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Thyroid function, sex hormones and sexual function: a Mendelian randomization study

  • ENDOCRINE DISEASE EPIDEMIOLOGY
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Abstract

Hypothyroidism and hyperthyroidism are observationally associated with sex hormone concentrations and sexual dysfunction, but causality is unclear. We investigated whether TSH, fT4, hypo- and hyperthyroidism are causally associated with sex hormones and sexual function. We used publicly available summary statistics from genome-wide association studies on TSH and fT4 and hypo- and hyperthyroidism from the ThyroidOmics Consortium (N ≤ 54,288). Outcomes from UK Biobank (women ≤ 194,174/men ≤ 167,020) and ReproGen (women ≤ 252,514) were sex hormones (sex hormone binding globulin [SHBG], testosterone, estradiol, free androgen index [FAI]) and sexual function (ovulatory function in women: duration of menstrual period, age at menarche and menopause, reproductive lifespan, and erectile dysfunction in men). We performed two-sample Mendelian randomization (MR) analyses on summary level, and unweighted genetic risk score (GRS) analysis on individual level data. One SD increase in TSH was associated with a 1.332 nmol/L lower (95% CI: − 0.717,− 1.946; p = 2 × 10–5) SHBG and a 0.103 nmol/l lower (− 0.051,V0.154; p = 9 × 10–5) testosterone in two-sample MR, supported by the GRS approach. Genetic predisposition to hypothyroidism was associated with decreased and genetic predisposition to hyperthyroidism with increased SHBG and testosterone in both approaches. The GRS for fT4 was associated with increased testosterone and estradiol in women only. The GRS for TSH and hypothyroidism were associated with increased and the GRS for hyperthyroidism with decreased FAI in men only. While genetically predicted thyroid function was associated with sex hormones, we found no association with sexual function.

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Data Availability

All data analyzed during this study are either publically available through http://www.nealelab.is/uk-biobank and https://www.reprogen.org/data_download.html, or available through application to the UK Biobank Resource.

Code availability

We used standard statistical software (STATA and R) and packages to perform the analyses.

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Acknowledgements

The two-sample MR approach is based on data freely available from the public domain. The authors would like to thank the ThyroidOmics consortium, 23andMe, UK Biobank, Neale lab, and ReproGen for sharing the data and making this project possible. This research has been conducted using the UK Biobank Resource under Application Number 53723.

Funding

ADK is funded by an unrestricted grant by Novo Nordisk. AK is supported by the Exchange in Endocrinology Expertise (3E) program of the European Union of Medical Specialists (UEMS), Section and Board of Endocrinology. AP is funded by the NIHR Barts Biomedical Research Centre.

Author information

Authors and Affiliations

  1. Steno Diabetes Center Aarhus, Aarhus University Hospital, Hedeager 3, Aarhus, Denmark

    Alisa D. Kjaergaard

  2. Barts and The London School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of London, London, UK

    Eirini Marouli, Areti Papadopoulou & Panos Deloukas

  3. National Institute of Health Research Barts Biomedical Research Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK

    Areti Papadopoulou

  4. Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia

    Panos Deloukas

  5. Department of Internal Medicine, Academic Center for Thyroid Diseases, Erasmus Medical Center, Rotterdam, The Netherlands

    Aleksander Kuś & Rosalie Sterenborg

  6. Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands

    Aleksander Kuś, Rosalie Sterenborg & Marco Medici

  7. Department of Internal Medicine and Endocrinology, Medical University of Warsaw, Warsaw, Poland

    Aleksander Kuś

  8. Department of Internal Medicine, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands

    Rosalie Sterenborg

  9. Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany

    Alexander Teumer

  10. Partner site Greifswald, DZHK (German Center for Cardiovascular Research), Greifswald, Germany

    Alexander Teumer

  11. MRC Biostatistics Unit, University of Cambridge, Cambridge, UK

    Stephen Burgess

  12. Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK

    Stephen Burgess

  13. Department of Public Health and Nursing, K.G. Jebsen Center for Genetic Epidemiology, NTNU, Norwegian University of Science and Technology, Trondheim, Norway

    Bjørn O. Åsvold

  14. Department of Public Health and Nursing, HUNT Research Center, , NTNU, Norwegian University of Science and Technology, Trondheim, Norway

    Bjørn O. Åsvold

  15. Department of Endocrinology, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway

    Bjørn O. Åsvold

  16. Harvard Medical School, Boston, MA, USA

    Daniel I. Chasman

  17. Program in Medical and Population Genetics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Daniel I. Chasman

  18. Division of Preventive Medicine, Brigham and Women’s Hospital, Boston, MA, USA

    Daniel I. Chasman

  19. Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands

    Marco Medici

  20. Department of Internal Medicine, Academic Center for Thyroid Diseases, , Rotterdam, The Netherlands

    Marco Medici

  21. Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, 2200, Copenhagen, Denmark

    Christina Ellervik

  22. Department of Pathology, Harvard Medical School, Boston, MA, 02215, USA

    Christina Ellervik

Authors
  1. Alisa D. Kjaergaard
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  2. Eirini Marouli
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  3. Areti Papadopoulou
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  4. Panos Deloukas
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  5. Aleksander Kuś
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  6. Rosalie Sterenborg
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  7. Alexander Teumer
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  8. Stephen Burgess
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  9. Bjørn O. Åsvold
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  10. Daniel I. Chasman
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  11. Marco Medici
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  12. Christina Ellervik
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Contributions

Study conception and design: ADK, CE, AK, MM. Analyses: ADK, EM, AP. Draft: ADK, CE. Supervision: CE. Interpretation of results, critical editing and agreement to submit the manuscript: all authors.

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Correspondence to Alisa D. Kjaergaard.

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Kjaergaard, A.D., Marouli, E., Papadopoulou, A. et al. Thyroid function, sex hormones and sexual function: a Mendelian randomization study. Eur J Epidemiol 36, 335–344 (2021). https://doi.org/10.1007/s10654-021-00721-z

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