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

Alisa D. Kjaergaard; Eirini Marouli; Areti Papadopoulou; Panos Deloukas; Aleksander Kuś; Rosalie Sterenborg; Alexander Teumer; Stephen Burgess; Bjørn O. Åsvold; Daniel I. Chasman; Marco Medici; Christina Ellervik

doi:10.1007/s10654-021-00721-z

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

Alisa D. Kjaergaard^*, Eirini Marouli, Areti Papadopoulou, Panos Deloukas, Aleksander Kuś, Rosalie Sterenborg, Alexander Teumer, Stephen Burgess, Bjørn O. Åsvold, Daniel I. Chasman, Marco Medici, Christina Ellervik

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
Pages (from-to)	335-344
Number of pages	10
Journal	European Journal of Epidemiology
Volume	36
Issue number	3
DOIs	https://doi.org/10.1007/s10654-021-00721-z
Publication status	Published - Mar 2021

Bibliographical note

Funding Information:
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.

Funding Information:
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.

Publisher Copyright:
© 2021, Springer Nature B.V.

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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7612952

Cite this

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

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.",

author = "Kjaergaard, {Alisa D.} and Eirini Marouli and Areti Papadopoulou and Panos Deloukas and Aleksander Ku{\'s} and Rosalie Sterenborg and Alexander Teumer and Stephen Burgess and {\AA}svold, {Bj{\o}rn O.} and Chasman, {Daniel I.} and Marco Medici and Christina Ellervik",

note = "Funding Information: 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. Funding Information: 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. Publisher Copyright: {\textcopyright} 2021, Springer Nature B.V.",

year = "2021",

month = mar,

doi = "10.1007/s10654-021-00721-z",

language = "English",

volume = "36",

pages = "335--344",

journal = "European Journal of Epidemiology",

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AU - Kjaergaard, Alisa D.

AU - Marouli, Eirini

AU - Papadopoulou, Areti

AU - Deloukas, Panos

AU - Kuś, Aleksander

AU - Sterenborg, Rosalie

AU - Teumer, Alexander

AU - Burgess, Stephen

AU - Åsvold, Bjørn O.

AU - Chasman, Daniel I.

AU - Medici, Marco

AU - Ellervik, Christina

N1 - Funding Information: 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. Funding Information: 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. Publisher Copyright: © 2021, Springer Nature B.V.

PY - 2021/3

Y1 - 2021/3

N2 - 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.

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

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