Mediation analysis of the testosterone treatment effect to prevent type 2 diabetes in the Testosterone for Prevention of Type 2 Diabetes Mellitus trial

OBJECTIVE: To determine if testosterone treatment effect on glycaemia is mediated through changes in total fat mass, abdominal fat mass, skeletal muscle mass, non-dominant handgrip, oestradiol (E2), and sex hormone-binding globulin (SHBG). DESIGN: Mediation analysis of a randomised placebo-controlled trial of testosterone. METHODS: Six Australian tertiary care centres recruited 1007 males, aged 50-74 years, with waist circumference ≥ 95 cm, serum total testosterone ≤ 14 nmol/L (immunoassay) and either impaired glucose tolerance or newly diagnosed type 2 diabetes on an oral glucose tolerance test (OGTT). Participants were enrolled in a lifestyle program and randomised 1:1 to 3 monthly injections of 1000 mg testosterone undecanoate or placebo for 2 years. Complete data were available for 709 participants (70%). Mediation analyses for the primary outcomes of type 2 diabetes at 2-years (OGTT ≥ 11.1 mmol/L and change in 2-hour glucose from baseline), incorporating potential mediators: changes in fat mass, % abdominal fat, skeletal muscle mass, non-dominant hand-grip strength, E2, and SHBG was performed. RESULTS: For type 2 diabetes at 2-years, the unadjusted OR for treatment was 0.53 (95% CI:0.35-0.79), which became 0.48 (95% CI:0.30-0.76) after adjustment for covariates. Including potential mediators attenuated the treatment effect (OR 0.77; 95% CI:0.44-1.35; direct effect) with 65% mediated. Only fat mass remained prognostic in the full model (OR: 1.23; 95% CI: 1.09-1.39; p < 0.001). CONCLUSION: At least part of the testosterone treatment effect was found to be mediated by changes in fat mass, abdominal fat, skeletal muscle mass, grip strength, SHBG, and E2, but predominantly by changes in fat mass.Kristy P. Robledo, Ian C. Marschner, David J. Handelsman, Karen Bracken, Bronwyn G.A. Stuckey, Bu B. Yeap, Warrick Inder, Mathis Grossmann, David Jesudason, Carolyn A. Allan, and Gary Witter

Effect of Testosterone treatment on bone microarchitecture and bone mineral density in men: a two-year RCT

CONTEXT: Testosterone treatment increases bone mineral density (BMD) in hypogonadal men. Effects on bone microarchitecture, a determinant of fracture risk, are unknown. OBJECTIVE: Determine the effect of testosterone treatment on bone microarchitecture using high resolution-peripheral quantitative computed tomography (HR-pQCT). DESIGN, SETTING, PARTICIPANTS: Men>50 years were recruited from six Australian centres. INTERVENTIONS: Injectable testosterone undecanoate or placebo over 2 years on the background of a community-based lifestyle program. MAIN OUTCOMES: Primary endpoint was cortical volumetric BMD (vBMD) at the distal tibia, measured using HR-pQCT in 177 men (one centre). Secondary endpoints included other HR-pQCT parameters and bone remodelling markers. Areal BMD (aBMD) was measured by dual energy X-ray absorptiometry (DXA) in 601 men (five centres). Using a linear mixed model for repeated measures, the mean adjusted differences (MAD) [95% CI] at 12 and 24 months between groups are reported as treatment effect. RESULTS: Over 24 months, testosterone treatment, compared to placebo, increased tibial cortical vBMD), 9.33mgHA/cm 3[3.96;14.71],p50 years, testosterone treatment for 2 years increased volumetric bone density, predominantly via effects on cortical bone. Implications for fracture risk reduction require further study.Mark Ng Tang Fui, Rudolf Hoermann, Karen Bracken, David J Handelsman, Warrick J Inder, Bronwyn G A Stuckey ... et al