Causal relationship analysis between 35 blood/urine metabolites and gastroesophageal reflux disease: A Mendelian randomization combined meta-analysis study.

Gastroesophageal reflux disease (GERD) is a common condition worldwide. Despite numerous studies on GERD, the causal relationships between blood/urine metabolites and GERD remain unclear. This study aims to explore the causal relationships between GERD and 35 blood/urine metabolites. In this study, we conducted Mendelian randomization (MR) analyses for 35 blood/urine metabolites with GERD phenotypes from the FinnGen R10 and UKB databases separately. We then performed a meta-analysis of the inverse variance weighted results from the 2 MR analyses and applied multiple corrections to the significant P values from the meta-analysis. Finally, we conducted reverse causality validation for the corrected positive blood/urine metabolite phenotypes with GERD. After conducting MR analysis combined with meta-analysis and performing multiple corrections, we found significant positive causal associations between only 3 blood/urine metabolites and GERD, with no significant reverse associations. Among them, 2 are risk factors for the occurrence of GERD: alanine aminotransferase levels (odds ratio (OR) = 1.120, 95% confidence interval (CI) = 1.064-1.180, P = .0005) and urate levels (OR = 1.095, 95% CI = 1.044-1.147, P = .005). Additionally, sex hormone-binding globulin levels are protective against GERD (OR = 0.928, 95% CI = 0.896-0.961, P = .0009). Elevated levels of the metabolites alanine aminotransferase and urate are associated with an increased risk of GERD, identifying them as risk factors for the condition. In contrast, higher levels of SHBG are linked to a decreased risk of GERD, indicating that SHBG is a protective factor against the disease.

[Genetic Causation Analysis of Hyperandrogenemia Testing Indicators and Preeclampsia]. / é«˜é›„æ¿€ç´ è¡€ç—‡æ£€æµ‹æŒ‡æ ‡ä¸Žå­ç—«å‰æœŸçš„é—ä¼ å› æžœæ€§ç ”ç©¶.

Objective: Some epidemiological studies have shown that pregnant women who develop preeclampsia (PE) have elevated levels of testosterone in their maternal plasma compared to women with normal blood pressure during pregnancy, revealing a potential association between hyperandrogenism in women and PE. To explore the causal relationship between hyperandrogenism and PE, this study selected total testosterone (TT), bioavailable testosterone (BIOT), and sex hormone binding globulin (SHBG) as exposure factors and PE and chronic hypertension with superimposed PE as disease outcomes. Two-sample Mendelian randomization (MR) analyses were used to genetically dissect the causal relationships between the three exposure factors (TT, BIOT, and SHBG) and the outcomes of PE and chronic hypertension with superimposed PE. Methods: Two independent genome-wide association study (GWAS) databases were used for the two-sample MR analysis. In the GWAS data of female participants from the UK Biobank cohort, single nucleotide polymorphisms (SNPs) associated with TT, BIOT, and SHBG were analyzed, involving 230454, 188507, and 188908 samples, respectively. GWAS data on PE and chronic hypertension with superimposed PE from the Finnish database were used to calculate SNP, involving 3556 PE cases and 114735 controls, as well as 38 cases of chronic hypertension with superimposed PE and 114735 controls. To meet the assumptions of instrumental relevance and independence in MR analysis, SNPs associated with exposure were identified at the genome-wide level (P<5.0×10-8), and those in linkage disequilibrium interference were excluded based on clustering thresholds of R 2<0.001 and an allele distance greater than 10000 kb. Known confounding factors, including previous PE, chronic kidney disease, chronic hypertension, diabetes, systemic lupus erythematosus, or antiphospholipid syndrome, were also identified and the relevant SNPs were removed. Finally, we extracted the outcome data based on the exposure-related SNPs in the outcome GWAS, integrating exposure and outcome data, and removing palindromic sequences. Five genetic causal analysis methods, including inverse variance-weighted method (IVW), MR-Egger regression, weighted median method, simple mode method, and weighted mode method, were used to infer causal relationships. In the IVW, it was assumed that the selected SNPs satisfied the three assumptions and provided the most ideal estimate of the effect. IVW was consequently used as the primary analysis method in this study. Considering the potential heterogeneity among the instrumental variables, random-effects IVW was used for MR analysis. The results were interpreted using odds ratios (OR) and the corresponding 95% confidence interval (CI) to explain the impact of exposure factors on PE and chronic hypertension with superimposed PE. If the CI did not include 1 and had a P value less than 0.05, the difference was considered statistically significant. Sensitivity analysis was conducted to assess heterogeneity and pleiotropy. Heterogeneity was examined using Cochran's Q test, and pleiotropy was assessed using MR-Egger intercept analysis. Additionally, leave-one-out analysis was conducted to examine whether individual SNPs were driving the causal associations. To further validate the findings, MR analyses were performed using the same methods and outcome variables, but with different exposure factors, including waist-to-hip ratio adjusted for BMI (WHRadjBMI) and 25-hydroxyvitamin D levels, with MR results for WHRadjBMI and PE serving as the positive controls and MR results for 25-hydroxyvitamin D levels and PE as the negative controls. Results: According to the criteria for selecting genetic instrumental variables, 186, 127, and 262 SNPs were identified as genetic instrumental variables significantly associated with testosterone indicators TT, BIOT, and SHBG. MR analysis did not find a causal relationship between the TT, BIOT, and SHBG levels and the risk of developing PE and chronic hypertension with superimposed PE. The IVW method predicted that genetically predicted TT (OR [95% CI]=1.018 [0.897-1.156], P=0.78), BIOT (OR [95% CI]=1.11 [0.874-1.408], P=0.392), and SHBG (OR [95% CI]=0.855 [0.659-1.109], P=0.239) were not associated with PE. Similarly, genetically predicted TT (OR [95% CI]=1.222 [0.548-2.722], P=0.624), BIOT (OR [95% CI]=1.066 [0.242-4.695], P=0.933), and SHBG (OR [95% CI]=0.529 [0.119-2.343], P=0.402) were not significantly associated with chronic hypertension with superimposed PE. Additionally, MR analysis using the MR-Egger method, weighted median method, simple mode method, and weighted mode method yielded consistent results, indicating no significant causal relationship between elevated testosterone levels and PE or chronic hypertension with superimposed PE. Heterogeneity was observed for SHBG in the analysis with PE (Cochran's Q test, P=0.01), and pleiotropy was detected for BIOT in the analysis with PE (MR-Egger intercept analysis, P=0.014), suggesting that the instrumental variables did not affect PE through BIOT. Other instrumental variables did not show significant heterogeneity or pleiotropy. Leave-one-out analysis confirmed that the results of the MR analysis were not driven by individual instrumental variables. Consistent with previous MR studies, the results of the control MR analyses using WHRadjBMI and 25-hydroxyvitamin D levels supported the accuracy of the MR analysis approach and the methods used in this study. Conclusion: The MR analysis results suggest that current genetic evidence does not support a causal relationship between TT, BIOT, and SHBG levels and the development of PE and chronic hypertension with superimposed PE. This study suggests that elevated testosterone may be a risk factor for PE but not a direct cause.

