Background:

Alcohol intake may influence breast cancer risk in women through hormonal changes, but the evidence to date is inconclusive. We investigated cross-sectional associations between habitual alcohol intake and serum concentrations of testosterone, sex hormone binding globulin (SHBG), insulin-like growth factor-1 (IGF-1), and estradiol (premenopausal women only) in UK Biobank.

Methods:

We included 30,557 premenopausal and 134,029 postmenopausal women aged between 40 and 69 years when recruited between 2006 and 2010. At their initial assessment visit, habitual alcohol intake was assessed using a touchscreen questionnaire, and serum hormone concentrations were assayed. Multivariable linear regression analysis was performed.

Results:

Per 10 g/day increment in alcohol intake, testosterone concentration was 3.9% [95% confidence intervals (CI): 3.3%–4.5%] higher in premenopausal women and 2.3% (1.8%–2.7%) higher in postmenopausal women (Pheterogeneity < 0.0001); SHBG concentration was 0.7% (0.2%–1.1%) higher in premenopausal women and 2.4% (2.2%–2.6%) lower in postmenopausal women (Pheterogeneity < 0.0001); and IGF-1 concentration was 1.9% (1.7%–2.1%) lower in premenopausal women and 0.8% (0.6%–0.9%) lower in postmenopausal women (Pheterogeneity < 0.0001). In premenopausal women, there was no significant overall association of alcohol with estradiol but a positive association was observed in the early and mid-luteal phases: 1.9% (95% CI: 0.2%–3.6%) and 2.4% (95% CI: 0.7%–4.2%) higher, respectively.

Conclusions:

This study confirms significant but modest associations between alcohol intake and hormones, with evidence of heterogeneity by menopausal status.

Impact:

The findings facilitate better understanding of whether alcohol intake influences hormone concentrations, but further work is necessary to fully understand the mechanisms linking alcohol with cancer risk.

Alcohol use is prevalent in many countries globally (1) and is a leading risk factor for several diseases including cancer (2). Alcoholic beverages have been judged to be “carcinogenic to humans” (3), but the underlying mechanisms are not fully understood. Potential mechanisms include actions of acetaldehyde, inhibition of DNA methylation, oxidative stress, and changes in metabolism, immune function, and hormones (4, 5).

Sex hormones and growth factors play a role in carcinogenesis, probably by promoting cell proliferation and therefore increasing the chances of random genetic errors occurring and being replicated (6). Circulating estrogens, androgens, and insulin-like growth factor 1 (IGF-1) have been associated with an increased risk of breast cancer in women, whereas sex hormone-binding globulin (SHBG) is inversely associated with the risk (7–10). Breast cancer is also related to alcohol intake (11, 12), suggesting that hormones, if influenced by the latter, may at least in part explain this effect.

Alcohol intake has been associated with sex hormones and growth factors (7, 9, 13). In general, a positive association was observed with estrogens and androgens, and an inverse association with IGF-1, but the results to date have been less conclusive for hormones in premenopausal women due to fewer data being available as well as the fluctuations of hormone concentrations across the menstrual cycle.

We therefore investigated, using data from UK Biobank, the associations between habitual alcohol intake and serum concentrations of testosterone, SHBG and IGF-1 in both pre- and postmenopausal women, and the association of alcohol with estradiol in premenopausal women only. As far as we are aware, this is the largest study on this topic, including over 30,000 premenopausal and 134,000 postmenopausal women.

Data source

We analyzed data from UK Biobank (project reference number 3248, approved August 2013; ref. 14).

Study setting

UK Biobank is a prospective cohort study involving about 500,000 adults aged between 40 and 69 years when recruited in 2006 to 2010. At the initial assessment visit, information was collected on socio-demographics, lifestyle and psychosocial factors, and health status, using a self-administered touchscreen questionnaire (15). Physical measurements were undertaken, and blood and urine samples were collected. Dietary intake was also assessed in a subsample of the participants who were recruited in 2009 to 2010, using the Oxford WebQ, a web-based validated 24-hour dietary assessment questionnaire (16).

Study participants included

This analysis included premenopausal women, who reported they had not had their menopause, i.e., periods stopped, and were younger than 50 years of age, and postmenopausal women, who reported they had gone through menopause, or were 55 years or older, or reported a bilateral oophorectomy. We excluded women who reported being pregnant or currently using hormone therapy [oral contraceptive pills (OCP) or hormone replacement therapy (HRT)], had a prior diagnosis of cancer (except for nonmelanoma skin cancer), or had missing data on time since last menstrual period (premenopausal women), concentrations of one or more hormones or SHBG, or alcohol intake (Supplementary Fig. S1).

Alcohol intake

Habitual alcohol intake (main exposure of interest) was assessed in all participants using the touchscreen questionnaire. Women were asked how frequently they drank alcohol, and current drinkers were asked about the amount of red wine, white wine or champagne, fortified wine, beer or cider, spirits or liqueurs, and other alcoholic drinks they would drink in an average week or month. Alcohol intake in units per day was calculated by summing the average individual drinks per day, assuming that a glass of red or white wine (six glasses in a standard bottle) contains 1.5 units of pure alcohol, a pint of beer contains 2.5 units, and a glass of fortified wine (12 glasses in an average bottle), a measure of spirits (25 standard measures in a normal-sized bottle) or a glass of other alcoholic drinks contains 1 unit (17). The units were then converted to grams assuming that one unit equals 8 g. Intakes of alcohol from wine (red, white or fortified), beer or cider, and spirits or liqueur were also calculated.

In a subsample of participants, alcohol intake in the 24 hours before blood sampling (24-hour alcohol intake) was assessed at their initial assessment visit using the Oxford WebQ questionnaire. These women were asked to recall if they consumed alcohol in the previous 24 hours, and if so the amount of red wine, rosé wine, white wine, fortified wine, beer or cider, spirits, and other alcoholic drinks consumed. Twenty-four hour alcohol intake in grams was calculated as described above.

