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Epidemiology

Testosterone, sex hormone-binding globulin, insulin-like growth factor-1 and endometrial cancer risk: observational and Mendelian randomization analyses

British Journal of Cancer volume 125, pages 1308–1317 (2021)Cite this article

Subjects

Abstract

Background

Dysregulation of endocrine pathways related to steroid and growth hormones may modify endometrial cancer risk; however, prospective data on testosterone, sex hormone-binding globulin (SHBG) and insulin-like growth factor (IGF)−1 are limited. To elucidate the role of these hormones in endometrial cancer risk we conducted complementary observational and Mendelian randomization (MR) analyses.

Methods

The observational analyses included 159,702 women (80% postmenopausal) enrolled in the UK Biobank. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models. For MR analyses, genetic variants associated with hormone levels were identified and their association with endometrial cancer (12,906 cases/108,979 controls) was examined using two-sample MR.

Results

In the observational analysis, higher circulating concentrations of total (HR per unit inverse normal scale = 1.38, 95% CI = 1.22–1.57) and free testosterone (HR per unit log scale = 2.07, 95% CI = 1.66–2.58) were associated with higher endometrial cancer risk. An inverse association was found for SHBG (HR per unit inverse normal scale = 0.76, 95% CI = 0.67–0.86). Results for testosterone and SHBG were supported by the MR analyses. No association was found between genetically predicted IGF-1 concentration and endometrial cancer risk.

Conclusions

Our results support probable causal associations between circulating concentrations of testosterone and SHBG with endometrial cancer risk.

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Fig. 1: Observational and Mendelian randomization estimates for total testosterone, free testosterone, sex hormone-binding globulin (SHBG) and insulin-like growth factor-1 (IGF-1) and endometrial cancer risk.
Fig. 2: Subgroup analyses of association between total testosterone concentration and endometrial cancer risk in the UK Biobank (per unit inverse normal scale).
Fig. 3: Subgroup analyses of association between sex-hormone-binding globulin (SHBG) concentration and endometrial cancer risk in the UK Biobank (per unit inverse normal scale).

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Data availability

Data used in the MR analyses can be found in supplementary material. Researchers can apply to use the UK Biobank dataset by registering and applying at http://ukbiobank.ac.uk/register-apply/.

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Acknowledgements

This work has been conducted using the UK Biobank Resource under Application Numbers 8294, and we express our gratitude to the participants and those involved in building the resource. UK Biobank is an open access resource. Bona fide researchers can apply to use the UK Biobank dataset by registering and applying at http://ukbiobank.ac.uk/register-apply/.

Funding

This work was supported by the French National Cancer Institute (INCa SHSESP17, grant no. 2017–127) and by Cancer Research UK (C18281/A29019).

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Author notes

  1. These authors contributed equally: Amy Mullee, Niki Dimou, Marc J. Gunter, Neil Murphy.

Authors and Affiliations

  1. School of Public Health, Physiotherapy and Sports Science, University College Dublin, Dublin, Ireland

    Amy Mullee

  2. School of Agriculture and Food Science, University College Dublin, Dublin, Ireland

    Amy Mullee

  3. Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France

    Amy Mullee, Niki Dimou, Marc J. Gunter & Neil Murphy

  4. Clinical Trial Service Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK

    Naomi Allen

  5. Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia

    Tracy O’Mara

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Contributions

AM, ND, MJG and NM: Designed the study and developed the methodology, analysed the data, interpreted the results, drafted the paper and approved the final version. NA and TO’M: Interpreted the results, edited the manuscript and approved the final version.

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Correspondence to Neil Murphy.

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The authors declare no competing interests.

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UK Biobank has approval from the North-West Multi-Centre Research Ethics Committee, the National Information Governance Board for Health & Social Care in England and Wales and the Community Health Index Advisory Group in Scotland. Written informed consent was provided by all participants.

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Mullee, A., Dimou, N., Allen, N. et al. Testosterone, sex hormone-binding globulin, insulin-like growth factor-1 and endometrial cancer risk: observational and Mendelian randomization analyses. Br J Cancer 125, 1308–1317 (2021). https://doi.org/10.1038/s41416-021-01518-3

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