Sex hormone-binding globulin is a valuable diagnostic indicator of gestational diabetes mellitus.

Objective: To assess the performance of the Sex Hormone-Binding Globulin (SHBG) assay as a diagnostic indicator of Gestational Diabetes Mellitus (GDM) in the study population. Design: Analytical cross-sectional study. Setting: Hospital-based, Benue State University Teaching Hospital (BSUTH), Makurdi, Nigeria. Participants: Women with singleton pregnancies at 24 to 28 weeks gestational age attending Antenatal care at BSUTH, Makurdi. Intervention: Serum SHBG levels were assayed by ELISA during a diagnostic 75-gram Oral Glucose Tolerance Test (OGTT) for assessment of GDM in the cohort of consecutively selected participants who met the inclusion criteria. Main Outcome Measures: Serum levels of SHBG and presence of GDM in the participants. Result: Serum SHBG was significantly negatively correlated (rpb = - 0.534, p-value < 0.001) with the presence of GDM. It had an area under the ROC curve of 0.897 (95% Confidence Interval = 0.858-0.935; p-value < 0.001). A cut-off value of 452.0 nmol/L indicative of GDM had a diagnostic odds ratio of 21.4 in the study population. Conclusion: SHBG is a valuable diagnostic indicator for GDM in the study population. Funding: None declared.

Correlation between serum sex hormone-binding globulin levels and nutrition indicators and malnutrition exposure risk in men and postmenopausal women with type 2 diabetes.

BACKGROUND: This study sought to investigate the correlation between serum sex hormone-binding globulin (SHBG) levels and nutrition indicators and the malnutrition exposure risk in men and postmenopausal women with type 2 diabetes mellitus (T2DM). METHODS: A cross-sectional analysis was conducted, involving patients diagnosed with T2DM at the Guangdong Provincial People's Hospital between May 2018 and December 2019. RESULTS: The study comprised 551 participants (363 men, mean age of 55.55 ± 11.57 years), among whom 167 (30.31%) were classified as with malnutrition exposure risk (GNRI ≤ 98). Multivariable logistic regression analysis revealed that SHBG (OR = 1.04, 95% CI: 1.02-1.05, P < 0.001), glycated hemoglobin (OR = 1.36, 95% CI: 1.22-1.51, P < 0.001), hemoglobin (OR = 0.96, 95% CI: 0.94-0.97, P < 0.001), and non-alcoholic fatty liver disease (OR = 0.41, 95% CI: 0.23-0.73, P < 0.003) were independently associated with the malnutrition exposure risk. SHBG was inversely correlated with body mass index (males: r = -0.34; postmenopausal females: r = -0.22), albumin (males: r = -0.30; postmenopausal females: r = -0.20), transferrin (males: r = -0.28; postmenopausal females: r = -0.19), and prealbumin (males: r = -0.35; postmenopausal females: r = -0.30) (all P < 0.05). CONCLUSIONS: Serum SHBG levels are correlated with nutritional indicators and the risk of malnutrition in men and postmenopausal women with T2DM. A multicenter prospective study is imperative to verify this result in the future.