Hormone assays

Hormones and SHBG were measured in blood samples collected at recruitment, using chemiluminescent immunoassays. Detailed information on the assay data has been reported elsewhere (18, 19). The coefficients of variation derived from the internal quality control data are also presented in Supplementary Table S1. Concentrations of free testosterone and free estradiol were calculated based on the law of mass action (20).

Some women had missing assay results for a given hormone due to a very low serum concentration (6% and 18%, respectively, for testosterone in pre- and postmenopausal women; <1% for SHBG and IGF-1; and 20% for estradiol in premenopausal women). These women were included in the analyses by setting the concentration at three quarters of the minimum reportable value. The minimum reportable values were 0.35 nmol/L for testosterone, 0.33 nmol/L for SHBG, 1.30 nmol/L for IGF-1 and 175 pmol/L for estradiol (18). Note that the expected median concentration of estradiol is ∼150 pmol/L in the early follicular phase (21). The estradiol data were not available for postmenopausal women because almost all of them had a concentration below the minimum reportable value of 175 pmol/L. A small proportion of women (<1%) had missing assay results for SHBG due to a very high serum concentration, and for these women the concentration was set at the maximum reportable value of 242 nmol/L (18).

Statistical analysis

Analyses were undertaken separately for pre- and postmenopausal women (at recruitment). STATA 16 (StataCorp) was used for all analyses.

Hormone concentrations were logarithmically transformed. In premenopausal women, concentrations were then standardized for day of the menstrual cycle with residuals from the mean for each day as described previously (7). Multivariable regression analysis was performed to compare geometric mean concentrations across the categories of habitual alcohol intake. The multivariable models were adjusted for age at recruitment (in 2-year categories for premenopausal women and in 5-year categories for postmenopausal women), ethnicity (White, Black, Asian, and mixed/others), smoking (never, past, current ≤10 cigarettes/day, current >10 cigarettes/day), body mass index (BMI; <22.5 kg/m2, 22.5–24.9 kg/m2, 25–27.4 kg/m2, 27.5–29.9 kg/m2, 30–34.9 kg/m2, ≥35 kg/m2), age at menopause (i.e., when periods stopped; <45 years, 45–49 years, 50–54 years, ≥55 years; postmenopausal women only), time of day of sample collection (hourly from 9:00 am to 8:00 pm) and quintiles of Townsend deprivation index (measure of material deprivation calculated based on postcode and data from the 2001 Census). The impact on the main findings of adjustment for other variables such as intakes of meat, fish, fruit and vegetable, parity, and time since last OCP/HRT use was also assessed in sensitivity analyses.

In women who reported drinking alcohol, trends in hormone concentrations and 95% confidence intervals (CI) per 10 g/day of habitual alcohol intake were estimated using the mean alcohol intake within each category of habitual alcohol intake. The multivariable models were adjusted as described above, and the Ptrend and Pheterogeneity were calculated.

Similar analyses were undertaken for intakes of alcohol from different drinks (wine, beer or cider, and spirits or liqueur), and these models were also adjusted for the intake of alcohol from other alcoholic drinks. Subgroup analyses were undertaken by smoking status at recruitment (never, past, and current) and by age groups (≤45 vs. >45 years in premenopausal women and ≤60 vs. >60 years in postmenopausal women). In premenopausal women, subgroup analyses were also undertaken by phase of the menstrual cycle. As time since last menstrual period was assessed using the question “How many days since your last menstrual period?” it was assumed that the days were counted from the last day of the most recent period and that the period lasted for three days [the 3-day period was chosen because this provided the distribution of estradiol concentrations across cycle phases similar to that observed previously (7)]. Cycle phases were defined by forward dating as: early follicular = days 0–5, late follicular = days 6–10, mid-cycle = days 11–14, early luteal = days 15–18, mid-luteal = days 19–24, and late luteal = days ≥25 (7). Sensitivity analyses were undertaken, which excluded women with self-reported endocrine disorders, those with irregular menstrual cycles (premenopausal women only) at recruitment and those with a concentration of testosterone or estradiol (premenopausal women only) which was below the reportable range.

In order to assess whether 24-hour alcohol intake was more predictive of serum hormone concentrations, the regression coefficients and 95% CI per 10 g of 24-hour alcohol intake were estimated in a subsample of women who completed the Oxford WebQ questionnaire on the day of recruitment. Subgroup analyses were also undertaken by time of day of blood collection (noon or earlier vs. after noon).

In total, 30,557 premenopausal and 134,029 postmenopausal women were included, of whom 28,180 and 120,309, respectively, reported drinking alcohol. Table 1 presents characteristics of the study participants.

Table 1.

Participant characteristics.

