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The relationship between klotho, testosterone, and sexual health parameters among US adult men

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Abstract

Background

Klotho is a pleotropic hormone involved in a multitude of biological processes necessary for healthy aging, and affords protection from adverse events such as cardiovascular disease, inflammation, and various cancers. Emerging evidence suggests that klotho is also an important component of biochemical pathways that regulate hormone balance, which may include those pathways governing testosterone production and men’s sexual health, though data are limited and results are mixed.

Objective

Using a cohort of 767 men from the NHANES 2015–2016 survey cycle, we set out to quantify the association between serum klotho levels and serum testosterone levels, as well as clinical markers of men’s sexual health (e.g., testosterone:estrogen ratio, bioavailable testosterone, and free testosterone).

Methods

Multivariable linear and logistic regression models while controlling for potential confounders were constructed to quantify the relationship between serum klotho and testosterone, as well as between serum klotho and odds of low testosterone (serum testosterone < 300 ng/dL).

Results

A positive association was observed between serum klotho and testosterone (β = 0.18, p = 0.04). Serum klotho levels were also stratified into quartiles, and we observed statistically significant increases in testosterone for increasing quartile level of klotho using the first quartile as the reference group (β = 90.51, p = 0.001, β = 106.93, p = 0.002, β = 95.33, p = 0.03 for quartiles 2, 3, and 4, respectively). The average testosterone values by quartiles of klotho were 306.9 ng/dL, 390 ng/dL, 409.3 ng/dL, and 436.6 ng/dL, respectively. We modeled important proxies for sexual health including bioavailable and free testosterone, the testosterone:estradiol ratio, and C-reactive protein. Men in the second quartile of klotho had a significantly lower odds of an abnormal testosterone:estradiol ratio compared to the first quartile [OR = 0.18, 95% CI = (0.03, 0.98)].We observed null associations between continuous serum klotho and odds of low testosterone [OR = 1.0, 95% CI = (1.0, 1.0)], and when stratified by quartile, we observed a significant decrease in the odds of low testosterone for individuals in the second quartile of klotho compared to the first quartile [OR = 0.21, 95% CI = (0.05, 0.91)]. In addition, C-reactive protein was inversely associated with testosterone in men (β = − 4.65, p = 0.001), and inversely associated with quartiles of klotho (β = − 2.28, p = 0.04, β = − 2.22, p = 0.04, β = − 2.28, p = 0.03, for quartiles 2, 3, and 4, respectively).

Conclusion

Our findings support previous studies suggesting a role for klotho in testosterone levels and sexual function among men. Future studies are warranted to corroborate these findings, determine clinical significance, and elucidate potential mechanisms underlying these associations.

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Availability of data and materials

A full list of data sets supporting the results in this research article can be found at: https://wwwn.cdc.gov/nchs/nhanes/continuousnhanes/default.aspx?BeginYear=2013.

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Funding

The authors received no external funding for this research study.

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Authors and Affiliations

  1. Emory University School of Medicine, Atlanta, GA, 30322, USA

    F. Glover

  2. Pharmacology Department, Emory University, Atlanta, GA, 30322, USA

    E. Sullivan

  3. Department of Urology, Stanford University School of Medicine, Stanford, CA, 94305, USA

    E. Mulloy & M. L. Eisenberg

  4. Department of Maternal-Infant and Urological Sciences, “Sapienza” Rome University, Policlinico Umberto I Hospital, Rome, Italy

    F. Belladelli & F. Del Giudice

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  1. F. Glover
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  2. E. Sullivan
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  3. E. Mulloy
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  4. F. Belladelli
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  5. F. Del Giudice
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  6. M. L. Eisenberg
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Contributions

FG is the primary author who drafted the manuscript, obtained references, performed most of the data analysis, and helped with the conceptualization of the study. FB and FDG both performed data analysis with the regression models, obtained background information for references, and proof read the manuscript drafts. ES and EM also performed extensive background research, as well as proofed all drafts of the manuscript and helped created figures and tables. MLE provided guidance at the conceptualization stage, proofed all drafts of the manuscript, and helped perform regression analysis.

Corresponding author

Correspondence to F. Glover.

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Ethical approval and consent to participate

Health information collected in the NHANES is kept in strictest confidence. During the informed consent process, survey participants were assured that data collected will be used only for stated purposes and will not be disclosed or released to others without the consent of the individual or the establishment in accordance with Section 308 (d) of the Public Health Service Act (42 U.S.C. 242m).

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Participants in this study agreed to consent for publication in accordance with Section 308 (d) of the Public Health Service Act (42 U.S.C. 242m).

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Glover, F., Sullivan, E., Mulloy, E. et al. The relationship between klotho, testosterone, and sexual health parameters among US adult men. J Endocrinol Invest 47, 523–533 (2024). https://doi.org/10.1007/s40618-023-02163-8

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  • DOI: https://doi.org/10.1007/s40618-023-02163-8

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