Gonadal hormones and metabolic syndrome in middle-aged and elderly males: results from a prospective cohort study in China.

Background: Research has shown that gonadal hormones are involved in metabolic pathways relevant to metabolic syndrome (MetS). Nevertheless, no longitudinal study has been conducted on the association between SHBG and MetS in Chinese. The objective of our study was to determine whether there is any association between middle-aged and elderly males in China. Methods: A total of 531 eligible male subjects, aged above 40 years or older, without MetS at baseline, were recruited. Sex hormone binding globulin (SHBG), total testosterone (TT), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) were measured. A harmonized definition and recommended thresholds for the Chinese population were used to determine metabolic syndrome. Results: During 3.2 years of follow-up, 20.7% of subjects had developed MetS. Compared with the non-MetS group, subjects in the new-onset MetS group had significantly lower SHBG (43.5 nmol/L [28.8, 74.9] vs 53.7nmol/L [33.8, 115.0], P=0.0018), TT (18.1nmol/L [13.6-21.7] vs 19.5nmol/L[15.0-23.6], P=0.0204), and LH (5.13mIU/L [3.63-7.29] vs 5.87mIU/L [4.05-8.36]) at baseline. The incidence of MetS was decreased according to elevated SHBG quartiles (Q1:26.9%, Q2:22.7%, Q3:21.1%, Q4:12.1%, P for trend =0.0035), TT (Q1: 25.2%, Q2:23.7%, Q3: 17.3%, Q4: 16.7%, P for trend=0.0425), and LH (Q1:25.0%, Q2:21.8%, Q3: 21.8%, Q4: 14.3%, P for trend=0.0411). Compared with those in quartile 4, the OR[CI] of incident MetS for participants in Quartile 1 was 2.33[1.13-4.79] after multiple adjustments. But associations between incident MetS and different quartiles of LH, TT, and FSH were not observed after multiple adjustments. In the subgroup analyses, the significant association between SHBG level and Mets was detected in subjects over 60 years or older, with normal BMI, without insulin resistance, and with eGFR ≥90 mL/min per 1.73m2. Conclusion: Compared with TT, LH, and FSH, a lower level of SHBG is significantly related to the incidence of MetS among middle-aged and elderly males in China.

Decoding connections in the European population: serum uric acid, sex hormone-binding globulin, total testosterone, estradiol, and female infertility - advanced bidirectional and mediative Mendelian randomization.

Background: Despite observational links between serum uric acid (SUA), sex hormone-related phenotypes, and female infertility, the causality behind these associations remains uncertain. Objective: This study utilizes Bidirectional Two-Sample and Mediation Mendelian Randomization to explore the causal relationships and mediation effects of sex hormone-binding globulin (SHBG), total testosterone (TT), and estradiol on these associations. Methods: We analyzed single-nucleotide polymorphisms (SNPs) associated with SUA and sex hormone levels using data from large-scale GWAS of European populations. Female infertility data were sourced from 6,481 cases and 75,450 controls in the FinnGen Consortium. We employed methods including Inverse Variance Weighted (IVW), Weighted Median, and MR-Egger regression to assess causality. Results: We found that elevated SUA levels causally increase the risk of female infertility (IVW OR: 1.13, P=0.047). Elevated SUA levels significantly decrease SHBG levels (ß=-0.261; P=2.177e-04), with SHBG mediating 27.93% of the effect of SUA on infertility (OR=0.854; 95%CI, 0.793-0.920; P=2.853e-05). Additionally, elevated TT levels, which were associated with decreased SUA levels (ß=-0.127), showed an indirect effect on infertility mediated by SUA (ß=-0.0187; 95% CI, -0.041 to -0.003; P=0.046). Conclusion: Our findings demonstrate causal links between high SUA and increased risk of female infertility mediated by hormonal factors such as SHBG and TT. These insights suggest new avenues for infertility treatment and highlight the need for further research into these mechanisms.

The relationship between follicle-stimulating hormone and metabolic dysfunction-associated fatty liver disease in men.