PremenopausalPostmenopausal
All (N = 30,557)Current drinkers (N = 28,180)All (N = 134,031)Current drinkers (N = 120,309)
Age at recruitment (years), mean (SD) 44.7 (2.7) 44.7 (2.7) 60.5 (5.3) 60.4 (5.3) 
White, % 90.8 93.1 95.5 96.7 
Townsend deprivation scoresa, median (IQR) −1.8 (4.5) −1.9 (4.3) −2.3 (3.9) −2.4 (3.7) 
Habitual alcohol intake (g/day), mean (SD) 10.7 (12.8) 11.6 (12.9) 9.4 (11.4) 10.4 (11.6) 
Current smoker, % 11 11.2 7.9 7.9 
Body mass index (kg/m2), mean (SD) 26.3 (5.2) 26.2 (5.2) 27.3 (5.1) 27.2 (5.0) 
Presence of self-reported endocrine disorder(s), % 6.7 6.4 14.1 13.2 
Age at menopause (years), mean (SD) — — 49.5 (5.7) 49.6 (5.6) 
Total testosterone (nmol/L), median (IQR) 1.12 (0.71) 1.12 (0.71) 0.85 (0.74) 0.86 (0.73) 
Calculated free testosterone (pmol/L), median (IQR) 12.5 (10.3) 12.5 (10.2) 10.5 (10.8) 10.5 (10.7) 
SHBG (nmol/L), median (IQR) 62.9 (38.3) 63.3 (37.8) 53.5 (33.6) 53.6 (33.2) 
IGF-1 (nmol/L), median (IQR) 23.4 (6.9) 23.4 (6.8) 20.0 (7.1) 20.1 (7.1) 
Total estradiol (pmol/L), median (IQR) 343.9 (368.1) 347.2 (364.8) — — 
Calculated free estradiol (pmol/L) median (IQR) 4.07 (4.30) 4.04 (4.19) — — 
PremenopausalPostmenopausal
All (N = 30,557)Current drinkers (N = 28,180)All (N = 134,031)Current drinkers (N = 120,309)
Age at recruitment (years), mean (SD) 44.7 (2.7) 44.7 (2.7) 60.5 (5.3) 60.4 (5.3) 
White, % 90.8 93.1 95.5 96.7 
Townsend deprivation scoresa, median (IQR) −1.8 (4.5) −1.9 (4.3) −2.3 (3.9) −2.4 (3.7) 
Habitual alcohol intake (g/day), mean (SD) 10.7 (12.8) 11.6 (12.9) 9.4 (11.4) 10.4 (11.6) 
Current smoker, % 11 11.2 7.9 7.9 
Body mass index (kg/m2), mean (SD) 26.3 (5.2) 26.2 (5.2) 27.3 (5.1) 27.2 (5.0) 
Presence of self-reported endocrine disorder(s), % 6.7 6.4 14.1 13.2 
Age at menopause (years), mean (SD) — — 49.5 (5.7) 49.6 (5.6) 
Total testosterone (nmol/L), median (IQR) 1.12 (0.71) 1.12 (0.71) 0.85 (0.74) 0.86 (0.73) 
Calculated free testosterone (pmol/L), median (IQR) 12.5 (10.3) 12.5 (10.2) 10.5 (10.8) 10.5 (10.7) 
SHBG (nmol/L), median (IQR) 62.9 (38.3) 63.3 (37.8) 53.5 (33.6) 53.6 (33.2) 
IGF-1 (nmol/L), median (IQR) 23.4 (6.9) 23.4 (6.8) 20.0 (7.1) 20.1 (7.1) 
Total estradiol (pmol/L), median (IQR) 343.9 (368.1) 347.2 (364.8) — — 
Calculated free estradiol (pmol/L) median (IQR) 4.07 (4.30) 4.04 (4.19) — — 

Abbreviations: IQR, interquartile range; SD, standard deviation.

aNegative values indicate relatively more affluent areas.

Total and calculated free testosterone

In both pre- and postmenopausal women, habitual alcohol intake was positively associated with testosterone concentrations (Table 2; Fig. 1; Supplementary Table S2). The geometric mean concentrations of total testosterone in the highest alcohol intake category (≥40 g/day) were 0.21 nmol/L (premenopausal) and 0.07 nmol/L (postmenopausal) higher than in those who consumed <1 g/day, and the concentrations of calculated free testosterone were 2.3 pmol/L (premenopausal) and 1.6 pmol/L (postmenopausal) higher (Fig. 1; Supplementary Table S2). The association of alcohol intake with total testosterone was significantly greater in premenopausal than in postmenopausal women (Pheterogeneity < 0.0001).

Table 2.

Associations of habitual alcohol intake (per 10 g/day increment) with hormones and SHBG in pre- and postmenopausal women.

NAge-adjusted percent change (95% CI)aMultivariable-adjusted percent change (95% CI)bPtrendPheterogeneity
Total testosterone 
 Premenopausal 28,180 4.2 (3.6–4.9) 3.9 (3.3–4.5) <0.0001 <0.0001 
 Postmenopausal 120,309 1.7 (1.3–2.1) 2.3 (1.8–2.7) <0.0001  
Calculated free testosterone 
 Premenopausal 28,180 3.5 (2.8–4.2) 3.5 (2.8–4.2) <0.0001 0.4 
 Postmenopausal 120,309 2.2 (1.7–2.6) 3.9 (3.5–4.4) <0.0001  
SHBG 
 Premenopausal 28,180 1.2 (0.7–1.7) 0.7 (0.2–1.1) 0.002 <0.0001 
 Postmenopausal 120,309 −0.8 (−1.0 to −0.5) −2.4 (−2.6 to −2.2) <0.0001  
IGF-1 
 Premenopausal 28,180 −1.7 (−1.9 to −1.5) −1.9 (−2.1 to −1.7) <0.0001 <0.0001 
 Postmenopausal 120,309 −0.4 (−0.5 to −0.2) −0.8 (−0.9 to −0.6) <0.0001  
Total estradiol 
 Premenopausal 28,180 0.3 (−0.5 to 1.0) 0.5 (−0.3 to 1.3) 0.2 — 
Calculated free estradiol 
 Premenopausal 28,180 −0.3 (−1.0 to 0.5) 0.2 (−0.5 to 1.0) 0.6 — 
NAge-adjusted percent change (95% CI)aMultivariable-adjusted percent change (95% CI)bPtrendPheterogeneity
Total testosterone 
 Premenopausal 28,180 4.2 (3.6–4.9) 3.9 (3.3–4.5) <0.0001 <0.0001 
 Postmenopausal 120,309 1.7 (1.3–2.1) 2.3 (1.8–2.7) <0.0001  
Calculated free testosterone 
 Premenopausal 28,180 3.5 (2.8–4.2) 3.5 (2.8–4.2) <0.0001 0.4 
 Postmenopausal 120,309 2.2 (1.7–2.6) 3.9 (3.5–4.4) <0.0001  
SHBG 
 Premenopausal 28,180 1.2 (0.7–1.7) 0.7 (0.2–1.1) 0.002 <0.0001 
 Postmenopausal 120,309 −0.8 (−1.0 to −0.5) −2.4 (−2.6 to −2.2) <0.0001  
IGF-1 
 Premenopausal 28,180 −1.7 (−1.9 to −1.5) −1.9 (−2.1 to −1.7) <0.0001 <0.0001 
 Postmenopausal 120,309 −0.4 (−0.5 to −0.2) −0.8 (−0.9 to −0.6) <0.0001  
Total estradiol 
 Premenopausal 28,180 0.3 (−0.5 to 1.0) 0.5 (−0.3 to 1.3) 0.2 — 
Calculated free estradiol 
 Premenopausal 28,180 −0.3 (−1.0 to 0.5) 0.2 (−0.5 to 1.0) 0.6 — 

