Associations between serum total, free and bioavailable testosterone and non-alcoholic fatty liver disease in community-dwelling middle-aged and elderly women

Wang, Xu; Li, Qing; Pang, Juan; Lin, Jing; Liu, Yao; Xu, Zhongliang; Zhang, Hanyue; Shen, Tao; Xu, Chen; Ma, Jing; Xu, Xiping; Liu, Wenhua; Chen, Yuming

doi:10.1016/j.diabet.2020.09.007

Cited by 9 publications

(7 citation statements)

References 33 publications

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“…Therefore, FSH decreases due to an E2 increase, explaining the relationship between FSH and LFC. In addition, several studies indicated that compared with TT, FT and BT were more accurate in predicting NAFLD prevalence among women [30,31]. We also found that BT was positively correlated with MAFLD after adjusting for confounding factors and TT in women, consistent with the findings of previous studies.…”

Section: Discussionsupporting

confidence: 91%

Associations between sex hormones and metabolic-associated fatty liver disease in a middle-aged and elderly community

Cao

Shen

et al. 2022

Endocr J

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Metabolic-associated fatty liver disease (MAFLD) was proposed by an international expert consensus to replace non-alcoholic fatty liver disease (NAFLD) in 2020. Previous studies have shown that sex hormones are strongly linked to NAFLD development. This study aims to explore whether sex hormones are associated with MAFLD and liver fat content (LFC) in a middle-aged and elderly community. The study included 732 subjects aged 50-80 years enrolled from communities. MAFLD was diagnosed using the 2020 International Expert Consensus. LFC was calculated using parameters from abdominal ultrasound images. Serum estradiol (E2), total testosterone (TT), sex hormone-binding globulin (SHBG), FSH, and LH were measured by chemiluminescent microparticle immunoassay. MAFLD was diagnosed in 107/304 (35.2%) men and 154/428 (35.2%) women. After adjustments for confounding factors, logistic regression analysis showed that SHBG was negatively correlated with MAFLD in men (OR, 0.95 [0.93-0.97], p < 0.001). In women, SHBG and FSH were negatively correlated with MAFLD (OR, 0.95 [0.94-0.97], p < 0.001; OR, 0.97 [0.96-0.98], p < 0.001). Multivariate linear regression analysis showed that SHBG was a negative factor for LFC in both men (standardized β = -0.188, p < 0.001) and women (standardized β = -0.184, p < 0.001). FSH was a negative factor for LFC in women (standardized β = -0.082, p = 0.046). SHBG was negatively correlated with MAFLD in middle-aged and elderly men and women. Moreover, FSH was negatively correlated, and bioactive testosterone was positively correlated with MAFLD in women. These findings suggest a relationship between sex hormones and MAFLD.

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Section: Discussionsupporting

confidence: 91%

Associations between sex hormones and metabolic-associated fatty liver disease in a middle-aged and elderly community

Cao

Shen

et al. 2022

Endocr J

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“…After deduplication, 2459 references were screened on title and abstract. After screening and detailed full-text assessment, 16 studies [ 12 , 14 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 ] were eligible for the systematic review. The detailed characteristics of these studies (e.g., lead author, publication date, location, study design, adjustment for covariates) are outlined in Table 4 .…”

Section: Resultsmentioning

confidence: 99%

“…The meta-analysis for testosterone is based on 10 studies [ 12 , 14 , 35 , 38 , 39 , 40 , 45 , 46 , 47 ] among men and 7 studies [ 14 , 37 , 40 , 42 , 44 , 46 ] among women, the findings for SHBG and NAFLD derive from seven studies among men [ 14 , 35 , 41 , 43 , 45 ] and 7 studies among women [ 14 , 35 , 37 , 41 , 42 , 43 ], the results for estradiol and NAFLD include three studies [ 36 , 45 ] among men. The pooled ORs for NAFLD comparing T3 versus T1 of testosterone were 0.59 (95%CI 0.42–0.76, I 2 = 93%, p -value < 0.01) among men and 1.06 (95%CI 0.68–1.44, I 2 = 44%, p -value = 0.09) among women ( Figure 3 A).…”

Section: Resultsmentioning

confidence: 99%

Associations of Sex Steroids and Sex Hormone-Binding Globulin with Non-Alcoholic Fatty Liver Disease: A Population-Based Study and Meta-Analysis