OBJECTIVES: The present study aimed to investigate the relationship between male hormones and metabolic dysfunction-associated fatty liver disease (MAFLD) in males. METHODS: Data from the Fangchenggang Area Male Health and Examination Survey (FAMHES) were used to analyze the male hormone levels between MAFLD patients and controls. Univariate and multivariate logistic regression analyses were performed to identify risk factors for MAFLD. Receiver operating characteristic curve analysis was used to assess the diagnostic performance of male hormones for MAFLD. RESULT: A total of 1578 individuals were included, with 482 individuals (30.54%) of MAFLD, including 293 (18.57%) with mild disease and 189 (11.98%) with moderate-to-severe disease. The MAFLD patients were significantly older than those without MAFLD. The LH, FSH, and SHBG levels in the MAFLD patients were significantly greater than those in the control group. Age, FSH, LH, SHBG, and estradiol were all risk factors for MAFLD. Age, FSH, and LH were risk factors for moderate-to-severe MAFLD. FSH was an independent risk factor for MAFLD and moderate-to-severe MAFLD. FSH showed an excellent diagnostic value, with an AUC of 0.992 alone and 0.996 after adjusting age. CONCLUSIONS: Our findings indicate that FSH may be a potential diagnostic and predictive biomarker for MAFLD.

The role of sex hormone binding globulin levels in the association of surgical and natural premature menopause with incident type 2 diabetes.

OBJECTIVE: To examine associations of surgical and natural menopause before the age of 40 years with the risk of type 2 diabetes (T2D) in women. METHODS: A total of 273,331 women from the United Kingdom were recruited between 2006 and 2010 in the UK Biobank (UKB) study, and 146,343 women aged 40 to 69 years who were postmenopausal at baseline were included in the analysis. Surgical menopause and natural premature menopause were defined as bilateral oophorectomy before the age of 40 and menopause before the age of 40 without oophorectomy, respectively. Multivariable Cox regression models were used to estimate the hazard ratios (HRs) and 95 % confidence intervals (CIs) for the association between premature menopause and the incidence of T2D. RESULTS: During a median follow-up of 10.4 years, 47 women with surgical premature menopause, 244 women with natural premature menopause, and 4724 women without premature menopause developed T2D. Compared with women without premature menopause, both surgical premature menopause (adjusted HR = 1.46, 95 % CI: 1.09-1.95; P = 0.01) and natural premature menopause (adjusted HR = 1.20, 95 % CI: 1.06-1.37; P < 0.01) were associated with higher risks of incident T2D in the multivariable-adjusted models. Additionally, we observed a significant interaction between levels of sex hormone binding globulin (SHBG) (Pinteraction < 0.01) and the effects of premature menopause on incident T2D. The association between premature menopause and T2D risk appeared to be stronger in women with higher SHBG levels. Furthermore, a joint association was detected between premature menopause and the genetic risk score (GRS) of T2D, with a higher score indicating a higher risk of developingT2D. The highest risk of T2D was observed with higher T2D GRS and surgical premature menopause (adjusted HR = 2.61, 95 % CI: 1.65-4.12; P < 0.01). CONCLUSIONS: Surgical menopause and natural menopause before the age of 40 years were associated with an increased risk of T2D among postmenopausal women. The findings also suggest potential interactions of premature menopause with SHBG levels, with the association appearing to be stronger in higher SHBG levels, as well as a joint association between menopause status and genetic risk factors on T2D incidence.

Levels of Sex Hormones and Abdominal Muscle Composition in Men from The Multi-Ethnic Study of Atherosclerosis.

Information on the associations of testosterone levels with abdominal muscle volume and density in men is limited, while the role of estradiol and SHBG on these muscle characteristics are unclear. Therefore, this study aimed to investigate the association between fasting serum sex hormones and CT-derived abdominal muscle area and radiodensity in adult men. Conducted as a cross sectional observational study using data from the Multi-Ethnic Study of Atherosclerosis, our analyses focused on a community-based sample of 907 men aged 45-84 years, with 878 men having complete data. CT scans of the abdomen were interrogated for muscle characteristics, and multivariable linear regressions were used to test the associations. After adjustment for relevant factors, higher levels of both total testosterone and estradiol were associated with higher abdominal muscle area (1.74, 0.1-3.4, and 1.84, 0.4-3.3, respectively). In the final analyses, levels of total testosterone showed a positive association, while an inverse relationship was observed for SHBG with abdominal muscle radiodensity (0.3, 0.0-0.6, and - 0.33, - 0.6 to - 0.1, respectively). Our results indicate a complex association between sex hormones and abdominal muscle characteristics in men. Specifically, total testosterone and estradiol were associated with abdominal muscle area, while only total testosterone was associated with muscle radiodensity and SHBG was inversely associated with muscle radiodensity.Clinical Trial: NCT00005487.

Examining the causal relationship between sex hormone-binding globulin (SHBG) and infertility: A Mendelian randomization study.

