A randomized double-blind single center study of testosterone replacement therapy or placebo in testicular cancer survivors with mild Leydig cell insufficiency (Einstein-intervention)

Introduction: Elevated luteinizing hormone (LH) in combination with low-normal testosterone (mild Leydig cell insufficiency) is common in testicular cancer (TC) survivors and is associated with impaired insulin sensitivity and metabolic syndrome. The aim was to evaluate if testosterone replacement therapy (TRT) improves metabolic health in this subgroup of TC survivors. Patients and Methods: This was a single-center, double-blind, randomized, controlled trial. The main eligibility criterion was LH above the age-adjusted upper limit of normal in combination with free testosterone in the lower half of the age-adjusted normal range (mild Leydig cell insufficiency) >1 year after TC treatment. Eligible patients were randomly assigned (1:1) to 12 months transdermal TRT (Tostran, gel, 2%) or placebo with a maximum daily dose of 40 mg. The primary outcome was difference in Δ2 hour glucose measured with oral glucose tolerance test between groups assessed at 12 months. Outcomes were assessed after 6-, 12- and 3 months post-treatment. The study was registered at www.clinicaltrial.gov (NCT02991209) and ended June 2019. Results: Between October 2016 and February 2018, 140 patients were screened for eligibility and 69 were randomized to testosterone (n = 35, 51%) or placebo (n = 34, 49%). TRT was not associated with a statistically significant difference in Δ2 hour glucose compared to placebo after 12 months of treatment (0.04 mmol/L (95% CI: -0.53, 0.60)). There was no statistically significant difference in Δ2 hour insulin between the groups after 12 months of treatment (28.23 pmol/L (95% CI: -34.40, 90.86)). Similarly, TRT was not associated with significant improvement in components of metabolic syndrome. TRT was associated with a decrease in fat mass after 12 months compared to placebo (-1.35 kg, (95% CI: -2.53, -0.18)). Conclusion: In TC survivors with mild Leydig cell insufficiency, TRT was not associated with improvement of metabolic health. These findings do no not support routine use of TRT in these patients.