aAdjusted for age.

bAs above + adjusted for ethnicity, smoking, BMI, presence of endocrine disorder(s), age at menopause (postmenopause), time of day of sample collection and deprivation. Ptrend and Pheterogeneity were calculated from this model.

Figure 1.

Geometric mean concentrations of hormones and SHBG by categories of habitual alcohol intake in pre- and postmenopausal women. Geometric mean concentrations adjusted for age, ethnicity, smoking, BMI, presence of endocrine disorder(s), age at menopause (postmenopause), time of day of sample collection and deprivation, and plotted against the mean alcohol intake within each category.

Figure 1.

Geometric mean concentrations of hormones and SHBG by categories of habitual alcohol intake in pre- and postmenopausal women. Geometric mean concentrations adjusted for age, ethnicity, smoking, BMI, presence of endocrine disorder(s), age at menopause (postmenopause), time of day of sample collection and deprivation, and plotted against the mean alcohol intake within each category.

Close modal

Similar associations were observed for intakes of alcohol from wine, beer or cider, and spirits or liqueur (Supplementary Table S3). In premenopausal women, there were no significant differences in the associations by smoking status (Supplementary Table S4), by age (Supplementary Table S5), or by phase of the menstrual cycle (Supplementary Table S6). In postmenopausal women, the association for calculated free testosterone was greater in current smokers (Pheterogeneity = 0.03; Supplementary Table S4).

SHBG

In premenopausal women, there was a weak positive association between habitual alcohol intake and SHBG concentration (Table 2; Fig. 1; and Supplementary Table S2). Compared with women who consumed <1 g/day, those who consumed ≥40 g/day had a 2.0 nmol/L higher concentration of SHBG (Fig. 1; Supplementary Table S2). The concentration was 0.7% (95% CI: 0.2%–1.1%) higher per 10 g/day increment in alcohol intake (Table 2). In contrast, there was a significant inverse association with SHBG in postmenopausal women (Table 2; Fig. 1; Supplementary Table S2). Women who consumed ≥40 g/day had a 5.7 nmol/L lower concentration of SHBG than those who consumed <1 g/day (Fig. 1; Supplementary Table S2). The concentration was 2.4% (95% CI: 2.2%–2.6%) lower per 10 g/day increment in alcohol intake (Table 2). The associations observed in pre- and postmenopausal women were significantly different (Pheterogeneity < 0.0001).

Similar associations were observed for intakes of alcohol from wine, beer or cider, and spirits or liqueur (Supplementary Table S3). The positive association in premenopausal women was greater in never smokers (Pheterogeneity = 0.02), whereas the inverse association in postmenopausal women was greater in current smokers (Pheterogeneity = 0.005; Supplementary Table S4). There were no significant differences in the associations by age (Supplementary Table S5) or by phase of the menstrual cycle (Supplementary Table S6).

IGF-1

In both pre- and postmenopausal women, there was a significant inverse association between habitual alcohol intake and IGF-1 concentration (Table 2; Fig. 1; Supplementary Table S2). The concentration was 2.5 nmol/L and 1.0 nmol/L lower, respectively, in pre- and postmenopausal women who consumed ≥40 g/day compared with those who consumed <1g/day (Fig. 1; Supplementary Table S2). Per 10 g/day increment in alcohol intake, the concentration was 1.9% (95% CI: 1.7%–2.1%) lower in premenopausal women and 0.8% (95% CI: 0.6%–0.9%) lower in postmenopausal women (Table 2). The association was significantly greater in premenopausal women (Pheterogeneity < 0.0001).

Similar associations were observed for intakes of alcohol from wine, beer or cider, and spirits or liqueur (Supplementary Table S3). In premenopausal women, there were no significant differences in the associations by smoking status (Supplementary Table S4), by age (Supplementary Table S5), or by phase of the menstrual cycle (Supplementary Table S6). The association in postmenopausal women was greater in those aged under 60 years (Pheterogeneity = 0.01; Supplementary Table S5).

Total and calculated free estradiol

The estradiol results were available for premenopausal women only. There was no significant overall association with habitual alcohol intake (Table 2; Fig. 1; Supplementary Tables S2–S5). However, in subgroup analyses by phase of the menstrual cycle, a significant positive association was observed in the early and mid-luteal phases (Pheterogeneity = 0.046 for total estradiol and 0.06 for calculated free estradiol; Supplementary Table S6); per 10 g/day increment in alcohol intake, the concentration of total estradiol was 1.9% (95% CI: 0.2%–3.6%) and 2.4% (95% CI: 0.7%–4.2%) higher, respectively, in the early and mid-luteal phases, and that of calculated free estradiol was 1.8% (95% CI: 0.1%–3.5%) higher in both phases.

Sensitivity analyses

Further adjustment for diet, parity and time since last OCP/HRT use did not have any material effect on the findings. Similar associations were observed after excluding women with self-reported endocrine disorders, premenopausal women with irregular menstrual cycles, and premenopausal women with a concentration of estradiol that was below the reportable range (Supplementary Table S7). The associations were slightly weaker after excluding women with a concentration of testosterone that was below the reportable range.