BACKGROUND: The causal relationship between sex hormone-binding globulin (SHBG) and infertility has remained unclear. Thus, we used Mendelian randomization (MR) to investigate this relationship. METHODS: Risk factors for SHBG were extracted from European individuals within the UK Biobank using single-nucleotide polymorphism (SNP) data. Summary-level data for infertility outcomes were obtained from the FinnGen dataset. The causal relationship between SHBG and infertility was examined using inverse variance weighted, weighted model, weighted median, and MR-Egger regression analyses. Additionally, Cochran's Q test and Egger intercept tests were used to confirm the heterogeneity and pleiotropy of identified instrumental variables (IVs). RESULTS: Our findings revealed a significant negative association between sex hormone-binding globulin (SHBG) levels and infertility, particularly with anovulation, a specific form of female infertility. However, SHBG did not exert a causal impact on male infertility or on female infertility of tubal origin. CONCLUSIONS: SHBG expression offers protection against the development of certain types of female infertility, suggesting it is a potential therapeutic target for infertility.

Genetically predicted high sex hormone binding globulin was associated with decreased risk of polycystic ovary syndrome.

BACKGROUND: Previous observational studies have indicated an inverse correlation between circulating sex hormone binding globulin (SHBG) levels and the incidence of polycystic ovary syndrome (PCOS). Nevertheless, conventional observational studies may be susceptible to bias. Consequently, we conducted a two-sample Mendelian randomization (MR) investigation to delve deeper into the connection between SHBG levels and the risk of PCOS. METHODS: We employed single-nucleotide polymorphisms (SNPs) linked to serum SHBG levels as instrumental variables (IVs). Genetic associations with PCOS were derived from a meta-analysis of GWAS data. Our primary analytical approach relied on the inverse-variance weighted (IVW) method, complemented by alternative MR techniques, including simple-median, weighted-median, MR-Egger regression, and MR Pleiotropy RESidual Sum and Outlier (MR-PRESSO) testing. Additionally, sensitivity analyses were conducted to assess the robustness of the association. RESULTS: We utilized 289 SNPs associated with serum SHBG levels, achieving genome-wide significance, as instrumental variables (IVs). Our MR analyses revealed that genetically predicted elevated circulating SHBG concentrations were linked to a reduced risk of PCOS (odds ratio (OR) = 0.56, 95% confidence interval (CI): 0.39-0.78, P = 8.30 × 10-4) using the IVW method. MR-Egger regression did not detect any directional pleiotropic effects (P intercept = 0.626). Sensitivity analyses, employing alternative MR methods and IV sets, consistently reaffirmed our results, underscoring the robustness of our findings. CONCLUSIONS: Through a genetic epidemiological approach, we have substantiated prior observational literature, indicating a potential causal inverse relationship between serum SHBG concentrations and PCOS risk. Nevertheless, further research is needed to elucidate the underlying mechanism of SHBG in the development of PCOS.

Association between systemic immunity-inflammation index and sex hormones in children and adolescents aged 6-19.

Objectives: This study aimed to evaluate the relationship between systemic immune-inflammation index (SII) and sex hormones in children and adolescents aged 6-19 years. Methods: Data were obtained from the National Health and Nutrition Examination Survey (NHANES) conducted between 2013 and 2016. Inclusion criteria comprised subjects aged 6-19 years with complete data on both SII and sex hormones. We employed weighted multiple regression analysis and subgroup analytical methods to independently estimate the relationship between SII and sex hormones. Results: In this study, a total of 3767 participants were included, with an average age of 12.32 ± 3.95 years. Males constituted 50.54%, and females 49.46%. Among males, a statistically significant negative correlation emerged between SII and sex hormone-binding globulin (SHBG). Similarly, in the female population, SII exhibited a statistically significant negative correlation with total testosterone (TT), SHBG, and the Ratio of TT to estradiol, while maintaining a positive correlation with free androgen index (FAI). Subgroup analysis underscored variances in the association between sex hormones and SII within cohorts distinguished by pubertal status or different body mass index (BMI). In addition, the relationship between SII and estradiol exhibited nonlinearity. Employing a two-segment linear regression model, we identified an inverted U-shaped association between SII and estradiol, with an inflection point of 748.09 (1000cell/ml). Conclusion: Our findings suggest that SII may be an independent risk factor for changes in sex hormones in both male and female children and adolescents. More prospective and experimental studies should be conducted to validate our results and elucidate the underlying molecular pathways.

The association between endometrial polyps and insulin resistance from the expression of PI3K and AKT proteins perspective.

