Association of sex hormones and sex hormone-binding globulin with liver fat in men and women: an observational and Mendelian randomization study

Front Endocrinol (Lausanne). 2023 Oct 13:14:1223162. doi: 10.3389/fendo.2023.1223162. eCollection 2023.

Abstract

Background: Sex hormones and sex hormone-binding globulin (SHBG) may play a role in fatty liver development. We sought to examine the association of various endogenous sex hormones, including testosterone (T), and SHBG with liver fat using complementary observational and Mendelian randomization (MR) analyses.

Methods: The observational analysis included a total of 2,239 participants (mean age 60 years; 35% postmenopausal women) from the population-based KORA study (average follow-up time: 6.5 years). We conducted linear regression analysis to investigate the sex-specific associations of sex hormones and SHBG with liver fat, estimated by fatty liver index (FLI). For MR analyses, we selected genetic variants associated with sex hormones and SHBG and extracted their associations with magnetic resonance imaging measured liver fat from the largest up to date European genome-wide associations studies.

Results: In the observational analysis, T, dihydrotestosterone (DHT), progesterone and 17α-hydroxyprogesterone (17-OHP) were inversely associated with FLI in men, with beta estimates ranging from -4.23 to -2.30 [p-value <0.001 to 0.003]. Whereas in women, a positive association of free T with FLI (β = 4.17, 95%CI: 1.35, 6.98) was observed. SHBG was inversely associated with FLI across sexes [men: -3.45 (-5.13, -1.78); women: -9.23 (-12.19, -6.28)]. No causal association was found between genetically determined sex hormones and liver fat, but higher genetically determined SHBG was associated with lower liver fat in women (β = -0.36, 95% CI: -0.61, -0.12).

Conclusion: Our results provide suggestive evidence for a causal association between SHBG and liver fat in women, implicating the protective role of SHBG against liver fat accumulation.

Keywords: European cohort; Mendelian randomization; fatty liver index; liver fat; sex hormone-binding globulin; sex hormones.

Publication types

  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dihydrotestosterone
  • Fatty Liver* / epidemiology
  • Fatty Liver* / genetics
  • Female
  • Humans
  • Male
  • Mendelian Randomization Analysis
  • Middle Aged
  • Sex Hormone-Binding Globulin* / analysis
  • Sex Hormone-Binding Globulin* / genetics

Substances

  • Sex Hormone-Binding Globulin
  • Dihydrotestosterone

Grants and funding

The KORA research platform and the MONICA/KORA Augsburg studies are financed by the Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. Data collection in the KORA study is done in cooperation with the University Hospital of Augsburg. TZ is funded by the German Research Foundation, the EU Horizon 2020 programme, the EU ERANet and ERAPreMed Programmes, the German Centre for Cardiovascular Research (DZHK, 81Z0710102) and the German Ministry of Education and Research (BMBF).