Alcohol intake in the 24 hours before blood sampling

This analysis was restricted to a subsample of 4,751 pre- and 18,754 postmenopausal women who completed the Oxford WebQ questionnaire on the day of recruitment. Supplementary Table S8 presents characteristics of these women. The associations with 24-hour alcohol intake were slightly weaker compared with habitual alcohol intake (Supplementary Table S9). There were no significant differences in the associations by time of day of sample collection (Supplementary Table S10).

In this study, involving over 160,000 women, there were significant associations of habitual alcohol intake with serum concentrations of hormones and SHBG, with evidence of heterogeneity by menopausal status.

Total and calculated free testosterone

We found a positive association between habitual alcohol intake and testosterone concentrations in both pre- and postmenopausal women, as observed in previous collaborative reanalyses of data from seven prospective studies in premenopausal women (7) and 13 prospective studies in postmenopausal women (13). The stronger associations in premenopausal women have also been reported in a previous analysis of the EPIC (European Prospective Investigation into Cancer and Nutrition) cohort (22).

An acute elevation in testosterone concentrations after alcohol intake has been reported in some intervention studies (23–25), although no significant change was observed in others (26, 27). However, in the current analysis, the associations with 24-hour alcohol intake were weaker than those for habitual intake; we may have had limited power to detect a short-term effect because alcohol is mostly consumed in the evening and the half-life of testosterone is short (20–100 minutes; ref. 28).

The physiologic mechanisms underlying the observed associations between alcohol intake and testosterone concentrations are not well understood. It has been proposed that alcohol may increase testosterone concentrations by stimulating its secretion from the ovaries and adrenal glands or by inhibiting its metabolism in the liver (29).

SHBG

We found a weak positive association between habitual alcohol intake and SHBG concentration in premenopausal women but a stronger inverse association in postmenopausal women. A similar positive association in premenopausal women was observed in the Nurses' Health Study II (30), but the association was not significant in a collaborative reanalysis of data from seven prospective studies (7). The evidence in postmenopausal women was more consistent; alcohol intake has been inversely associated with SHBG in a previous collaborative reanalysis of data from 13 prospective studies (13).

In this analysis, we did not find a stronger association of SHBG with 24-hour alcohol intake. Similarly, no significant change in SHBG concentration after alcohol intake was observed in earlier intervention studies (26, 27).

SHBG is synthesized in the liver, and its plasma concentration is regulated by estrogens, androgens, insulin, and other hormones (31) as well as by pro- and anti-inflammatory cytokines (32). It is possible that alcohol influences SHBG concentration by affecting hormonal balance, altering cytokine levels, increasing hepatic synthesis/release, or decreasing blood clearance (33, 34), but the exact mechanism is unknown.

IGF-1

We found an inverse association between habitual alcohol intake and IGF-1 concentration in both pre- and postmenopausal women. A similar association has been shown in a previous collaborative reanalysis of data from 17 prospective studies (9), and a lower IGF-1 concentration in heavy alcohol consumers has been reported (35–37). A decline in the IGF-1 concentration after daily intake of alcohol for 2 to 3 months has also been shown in previous cross-over trials (38, 39).

An acute decline in IGF-1 concentration within hours after alcohol intake has been reported in a previous intervention study (40). As the half-life of IGF-1 is 16 hours or more (41), we hypothesized that we might see a bigger association with alcohol intake in the previous day, but it was weaker than that of habitual intake.

IGF-1 is synthesized in the liver, and its circulating concentration is regulated by growth hormones and to a lesser extent by insulin and nutritional status (42). Higher alcohol intake may decrease IGF-1 through its inhibitory effect on growth hormone secretion (43), liver dysfunction (35), and/or malnutrition.

Total and calculated free estradiol in premenopausal women

Alcohol intake has been positively associated with estradiol concentrations in a previous collaborative reanalysis of data from seven prospective studies (7). We found no significant overall association with total or calculated free estradiol, but in our subgroup analyses by phase of the menstrual cycle, there was a positive association in the early and mid-luteal phases. Variations by cycle phase have also been reported but the results varied; a positive association with luteal estradiol was reported in the Nurses' Health Study II (30), but in an earlier cross-over trial, after daily intake of 30 g of alcohol for three consecutive menstrual cycles, a significant increase in estradiol concentration (27.5%) was observed only at mid-cycle (26).

We did not find any significant association of estradiol with 24-hour alcohol intake, but a short-term increase in concentration after alcohol intake has been reported in earlier intervention studies (44, 45). We may have missed this potential association because the half-life of estradiol is short (∼3 hours; ref. 46).

Alcohol may influence estradiol concentration by altering its metabolism and clearance (44, 45, 47) or by affecting aromatization of androgens to estrogens (48). The overall null finding in our analysis may be due to certain limitations in the data for estradiol. First, the chemiluminescent immunoassays used in the UK Biobank were not as sensitive as more specialized assays for estradiol (49), the assay CV (coefficient of variation) at the concentrations we observed was relatively high (∼15%), and serum concentrations were too low to be measured by the assay in 20% of premenopausal women; we included these women in our analyses by setting the concentration at three quarters of the minimum reportable value, but this approach would be expected to reduce statistical power. Second, because the date of the menstrual period following blood collection was not recorded, it was not possible to use backward dating to define cycle phase, which is a more reliable categorization (50).

Potential role of hormones in alcohol-induced breast carcinogenesis

Alcohol has been judged to be a carcinogen for many cancer sites including female breast cancer (3). The increase in risk is of moderate size, for example, previous analysis of the Million Women Study reported that the relative risk of breast cancer was 1.12 per 10 g/day increment in alcohol intake (12).