BACKGROUND: Insulin resistance (IR) induces hyperinsulinemia, which activates downstream signaling pathways such as the phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) pathway, ultimately leading to abnormal proliferation and apoptosis of endometrial cells. This is thought to be a key pathogenic mechanism underlying the development of endometrial polyps (EP). This study aims to investigate the relationship between IR and the development of EP, the expression levels of downstream signaling molecules, including PI3K and AKT, and related laboratory parameters were examined. METHODS: A total of 100 patients who visited the gynecology outpatient clinic of Zhongda Hospital affiliated with Southeast University from May 2021 to March 2023 and were diagnosed with abnormal endometrial echoes by vaginal ultrasound and underwent hysteroscopic diagnostic curettage were enrolled in this study. General data and relevant hematological indicators were compared, and intraoperative specimens were obtained for pathological examination. Possible factors influencing the development of endometrial polyps were analyzed using Pearson correlation analysis and logistic regression analysis. RESULTS: In terms of body mass index, waist circumference, fasting insulin, insulin resistance index, serum total testosterone, and free testosterone index, women of childbearing age in the endometrial polyp group had higher values than those in the non-polyp group, while sex hormone-binding globulin in the endometrial polyp group was lower than that in the non-polyp group, and the differences were statistically significant (P < 0.05). The expression scores and mRNA expression levels of PI3K and AKT proteins were higher in the EP group than in the non-EP group (p < 0.05). Pearson correlation analysis showed a positive correlation between HOMA-IR and the expression scores of PI3K and AKT proteins (p < 0.01). CONCLUSIONS: Insulin resistance and abnormal activation of the phosphatidylinositol 3-kinase/protein kinase B signaling pathway may be potential pathogenic mechanisms for the development of endometrial polyps.

Recent Advances on Sex Hormone-Binding Globulin Regulation by Nutritional Factors: Clinical Implications.

Sex hormone-binding globulin (SHBG) is a homodimeric glycoprotein produced by the human liver and secreted into the systemic circulation where it binds with high affinity sex steroids regulating their availability in blood and accessibility to target tissues. Plasma SHBG levels are altered in metabolic disorders such as obesity, anorexia, and insulin resistance. Several reports have shown that diets in terms of total calories or fat, fiber, or protein content can alter plasma SHBG levels. However, there are many components in a diet that can affect SHBG gene expression in the liver. In order to unravel the molecular mechanisms by which diets regulate SHBG production, it would be necessary to analyze single diet components and/or nutritional factors. This review summarizes the recent advances in identifying different nutritional factors regulating SHBG production and the related molecular mechanism, as well as the clinical implications.

Hyperglycemia Inhibits Hepatic SHBG Synthesis Through the NGBR-AMPK-HNF4 Pathway in Rats with Polycystic Ovary Syndrome Induced by Letrozole in Combination with a High-Fat Diet.

SCOPE: Polycystic ovary syndrome (PCOS) is closely related to non-alcoholic fatty liver disease (NAFLD), and sex hormone-binding globulin (SHBG) is a glycoprotein produced by the liver. Hepatic lipogenesis inhibits hepatic SHBG synthesis, which leads to hyperandrogenemia and ovarian dysfunction in PCOS. Therefore, this study aims to characterize the mechanism whereby liver lipogenesis inhibits SHBG synthesis. METHODS AND RESULTS: This study establishes a rat model of PCOS complicated by NAFLD using a high-fat diet in combination with letrozole and performs transcriptomic analysis of the liver. Transcriptomic analysis of the liver shows that the expression of neurite growth inhibitor-B receptor (NgBR), hepatocyte nuclear factor 4α (HNF4α), and SHBG is low. Meantime, HepG2 cells are treated with palmitic acid (PA) to model NAFLD in vitro, which causes decreases in the expression of NgBR, HNF4α, and SHBG. However, the expression of HNF4α and SHBG is restored by treatment with the AMP-activated protein kinase (AMPK) agonist AICAR. CONCLUSIONS: NgBR regulates the expression of HNF4α by activating the AMPK signaling pathway, thereby affecting the synthesis of SHBG in the liver. Further mechanistic studies regarding the effect of liver fat on NGBR expression are warranted.

Sex hormone binding globulin (SHBG) modulates mitochondrial dynamics in PPARγ-depleted equine adipose derived stromal cells.

