies looking at the effect of alcohol on oestradiol levels, only
eight report a significant increase, one of which was in women on HRT only. Two report
no association, and three report a non-significant trend. While these results are intriguing
and should be examined further, they do not yet confirm a causal association between
alcohol ingestion and increased serum sex hormone levels.
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Alcohol effects on plasma
Positive association(all reported assignificant)
(same cohort asabove)Gavaler et al.
(1993) (samecohort as above)Ginsburg et al.
with ≥2 drinksper dayr
= 0.17, p
Alcohol effects on urinary hormone concentrations
< 0.009 (peri-ovulatoryphase)22% increasep
< 0.02 (luteal phase)
Dr Dominic Heaney MA MRCP PhD ______________________________________________________________________________ Curriculum Vitae Dr Dominic Heaney MA (Cantab) MB BCh (Oxon) Consultant Neurologist and Honorary Senior LecturerNational Hospital for Neurology and Neurosurgery Dr Dominic Heaney MA MRCP PhD ______________________________________________________________________________ Con
CRAIG V. COMITER, M.D. I. PERSONAL Address: Stanford University Medical Center, Department of Urology, 300 Pasteur Drive, Room S-287, Stanford, CA 94305-5118 Telephone: (650) 725-6493 CHRONOLOGY OF EDUCATION Fellow, Neurourology and Female Urology Clinical Instructor, University of California, Los Angeles, Los Angeles, CA Urology, Resident, Harvard Program in Urology, Boston, Ma