Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Oct 8;24(1):66.
doi: 10.1186/s13058-022-01553-9.

Sex steroid hormones and risk of breast cancer: a two-sample Mendelian randomization study

Aayah Nounu  1 , Siddhartha P Kar  2 , Caroline L Relton  2 , Rebecca C Richmond  2
Affiliations

Sex steroid hormones and risk of breast cancer: a two-sample Mendelian randomization study

Aayah Nounu et al. Breast Cancer Res. .

Abstract

Background: Breast cancer (BC) has the highest cancer incidence and mortality in women worldwide. Observational epidemiological studies suggest a positive association between testosterone, estradiol, dehydroepiandrosterone sulphate (DHEAS) and other sex steroid hormones with postmenopausal BC. We used a two-sample Mendelian randomization analysis to investigate this association.

Methods: Genetic instruments for nine sex steroid hormones and sex hormone-binding globulin (SHBG) were obtained from genome-wide association studies (GWAS) of UK Biobank (total testosterone (TT) N: 230,454, bioavailable testosterone (BT) N: 188,507 and SHBG N: 189,473), The United Kingdom Household Longitudinal Study (DHEAS N: 9722), the LIFE-Adult and LIFE-Heart cohorts (estradiol N: 2607, androstenedione N: 711, aldosterone N: 685, progesterone N: 1259 and 17-hydroxyprogesterone N: 711) and the CORtisol NETwork (CORNET) consortium (cortisol N: 25,314). Outcome GWAS summary statistics were obtained from the Breast Cancer Association Consortium (BCAC) for overall BC risk (N: 122,977 cases and 105,974 controls) and subtype-specific analyses.

Results: We found that a standard deviation (SD) increase in TT, BT and estradiol increased the risk of overall BC (OR 1.14, 95% CI 1.09-1.21, OR 1.19, 95% CI 1.07-1.33 and OR 1.03, 95% CI 1.01-1.06, respectively) and ER + BC (OR 1.19, 95% CI 1.12-1.27, OR 1.25, 95% CI 1.11-1.40 and OR 1.06, 95% CI 1.03-1.09, respectively). An SD increase in DHEAS also increased ER + BC risk (OR 1.09, 95% CI 1.03-1.16). Subtype-specific analyses showed similar associations with ER+ expressing subtypes: luminal A-like BC, luminal B-like BC and luminal B/HER2-negative-like BC.

Conclusions: TT, BT, DHEAS and estradiol increase the risk of ER+ type BCs similar to observational studies. Understanding the role of sex steroid hormones in BC risk, particularly subtype-specific risks, highlights the potential importance of attempts to modify and/or monitor hormone levels in order to prevent BC.

Keywords: Breast cancer; Mendelian randomization; Sex steroid hormones.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Sex steroid hormone metabolism pathway. Metabolites/hormones are displayed in black text and the enzymes that catalyse the reaction are in blue text. The hormones that are investigated in this analysis are shown in purple boxes. This diagram was adapted from Pott et al. [37]
Fig. 2
Fig. 2
Forest plot showing the MR associations between sex hormones and overall, ER+ and ER–BC risk. IVW analysis was carried out to assess the association between an SD increase in total testosterone, bioavailable testosterone, SHBG, DHEAS, estradiol, androstenedione, aldosterone, cortisol, progesterone and 17-OHP on risk of incidence of overall BC (black), ER + BC (grey) and ER–BC (red). OR odds ratio, TT total testosterone, BT bioavailable testosterone, SHBG sex hormone-binding globulin, DHEAS dehydroepiandrosterone sulphate, E2 estradiol, ANDRO androstenedione, ALDO aldosterone, CORT cortisol, PROG progesterone, 17OHP 17-hydroxyprogesterone
Fig. 3
Fig. 3
Forest plot showing the MR associations between sex hormones and risk of six BC subtypes. IVW analysis was carried out to assess the association between an SD increase in total testosterone, bioavailable testosterone, SHBG, DHEAS, estradiol, androstenedione, aldosterone, cortisol, progesterone and 17-OHP on risk of luminal A BC (black), luminal B (grey), luminal B and HER2-negative BC (red), HER2-enriched BC (green), triple-negative BC (blue) and BRCA1 mutated triple-negative BC (purple). OR odds ratio, TT total testosterone, BT bioavailable testosterone, SHBG sex hormone-binding globulin, SHBG adjusted SHBG adjusted for BMI, DHEAS dehydroepiandrosterone sulphate, E2 estradiol, ANDRO androstenedione, ALDO aldosterone, CORT cortisol, PROG progesterone, 17OHP 17-hydroxyprogesterone, TNBC triple-negative BC
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71:1–41. doi: 10.3322/caac.21660. - DOI - PubMed
    1. Hamajima N, Hirose K, Tajima K, Rohan T, Friedenreich CM, Calle EE, et al. Menarche, menopause, and breast cancer risk: Individual participant meta-analysis, including 118 964 women with breast cancer from 117 epidemiological studies. Lancet Oncol. 2012;13(11):1141–1151. doi: 10.1016/S1470-2045(12)70425-4. - DOI - PMC - PubMed
    1. Chavez-MacGregor M, Elias SG, Charlotte Onland-Moret N, Van Der Schouw YT, Van GCH, Monninkhof E, et al. Postmenopausal breast cancer risk and cumulative number of menstrual cycles. Cancer Epidemiol Biomarkers Prev. 2005;14(4):799–804. doi: 10.1158/1055-9965.EPI-04-0465. - DOI - PubMed
    1. Atashgaran V, Wrin J, Barry SC, Dasari P, Ingman WV. Dissecting the biology of menstrual cycle-associated breast cancer risk. Front Oncol. 2016;6:267. doi: 10.3389/fonc.2016.00267. - DOI - PMC - PubMed
    1. Gierisch JM, Coeytaux RR, Urrutia RP, Havrilesky LJ, Moorman PG, Lowery WJ, et al. Oral contraceptive use and risk of breast, cervical, colorectal, and endometrial cancers: a systematic review. Cancer Epidemiol Biomarkers Prev. 2013;22(11):1931–1943. doi: 10.1158/1055-9965.EPI-13-0298. - DOI - PubMed

Publication types