Peroxisome proliferator-activated receptor gamma (PPARγ) is a transcription factor that promotes adipogenesis, lipid uptake and storage, insulin sensitivity, and glucose metabolism. Hence, defects in PPARγ have been associated to the development of metabolic disorders. Sex hormone-binding globulin (SHBG) is a glycoprotein primarily produced in the liver that regulates the bioavailability of sex hormones. Alike PPARγ, low SHBG levels have been correlated with insulin resistance and associated endocrine abnormalities. Therefore, this study aimed to verify whether SHBG may restore depleted PPARγ functions and thus serve as a new candidate for the management of metabolic conditions. A model of equine adipose-derived stromal cells (EqASCs) has been used, in which a PPARγ silencing and SHBG treatment have been achieved to determine the changes in cell viability, premature senescence, oxidative stress, and mitochondrial functions. Obtained data demonstrated that loss in PPARγ triggers cell apoptosis which is not reversed by SHBG application. Moreover, PPARγ knockdown cells exhibited premature senescence, which has been substantially alleviated by SHBG concomitantly to increased BAX/BCL2 ratio, suggesting a possible effect on senescence-induced apoptosis resistance. Interestingly, PPARγ silencing induced a significant alteration in mitochondrial membrane potential as well as the expression of dynamics and metabolism-related markers. SHBG treatment enabled to ameliorate the transmembrane potential, to normalize the expression levels of key dynamics and metabolism mediators, and to restore the protein levels of PINK, which is critically involved in mitochondria recycling machinery. Presented data suggest that SHBG may provide new mechanistic insights into the regulation of PPARγ functions, and thus offers a preliminary picture on a possible SHBG-PPARγ metabolic crosstalk. KEY MESSAGES : PPARγ is a transcription factor that tightly regulates cell metabolism. Low SHBG levels correlate with insulin resistance and associated endocrine abnormalities. PPARγ silencing reduces cell viability, triggers premature senescence and profound mitochondrial failure in equine ASCs. SHBG protein reverses senescent phenotype and apoptosis resistance of PPARγ- ASCs. SHBG improves mitochondrial dynamics and metabolism following PPARγ knockdown. SHBG might serve as a PPARγ potential mimicking agent for the modulation of ASCs metabolic processes.

Urinary haloacetic acid concentrations in relation to sex and thyroid hormones among reproductive-aged men.

Sex and thyroid hormones are critical for male reproductive health. However, the associations between haloacetic acid (HAA) exposure - a known endocrine disruptor - and sex and thyroid hormones in humans remains unclear. We thus recruited 502 male participants seeking fertility evaluation from a reproductive center. We measured concentrations of sex and thyroid hormones in a single blood sample and dichloroacetic acid (DCAA) and trichloroacetic acid (TCAA) in repeated urine samples. Multivariable linear regression models were constructed to evaluate the associations between HAA concentrations and hormone measurements. After adjusting for potential confounders and urinary creatinine concentrations, urinary concentrations of TCAA were inversely associated with serum levels of sex hormone-binding globulin (SHBG), testosterone (T), T/luteinizing hormone ratio (T/LH), and thyroid stimulating hormone (TSH) (all P for trend < 0.10). Compared with participants in the lowest quartile of TCAA concentrations, those in the highest quartile had reduced serum levels of SHGB by 14.2 % (95% CI: -26.7, -3.0 %), T by 11.1 % (95% CI: -21.7, -1.3 %), T/LH by 21.0 % (95% CI: -36.7, -7.1 %), and TSH by 19.1 % (95% CI: -39.7, -1.5 %). Additionally, we observed inverse associations between continuous measurements of urinary HAAs and serum levels of free T, bioactive T, and estradiol. Our findings suggest that male HAA exposure may be associated with disrupted sex and thyroid function.

Association of genetically determined chronotype with circulating testosterone: a Mendelian randomization study.

Low testosterone levels in men have been linked to decreased physical and mental function, as well as a reduced quality of life. Previous prospective observational studies have suggested an association between testosterone and sleep traits, but the causality of this relationship remains unclear. We aimed to explore the potential causal link between genetically determined sleep traits and testosterone levels in men using Mendelian randomization (MR) analysis from the UK Biobank dataset. Our exposures were genetic variants associated with sleep traits (chronotype and sleep duration), whereas our outcomes were traits of sex steroid hormones (total testosterone, TT; bioavailable testosterone, BAT; and sex hormone-binding globulin, SHBG). We employed inverse variance weighted (IVW) and weighted median (WM) methods to assess the causal associations. The IVW method offers a robust estimate of causality, whereas the WM method provides reliable results even when some genetic variants are invalid instruments. Our main analysis involving sex steroid hormones and chronotype identified 155 chronotype-related variants. The primary findings from the analysis, which used chronotype as the exposure and sex steroid hormones as the outcomes, showed that a genetically predicted chronotype score was significantly associated with an increased levels of TT (association coefficient ß, 0.08; 95% confidence interval [CI], 0.02-0.14; P = 0.008) and BAT (ß, 0.08; 95% CI, 0.02-0.14; P = 0.007), whereas there was no significant association with SHBG (ß, 0.01; 95% CI, -0.02-0.03; P = 0.64). Meanwhile, MR analysis of sex steroid hormones and sleep duration was performed, and 69 variants associated with sleep duration were extracted. There were no significant association between sleep duration and sex steroid hormones (TT, P = 0.91; BAT, P = 0.82; and SHBG, P = 0.95). Our data support a causal association between chronotype and circulating testosterone levels in men. These findings underscore a potential causal relationship between chronotype and testosterone levels in men, suggesting that lifestyle adjustments are crucial for men's health. Recognizing factors that influence testosterone is essential. One limitation of this study is the use of one-sample MR, which can introduce potential bias due to non-independence of genetic associations for exposure and outcome. In conclusion, our findings indicate that a morning preference is correlated with circulating testosterone levels, emphasizing the potential impact of lifestyle habits on testosterone levels in men.