Zhang

Mou

Aribas

et al. 2022

Genes

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Background: Prior studies have reported inconsistent results or less well-explored associations between sex hormones and non-alcoholic fatty liver disease (NAFLD). Here, we aimed to investigate the associations of NAFLD with sex steroids and sex hormone-binding globulin (SHBG) in the population-based study and conduct a comprehensive systematic review and meta-analysis of all published observational studies. Methods: Analyses included 755 men and 1109 women with available data on sex steroids, SHBG, and ultrasound-based NAFLD from the Rotterdam Study. Multivariable regression models were used to examine the associations. Additionally, we searched five databases from inception to 1 April 2022 and performed a systematic review and meta-analysis. Random-effects (DerSimonian-Laird) method was used for meta-analysis, odds ratios (ORs) were calculated for the effect estimate, subgroup and leave-one-out sensitivity analyses were conducted, and meta-regression was performed to explore the pooled statistics with high heterogeneity. Results: In the Rotterdam Study, lower levels of SHBG were associated with NAFLD in both sexes, while lower testosterone was associated with NAFLD only among women. Similarly, the meta-analysis of 16 studies indicated no sex-specific association between SHBG and NAFLD (men: OR = 0.37, 95%CI 0.21–0.53; women: OR = 0.40, 95%CI 0.21–0.60), yet there was a sex-specific association between testosterone and NAFLD (men: OR = 0.59, 95%CI 0.42–0.76; women: OR = 1.06, 95%CI 0.68–1.44). Moreover, men with NAFLD had lower estradiol levels than those without NAFLD. Conclusions: Lower SHBG levels were associated with NAFLD in both sexes, but testosterone levels were associated in a sex-specific manner. In addition, our results showed estradiol with the potential as a protective factor for NAFLD in healthy men.

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“…Testosterone circulates in three distinct forms: free testosterone (FT), albumin‐bound testosterone, and SHBG‐bound testosterone. FT is the fraction of total testosterone (TT) not bound to any transport protein; BioT level is the sum of FT plus albumin‐bound testosterone 40 . FT is easily accessible to cells, but BioT is more readily used by the body and more effective in activating signaling pathways connected to testosterone 41 .…”

Section: Discussionmentioning

confidence: 99%

Mendelian randomization analyses identified bioavailable testosterone mediates the effect of sex hormone‐binding globulin on prostate cancer

Wan

2023

Andrology

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Objective A better knowledge of the hormonal etiology of prostate cancer is essential for its prevention and treatment. The goal of this study was to provide causal estimates of the connection between sex hormone‐binding globulin and prostate cancer and investigate the possible mediating function of other modifiable risk indicators. Methods We used two‐step, two‐sample multivariable Mendelian randomization using single‐nucleotide polymorphisms as instrumental variables for exposure and mediators. Single‐nucleotide polymorphisms associated with sex hormone‐binding globulin and bioavailable testosterone were screened via a genome‐wide association study enrolling European‐descent adult male individuals. Summary‐level data for prostate cancer (79,148 cases and 61,106 controls) were extracted from the PRACTICAL consortium. The total effect of sex hormone‐binding globulin on prostate cancer risk was decomposed into direct and indirect effects through the mediator, bioavailable testosterone. An inverse‐variance‐weighted method was the primary Mendelian randomization analysis method. Sensitivity analyses were performed via Mendelian randomization–Egger regression, heterogeneity test, pleiotropy test, and leave‐one‐out test. The directionality that exposure causes the outcome was verified using Mendelian randomization–Steiger test. Results In the univariable Mendelian randomization analysis, genetically predicted higher sex hormone‐binding globulin levels had a causal association with lower prostate cancer risk (odds ratio = 0.944, 95% confidence interval = 0.897–0.993, p = 0.027) and an inverse association with bioavailable testosterone level (odds ratio = 0.945, 95% confidence interval = 0.926–0.965, p = 1.62E‐07) without controlling for other factors. Moreover, an increase of one standard deviation (59.5 pmol/L) in genetically predicted bioavailable testosterone level was significantly associated with a 22.0% increase in the overall prostate cancer risk (odds ratio = 1.220, 95% confidence interval = 1.064–1.398, p = 0.004) after adjusting for sex hormone‐binding globulin level. The effect size ratio of bioavailable testosterone‐mediated sex hormone‐binding globulin to prostate cancer was further analyzed to clarify the importance of the mediating effect. Notably, the mediator bioavailable testosterone explained 19.28% (95% confidence interval = 10.76%, 73.78%) of the total effect of sex hormone‐binding globulin level on prostate cancer risk. Conclusion The results support the potentially protective causal effect of genetically predicted higher sex hormone‐binding globulin levels against prostate cancer with mediation by the modifiable risk factor, bioavailable testosterone. More research is needed to determine how this possible sex hormone‐binding globulin–bioavailable testosterone–prostate cancer link works. Targeting sex hormone‐binding globulin and bioavailable testosterone traits may be a valuable strategy for preventing prostate cancer.

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Associations between serum total, free and bioavailable testosterone and non-alcoholic fatty liver disease in community-dwelling middle-aged and elderly women

Cited by 9 publications

References 33 publications

Associations between sex hormones and metabolic-associated fatty liver disease in a middle-aged and elderly community

Associations between sex hormones and metabolic-associated fatty liver disease in a middle-aged and elderly community

Associations of Sex Steroids and Sex Hormone-Binding Globulin with Non-Alcoholic Fatty Liver Disease: A Population-Based Study and Meta-Analysis

Mendelian randomization analyses identified bioavailable testosterone mediates the effect of sex hormone‐binding globulin on prostate cancer

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