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Causal effects of serum testosterone levels on brain volume: a sex-stratified Mendelian randomization study

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Abstract

Purpose

To assess the causal effects of serum testosterone and sex hormone-binding globulin levels on brain volumetric measurements in women and men.

Methods

We performed a sex-stratified two-sample Mendelian randomization study using the random-effects inverse variance-weighted method as the primary analysis method. Sex-specific genetic instruments were obtained from a study with up to 194,453 men and 230,454 women. For testosterone, variants with dominant effects on both total and bioavailable testosterone but no aggregate effect on sex hormone-binding globulin were used as the main genetic instruments. Sex-specific summary-level data for magnetic resonance imaging brain volumetric measurements were obtained from a study with 11,624 women and 10,514 men.

Results

Analyses showed per standard deviation (approximately 3.7 nmol/L) higher testosterone levels in men were suggestively associated with larger gray matter volume (beta = 0.208, 95% confidence interval = 0.067 to 0.349, p = 0.004). The association remained in sensitivity analyses and multivariable analyses. Further analyses showed the effect was mainly act on peripheral cortical gray matter, but not on subcortical gray matter. Testosterone in men was not associated with hippocampal volume. Testosterone in women and sex hormone binding globulin in both sexes had no effect on all outcomes.

Conclusion

Our findings overall support previous evidence that testosterone might have neuroprotective properties in elderly men. Future larger trials with long duration of intervention are warranted to assess the efficacy of testosterone for elderly men with cognitive impairment, especially in those with hypoandrogenism.

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Data availability statement

The data supporting the findings of this study are available in the article’s supplementary files, and in the studies cited in this article.

Abbreviations

CI:

Confidence interval

GWAS:

Genome wide association study

MR:

Mendelian randomization

MR-PRESSO:

MR pleiotropy residual sum and outlier

IVW:

Inverse variance-weighted

SNP:

Single nucleotide polymorphism

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Acknowledgements

We want to acknowledge the participants and investigators of the FinnGen study and the UK Biobank. We also want to acknowledge the participants and investigators of all other studies.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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  1. Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Jian She Road 1#, Zhengzhou, 450000, China

    P.-P. Niu, X. Wang & Y.-M. Xu

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  2. X. Wang
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Contributions

P-PN: conceptualization, formal analysis, methodology, writing original draft. XW: data curation, writing original draft. Y-MX: project administration, Supervision, reviewing and editing manuscript.

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Correspondence to P.-P. Niu.

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Niu, PP., Wang, X. & Xu, YM. Causal effects of serum testosterone levels on brain volume: a sex-stratified Mendelian randomization study. J Endocrinol Invest 46, 1787–1798 (2023). https://doi.org/10.1007/s40618-023-02028-0

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