In this analysis, we found positive associations between alcohol intake and testosterone concentrations, but on the basis of the results from our previous analysis of the UK Biobank data (10), the difference in total testosterone concentrations between women who consumed ≥40 g/day of alcohol and those who consumed <1 g/day (0.21 nmol/L higher in premenopausal women and 0.07 nmol/L higher in postmenopausal women) would only predict an approximately 1.3% (premenopausal) and 2.3% (postmenopausal) higher risk of breast cancer. For SHBG, we observed a weak positive association in premenopausal women and an inverse association in postmenopausal women; the latter could possibly contribute to the increase in risk in postmenopausal women by increasing the proportion of free estradiol. For IGF-I, the association with alcohol intake was inverse; therefore, it is not likely to explain the higher cancer risk associated with alcohol intake. For estradiol, we found positive associations with alcohol intake in the early and mid-luteal phases. The associations were modest in this analysis possibly due to the limitations of data on this hormone but given a bigger effect observed in an earlier cross-over trial, estradiol is likely to make some contribution to the increase in cancer risk associated with alcohol intake in premenopausal women.

Overall, our findings suggest that the hormones we assessed are unlikely to explain all of the association between alcohol and breast cancer risk, but we did not have a comprehensive assessment of all potentially relevant hormones; therefore, no firm conclusion can be drawn. The published evidence suggests a slightly bigger effect of alcohol intake on ER (estrogen receptor) positive breast cancer than on ER-negative breast cancer (51, 52), which may support the potential role of hormones in alcohol-induced breast carcinogenesis. However, alcohol intake has also been associated with some increase in the risk of ER-negative breast cancer (except ER-negative progesterone receptor–negative breast cancer; refs. 51, 52), suggesting that other nonhormonal mechanisms may also be relevant.

Strengths and limitations

The main strength of this study is the very large sample size with hormones measured for the full cohort. The limitations of the data on estradiol and phase of the menstrual cycle have been discussed above. A similar limitation applies to the testosterone assay, for which 16% of women had values below the lower limit of detection; this would be expected to limit the statistical power. Other limitations include the cross-sectional design, use of self-reported alcohol intake, use of blood samples collected at a single point in time, the lack of data on other hormones such as progesterone and androgens other than testosterone, and the study sample comprising predominantly white women aged over 40 years.

Conclusions

The findings from this large study confirm significant but modest associations of alcohol with hormones and SHBG. The hormones we assessed are unlikely to explain all of the effects of alcohol on breast cancer risk, suggesting that other hormonal and nonhormonal mechanisms may also be important.

S. Tin Tin reports grants from Health Research Council of New Zealand during the conduct of the study. T.J. Key and G.K. Reeves report grants from Cancer Research UK during the conduct of the study.

S. Tin Tin: Conceptualization, formal analysis, funding acquisition, writing–original draft. T.J. Key: Conceptualization, resources, data curation, supervision, funding acquisition, writing–review and editing. G.K. Reeves: Conceptualization, resources, data curation, supervision, funding acquisition, writing–review and editing.

