Association Between Low Sex Hormone-Binding Globulin and Increased Risk of Type 2 Diabetes Is Mediated by Increased Visceral and Liver Fat: Results From Observational and Mendelian Randomization Analyses.

The aim of this study was to investigate the associations among sex hormone-binding globulin (SHBG), visceral adipose tissue (VAT), liver fat content, and risk of type 2 diabetes (T2D). In the Netherlands Epidemiology of Obesity study, 5,690 women (53%) and men (47%) without preexisting diabetes were included and followed for incident T2D. SHBG concentrations were measured in all participants, VAT was measured using MRI, and liver fat content was measured using proton magnetic resonance spectroscopy in a random subset of 1,822 participants. We examined associations between SHBG and liver fat using linear regression and bidirectional Mendelian randomization analyses and between SHBG and T2D using Cox regression adjusted for confounding and additionally for VAT and liver fat to examine mediation. Mean age was 56 (SD 6) years, mean BMI was 30 (SD 4) kg/m2, median SHBG was 47 (interquartile range [IQR] 34-65) nmol/L in women and 34 (26-43) nmol/L in men, and median liver fat was 3.4% (IQR 1.6-8.2%) in women and 6.0% (2.9-13.5%) in men. Compared with the highest SHBG quartile, liver fat was 2.9-fold (95% CI 2.4, 3.4) increased in women and 1.6-fold (95% CI 1.3, 1.8) increased in men, and the hazard ratio of T2D was 4.9 (95% CI 2.4, 9.9) in women and 1.8 (1.1, 2.9) in men. Genetically predicted SHBG was associated with liver fat content (women: SD -0.45 [95% CI -0.55, -0.35]; men: natural logarithm, -0.25 [95% CI -0.34, -0.16]). VAT and liver fat together mediated 43% (women) and 60% (men) of the SHBG-T2D association. To conclude, in a middle-aged population with overweight, the association between low SHBG and increased risk of T2D was, for a large part, mediated by increased VAT and liver fat.

Is there a need for liver enzyme monitoring in people using gender-affirming hormone therapy?

CONTEXT: Individuals with gender dysphoria can receive gender-affirming hormone therapy. Different guidelines mention a severe risk of liver injury within the first months after the start of treatment with anabolic androgenic steroids, anti-androgens, and oral contraceptives, which is potentially fatal. OBJECTIVE: The incidence of liver injury in a transgender population using gender-affirming hormone therapy. DESIGN: Multicentre prospective study with 1933 transgender individuals, who started with hormone therapy between 2010 and 2020. METHODS: The following parameters were analysed before hormone therapy, after 3 months, and after 12 months of hormone therapy: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and gamma-glutamyltransferase (GGT). Both male and female reference values were considered. Liver injury was defined as either an elevation of 2× upper limit of normal (ULN) of ALP, 3× ULN of ALT, or 3× ULN of AST. RESULTS: 889 transgender women and 1044 transgender men were included in the analysis. The incidence of liver injury within 12 months after the start of hormone therapy, without attribution to alcohol abuse, medical history, or comedication was 0.1 and 0.0%. in transgender women according to female and male reference intervals respectively, and 0.6 and 0.4% in transgender men (female and male reference intervals). CONCLUSION: The incidence of liver injury is found to be very low. We, therefore, conclude that liver enzyme monitoring within the frame of the risk of liver injury due to hormone therapy is not necessary for a transgender population.