Association between secondhand smoke exposure and serum sex hormone concentrations among US female adults: a cross-sectional analysis using data from the National Health and Nutrition Examination Survey, 2013-2016.

OBJECTIVE: To estimate the association between secondhand smoke (SHS) exposure and serum sex hormone concentrations in female adults (never smokers and former smokers). DESIGN: Cross-sectional analysis. SETTING: US National Health and Nutrition Examination Survey, 2013-2016. OUTCOME MEASURES: Serum sex hormone measures included total testosterone (TT) and oestradiol (E2), sex hormone-binding globulin (SHBG), the ratio of TT and E2 and free androgen index (FAI). Isotope dilution-liquid chromatography tandem mass spectrometry was used to measure serum TT and E2. SHBG was measured using immunoassay. The ratio of TT and E2 and FAI were calculated. SHS exposure was defined as serum cotinine concentration of 0.05-10 ng/mL. PARTICIPANTS: A total of 622 female participants aged ≥20 years were included in the analysis. RESULTS: For never smokers, a doubling of serum cotinine concentration was associated with a 2.85% (95% CI 0.29% to 5.47%) increase in TT concentration and a 6.29% (95% CI 0.68% to 12.23%) increase in E2 in fully adjusted models. The never smokers in the highest quartile (Q4) of serum cotinine level exhibited a 10.30% (95% CI 0.78% to 20.72%) increase in TT concentration and a 27.75% (95% CI 5.17% to 55.17%) increase in E2 compared with those in the lowest quartile (Q1). For former smokers, SHBG was reduced by 4.36% (95% CI -8.47% to -0.07%, p for trend=0.049) when the serum cotinine level was doubled, and the SHBG of those in Q4 was reduced by 17.58% (95% CI -31.33% to -1.07%, p for trend=0.018) compared with those in Q1. CONCLUSION: SHS was associated with serum sex hormone concentrations among female adults. In never smokers, SHS was associated with increased levels of TT and E2. In former smokers, SHS was associated with decreased SHBG levels.

Associations of Testosterone and Related Hormones With All-Cause and Cardiovascular Mortality and Incident Cardiovascular Disease in Men : Individual Participant Data Meta-analyses.

BACKGROUND: Whether circulating sex hormones modulate mortality and cardiovascular disease (CVD) risk in aging men is controversial. PURPOSE: To clarify associations of sex hormones with these outcomes. DATA SOURCES: Systematic literature review to July 2019, with bridge searches to March 2024. STUDY SELECTION: Prospective cohort studies of community-dwelling men with sex steroids measured using mass spectrometry and at least 5 years of follow-up. DATA EXTRACTION: Independent variables were testosterone, sex hormone-binding globulin (SHBG), luteinizing hormone (LH), dihydrotestosterone (DHT), and estradiol concentrations. Primary outcomes were all-cause mortality, CVD death, and incident CVD events. Covariates included age, body mass index, marital status, alcohol consumption, smoking, physical activity, hypertension, diabetes, creatinine concentration, ratio of total to high-density lipoprotein cholesterol, and lipid medication use. DATA SYNTHESIS: Nine studies provided individual participant data (IPD) (255 830 participant-years). Eleven studies provided summary estimates (n = 24 109). Two-stage random-effects IPD meta-analyses found that men with baseline testosterone concentrations below 7.4 nmol/L (<213 ng/dL), LH concentrations above 10 IU/L, or estradiol concentrations below 5.1 pmol/L had higher all-cause mortality, and those with testosterone concentrations below 5.3 nmol/L (<153 ng/dL) had higher CVD mortality risk. Lower SHBG concentration was associated with lower all-cause mortality (median for quintile 1 [Q1] vs. Q5, 20.6 vs. 68.3 nmol/L; adjusted hazard ratio [HR], 0.85 [95% CI, 0.77 to 0.95]) and lower CVD mortality (adjusted HR, 0.81 [CI, 0.65 to 1.00]). Men with lower baseline DHT concentrations had higher risk for all-cause mortality (median for Q1 vs. Q5, 0.69 vs. 2.45 nmol/L; adjusted HR, 1.19 [CI, 1.08 to 1.30]) and CVD mortality (adjusted HR, 1.29 [CI, 1.03 to 1.61]), and risk also increased with DHT concentrations above 2.45 nmol/L. Men with DHT concentrations below 0.59 nmol/L had increased risk for incident CVD events. LIMITATIONS: Observational study design, heterogeneity among studies, and imputation of missing data. CONCLUSION: Men with low testosterone, high LH, or very low estradiol concentrations had increased all-cause mortality. SHBG concentration was positively associated and DHT concentration was nonlinearly associated with all-cause and CVD mortality. PRIMARY FUNDING SOURCE: Medical Research Future Fund, Government of Western Australia, and Lawley Pharmaceuticals. (PROSPERO: CRD42019139668).