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[Preprint]. 2023 Aug 16:rs.3.rs-3249588.
doi: 10.21203/rs.3.rs-3249588/v1.

Alcohol intake and endogenous sex hormones in women: meta-analysis of cohort studies and Mendelian randomization

Sandar Tin Tin  1 , Karl Smith-Byrne  1 , Pietro Ferrari  2 , Sabina Rinaldi  2 , Marjorie L McCullough  3 , Lauren R Teras  3 , Jonas Manjer  4 , Graham Giles  5 , Loïc Le Marchand  6 , Christopher A Haiman  7 , Lynne R Wilkens  6 , Yu Chen  8 , Sue Hankinson  9 , Shelley Tworoger  10 , A Heather Eliassen  11 , Walter C Willett  11 , Regina G Ziegler  12 , Barbara J Fuhrman  13 , Sabina Sieri  14 , Claudia Agnoli  14 , Jane Cauley  13 , Usha Menon  15 , Evangelia Ounia Fourkala  15 , Thomas E Rohan  16 , Rudolf Kaaks  17 , Gillian K Reeves  1 , Timothy J Key  1
Affiliations

Alcohol intake and endogenous sex hormones in women: meta-analysis of cohort studies and Mendelian randomization

Sandar Tin Tin et al. Res Sq. .

Update in

Abstract

Background: The mechanisms underlying alcohol-induced breast carcinogenesis are not fully understood but may involve hormonal changes.

Methods: We investigated cross-sectional associations between self-reported alcohol intake and serum or plasma concentrations of oestradiol, oestrone, progesterone (in pre-menopausal women only), testosterone, androstenedione, DHEAS (dehydroepiandrosterone sulphate) and SHBG (sex hormone binding globulin) in 45 431 pre-menopausal and 173 476 post-menopausal women. We performed multivariable linear regression separately for UK Biobank, EPIC (European Prospective Investigation into Cancer and Nutrition) and EHBCCG (Endogenous Hormones and Breast Cancer Collaborative Group), and meta-analysed the results. For testosterone and SHBG, we also conducted two-sample Mendelian Randomization (MR) and colocalisation using the ADH1B (Alcohol Dehydrogenase 1B) variant (rs1229984).

Results: Alcohol intake was positively, though weakly, associated with all hormones (except progesterone in pre-menopausal women), with increments in concentrations per 10 g/day increment in alcohol intake ranging from 1.7% for luteal oestradiol to 6.6% for post-menopausal DHEAS. There was an inverse association of alcohol with SHBG in post-menopausal women but a small positive association in pre-menopausal women. MR identified positive associations of alcohol intake with total testosterone (difference per 10 g/day increment: 4.1%; 95% CI: 0.6%, 7.6%) and free testosterone (7.8%; 4.1%, 11.5%), and an inverse association with SHBG (-8.1%; -11.3%, -4.9%). Colocalisation suggested a shared causal locus at ADH1B between alcohol intake and higher free testosterone and lower SHBG (PP4: 0.81 and 0.97 respectively).

Conclusions: Alcohol intake was associated with small increases in sex hormone concentrations, including bioavailable fractions, which may contribute to its effect on breast cancer risk.

Keywords: alcohol drinking; androgens; breast cancer; oestrogens; sex hormones.

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Conflict of interest statement

Declarations Competing interests The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1. Associations of usual alcohol intake (per 10 g/day increment) with hormones and SHBG in pre- and post-menopausal women
EPIC = European Prospective Investigation into Cancer and Nutrition; EHBCCG = Endogenous Hormones and Breast Cancer Collaborative Group DHEAS = Dehydroepiandrosterone sulphate; SHBG = Sex hormone binding globulin * Percent difference in concentrations of hormones and SHBG per 10 g/day increment in usual alcohol intake ** p-value for heterogeneity by menopausal status *** Relative difference in concentrations of hormones and SHBG per 10 g/day increment in usual alcohol intake
Figure 2
Figure 2. Associations of usual alcohol intake (per 10 g/day increment) with hormones and SHBG by phase of the menstrual cycle in pre-menopausal women
* Percent difference in concentrations of hormones and SHBG per 10 g/day increment in usual alcohol intake ** Relative difference in concentrations of hormones and SHBG per 10 g/day increment in usual alcohol intake
Figure 3
Figure 3. Associations of usual alcohol intake (per 10 g/day increment) with hormones and SHBG by assay type
EPIC = European Prospective Investigation into Cancer and Nutrition; EHBCCG = Endogenous Hormones and Breast Cancer Collaborative Group DHEAS = Dehydroepiandrosterone sulphate; SHBG = Sex hormone binding globulin * Percent difference in concentrations of hormones and SHBG per 10 g/day increment in usual alcohol intake ** Relative difference in concentrations of hormones and SHBG per 10 g/day increment in usual alcohol intake
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