This research has been conducted using the UK Biobank resource under application number 3248. We wish to express our gratitude to the participants and those involved in building the resource. S. Tin Tin is supported by the Girdlers' New Zealand Health Research Council Fellowship (19/031). This research is also supported by Cancer Research UK (C570/A16491 and C8221/A29017).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1.
Manthey
J
,
Shield
KD
,
Rylett
M
,
Hasan
OSM
,
Probst
C
,
Rehm
J
. 
Global alcohol exposure between 1990 and 2017 and forecasts until 2030: a modelling study
.
Lancet
2019
;
393
:
2493
502
.
2.
Griswold
MG
,
Fullman
N
,
Hawley
C
,
Arian
N
,
Zimsen
SRM
,
Tymeson
HD
, et al
Alcohol use and burden for 195 countries and territories, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016
.
Lancet
2018
;
392
:
1015
35
.
3.
Baan
R
,
Straif
K
,
Grosse
Y
,
Secretan
B
,
El Ghissassi
F
,
Bouvard
V
, et al
Carcinogenicity of alcoholic beverages
.
Lancet Oncol
2007
;
8
:
292
3
.
4.
Seitz
HK
,
Stickel
F
. 
Molecular mechanisms of alcohol-mediated carcinogenesis
.
Nat Rev Cancer
2007
;
7
:
599
612
.
5.
Ratna
A
,
Mandrekar
P
. 
Alcohol and cancer: mechanisms and therapies
.
Biomolecules
2017
;
7
:
61
.
6.
Henderson
BE
,
Feigelson
HS
. 
Hormonal carcinogenesis
.
Carcinogenesis
2000
;
21
:
427
33
.
7.
Key
TJ
,
Appleby
PN
,
Reeves
GK
,
Travis
RC
,
Alberg
AJ
,
Barricarte
A
, et al
Sex hormones and risk of breast cancer in premenopausal women: a collaborative reanalysis of individual participant data from seven prospective studies
.
Lancet Oncol
2013
;
14
:
1009
19
.
8.
Key
TJ
,
Appleby
PN
,
Reeves
GK
,
Travis
RC
,
Brinton
LA
,
Helzlsouer
KJ
, et al
Steroid hormone measurements from different types of assays in relation to body mass index and breast cancer risk in postmenopausal women: reanalysis of eighteen prospective studies
.
Steroids
2015
;
99
:
49
55
.
9.
Key
TJ
,
Appleby
PN
,
Reeves
GK
,
Roddam
AW
. 
Insulin-like growth factor 1 (IGF1), IGF binding protein 3 (IGFBP3), and breast cancer risk: pooled individual data analysis of 17 prospective studies
.
Lancet Oncol
2010
;
11
:
530
42
.
10.
Tin Tin
S
,
Reeves
GK
,
Key
TJ
. 
Endogenous hormones and risk of invasive breast cancer in pre- and post-menopausal women: findings from the UK Biobank
.
Br J Cancer
2021
;
125
:
126
34
.
11.
Collaborative Group on Hormonal Factors in Breast Cancer
. 
Alcohol, tobacco and breast cancer – collaborative reanalysis of individual data from 53 epidemiological studies, including 58 515 women with breast cancer and 95 067 women without the disease
.
Br J Cancer
2002
;
87
:
1234
45
.
12.
Allen
NE
,
Beral
V
,
Casabonne
D
,
Kan
SW
,
Reeves
GK
,
Brown
A
, et al
Moderate alcohol intake and cancer incidence in women
.
J Natl Cancer Inst
2009
;
101
:
296
305
.
13.
Key
TJ
,
Appleby
PN
,
Reeves
GK
,
Roddam
AW
,
Helzlsouer
KJ
,
Alberg
AJ
, et al
Circulating sex hormones and breast cancer risk factors in postmenopausal women: reanalysis of 13 studies
.
Br J Cancer
2011
;
105
:
709
22
.
14.
Allen
N
,
Sudlow
C
,
Downey
P
,
Peakman
T
,
Danesh
J
,
Elliott
P
, et al
UK Biobank: current status and what it means for epidemiology
.
Health Policy Technol
2012
;
1
:
123
6
.
15.
UK Biobank touch-screen questionnaire: final version
.
Available from:
https://biobank.ndph.ox.ac.uk/ukb/ukb/docs/TouchscreenQuestionsMainFinal.pdf.
16.
Greenwood
DC
,
Hardie
LJ
,
Frost
GS
,
Alwan
NA
,
Bradbury
KE
,
Carter
M
, et al
Validation of the Oxford WebQ online 24-hour dietary questionnaire using biomarkers
.
Am J Epidemiol
2019
;
188
:
1858
67
.
18.
Fry
D
,
Almond
R
,
Moffat
S
,
Gordon
M
,
Singh
P
. 
UK Biobank Biomarker Project: companion document to accompany serum biomarker data
.
Available from:
https://biobank.ndph.ox.ac.uk/showcase/showcase/docs/serum_biochemistry.pdf.
19.
Allen
N
,
Arnold
M
,
Parish
S
,
Hill
M
,
Sheard
S
,
Callen
H
, et al
Approaches to minimising the epidemiological impact of sources of systematic and random variation that may affect biochemistry assay data in UK Biobank
.
Wellcome Open Res
2021
;
5
:
222
.
20.
Bartsch
W
. 
Interrelationships between sex hormone-binding globulin and testosterone, 5α-dihydrotestosterone and oestradiol-7β in blood of normal men
.
Maturitas
1980
;
2
:
109
18
.
21.
Stricker
R
,
Eberhart
R
,
Chevailler
MC
,
Quinn
FA
,
Bischof
P
,
Stricker
R
. 
Establishment of detailed reference values for luteinizing hormone, follicle stimulating hormone, estradiol, and progesterone during different phases of the menstrual cycle on the Abbott ARCHITECT analyzer
.
Clin Chem Lab Med
2006
;
44
:
883
7
.
22.
Rinaldi
S
,
Peeters
PHM
,
Bezemer
ID
,
Dossus
L
,
Biessy
C
,
Sacerdote
C
, et al
Relationship of alcohol intake and sex steroid concentrations in blood in pre- and post-menopausal women: the European Prospective Investigation into Cancer and Nutrition
.
Cancer Causes Control
2006
;
17
:
1033
43
.
23.
Sarkola
T
,
Adlercreutz
H
,
Heinonen
S
,
von der Pahlen
B
,
Eriksson
CJP
. 
The role of the liver in the acute effect of alcohol on androgens in women
.
J Clin Endocrinol Metab
2001
;
86
:
1981
5
.
24.
Sarkola
T
,
Fukunaga
T
,
Mäkisalo
H
,
Eriksson
CJP
. 
Acute effect of alcohol on androgens in premenopausal women
.
Alcohol Alcohol
2000
;
35
:
84
90
.
25.
Eriksson
CJP
,
Fukunaga
T
,
Lindman
R
. 
Sex hormone response to alcohol
.
Nature
1994
;
369
:
711
.
26.
Reichman
ME
,
Judd
JT
,
Longcope
C
,
Schatzkin
A
,
Clevidence
BA
,
Nair
PP
, et al
Effects of alcohol consumption on plasma and urinary hormone concentrations in premenopausal women
.
J Natl Cancer Inst
1993
;
85
:
722
7
.
27.
Dorgan
JF
,
Baer
DJ
,
Albert
PS
,
Judd
JT
,
Brown
ED
,
Corle
DK
, et al
Serum hormones and the alcohol-breast cancer association in postmenopausal women
.
J Natl Cancer Inst
2001
;
93
:
710
5
.
28.
Ruiz-Cortés
ZT
. 
Gonadal sex steroids: production, action and interactions in mammals
.
In:
Ostojic
SM
,
editor
.
Steroids – from physiology to clinical medicine
.
London
:
IntechOpen
; 
2012
;
p.
3
44
.
29.
Dorgan
JF
,
Reichman
ME
,
Judd
JT
,
Brown
C
,
Longcope
C
,
Schatzkin
A
, et al
The relation of reported alcohol ingestion to plasma levels of estrogens and androgens in premenopausal women (Maryland, United States)
.
Cancer Causes Control
1994
;
5
:
53
60
.
30.
Hirko
KA
,
Spiegelman
D
,
Willett
WC
,
Hankinson
SE
,
Eliassen
AH
. 
Alcohol consumption in relation to plasma sex hormones, prolactin, and sex hormone–binding globulin in premenopausal women
.
Cancer Epidemiol Biomarkers Prev
2014
;
23
:
2943
53
.
31.
Selby
C
. 
Sex hormone binding globulin: origin, function and clinical significance
.
Ann Clin Biochem
1990
;
27
:
532
41
.
32.
Simó
R
,
Sáez-López
C
,
Barbosa-Desongles
A
,
Hernández
C
,
Selva
DM
. 
Novel insights in SHBG regulation and clinical implications
.
Trends Endocrinol Metab
2015
;
26
:
376
83
.
33.
Achur
RN
,
Freeman
WM
,
Vrana
KE
. 
Circulating cytokines as biomarkers of alcohol abuse and alcoholism
.
J Neuroimmune Pharmacol
2010
;
5
:
83
91
.
34.
Iturriaga
H
,
Lioi
X
,
Valladares
L
. 
Sex hormone binding globulin in non-cirrhotic alcoholic patients during early withdrawal and after longer abstinence
.
Alcohol Alcohol
1999
;
34
:
903
9
.
35.
Santolaria
F
,
González-González
G
,
González-Reimers
E
,
Martínez-Riera
A
,
Milena
A
,
Rodgíguez-Moreno
F
, et al
Effects of alcohol and liver cirrhosis on the GH-IGF-I axis
.
Alcohol Alcohol
1995
;
30
:
703
8
.
36.
García-Marchena
N
,
Silva-Peña
D
,
Martín-Velasco
AI
,
Villanúa
,
Araos
P
,
Pedraz
M
, et al
Decreased plasma concentrations of BDNF and IGF-1 in abstinent patients with alcohol use disorders
.
PLoS One
2017
;
12
:
e0187634
.
37.
Röjdmark
S
,
Brismar
K
. 
Decreased IGF-I bioavailability after ethanol abuse in alcoholics: Partial restitution after short-term abstinence
.
J Endocrinol Invest
2001
;
24
:
476
82
.
38.
Lavigne
JA
,
Baer
DJ
,
Wimbrow
HH
,
Albert
PS
,
Brown
ED
,
Judd
JT
, et al
Effects of alcohol on insulin-like growth factor I and insulin-like growth factor binding protein 3 in postmenopausal women
.
Am J Clin Nutr
2005
;
81
:
503
7
.
39.
Lavigne
JA
,
Wimbrow
HH
,
Clevidence
BA
,
Albert
PS
,
Reichman
ME
,
Campbell
WS
, et al
Effects of alcohol and menstrual cycle on insulin-like growth factor-I and insulin-like growth factor binding protein-3
.
Cancer Epidemiol Biomarkers Prev
2004
;
13
:
2264
7
.
40.
Röjdmark
S
,
Rydvald
Y
,
Aquilonius
A
,
Brismar
K
. 
Insulin-like growth factor (IGF)-1 and IGF-binding protein-1 concentrations in serum of normal subjects after alcohol ingestion: evidence for decreased IGF-1 bioavailability
.
Clin Endocrinol
2000
;
52
:
313
8
.
41.
Allard
JB
,
Duan
C
. 
IGF-binding proteins: why do they exist and why are there so many?
Front Endocrinol
2018
;
9
:
117
.
42.
Froesch
ER
,
Zapf
J
. 
Insulin-like growth factors and insulin: comparative aspects
.
Diabetologia
1985
;
28
:
485
93
.
43.
Ekman
AC
,
Vakkuri
O
,
Ekman
M
,
Leppäluoto
J
,
Ruokonen
A
,
Knip
M
. 
Ethanol decreases nocturnal plasma levels of thyrotropin and growth hormone but not those of thyroid hormones or prolactin in man
.
J Clin Endocrinol Metab
1996
;
81
:
2627
32
.
44.
Välimäki
M
,
Härkönen
M
,
Ylikahri
R
. 
Acute effects of alcohol on female sex hormones
.
Alcohol Clin Exp Res
1983
;
7
:
289
93
.
45.
Mendelson
JH
,
Lukas
SE
,
Mello
NK
,
Amass
L
,
Ellingboe
J
,
Skupny
A
. 
Acute alcohol effects on plasma estradiol levels in women
.
Psychopharmacology
1988
;
94
:
464
7
.
46.
Ginsburg
ES
,
Gao
X
,
Shea
BF
,
Barbieri
RL
. 
Half-life of estradiol in postmenopausal women
.
Gynecol Obstet Invest
1998
;
45
:
45
8
.
47.
Ginsburg
ES
,
Walsh
BW
,
Shea
BF
,
Gao
X
,
Gleason
RE
,
Barbieri
RL
. 
The effects of ethanol on the clearance of estradiol in postmenopausal women
.
Fertil Steril
1995
;
63
:
1227
30
.
48.
Purohit
V
. 
Can alcohol promote aromatization of androgens to estrogens? A review
.
Alcohol
2000
;
22
:
123
7
.
49.
Newman
JD
,
Handelsman
DJ
. 
Challenges to the measurement of oestradiol: comments on an endocrine society position statement
.
Clin Biochem Rev
2014
;
35
:
75
9
.
50.
McIntosh
JE
,
Matthews
CD
,
Crocker
JM
,
Broom
TJ
,
Cox
LW
. 
Predicting the luteinizing hormone surge: relationship between the duration of the follicular and luteal phases and the length of the human menstrual cycle
.
Fertil Steril
1980
;
34
:
125
30
.
51.
Suzuki
R
,
Orsini
N
,
Mignone
L
,
Saji
S
,
Wolk
A
. 
Alcohol intake and risk of breast cancer defined by estrogen and progesterone receptor status–a meta-analysis of epidemiological studies
.
Int J Cancer
2008
;
122
:
1832
41
.
52.
Jung
S
,
Wang
M
,
Anderson
K
,
Baglietto
L
,
Bergkvist
L
,
Bernstein
L
, et al
Alcohol consumption and breast cancer risk by estrogen receptor status: in a pooled analysis of 20 studies
.
Int J Epidemiol
2016
;
45
:
916
28
.
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