Low Testosterone in Men With Type 2 Diabetes: The Role of Estrogen Excess and Aromatase Activity

Objective Low testosterone is common in men with type 2 diabetes and is associated with adverse metabolic outcomes. Our objective was to identify factors associated with low total and calculated free testosterone (CFT) in men with type 2 diabetes, with a focus on relative estrogen excess and subcutaneous adipose aromatase expression. Design Cross‐sectional study. Patients One hundred eighty men with type 2 diabetes and 92 healthy men in the reference cohort. Measurements Sex steroid hormones were measured alongside body composition, metabolic biomarkers, adipose tissue aromatase gene expression, and genetic variants of aromatase. T‐scores for testosterone and estradiol were calculated using a healthy reference cohort. Results HbA1c ( p < 0.001), BMI ( p = 0.007), leptin ( p = 0.009) and insulin resistance ( p = 0.026) were associated with lower total testosterone (<10 nM). Lower CFT (<220pM) was associated with age ( p = 0.049), BMI ( p < 0.001), interleukin‐6 ( p < 0.001), leptin ( p = 0.003) and insulin ( p = 0.020). Men with type 2 diabetes and low testosterone had relative estrogen excess (Estradiol T score−Testosterone T score 1.63 [0.94, 2.76]) compared to healthy controls (0.06 [−0.74, 0.51], p < 0.001). A common CYP19A1 variant was associated with increased adipose CYP19A1 expression ( p = 0.044) and low CFT ( p = 0.042). Multivariable analysis identified BMI ( p < 0.001), CYP19A1 expression ( p = 0.020) and HbA1c ( p = 0.006) as independently associated with CFT. Conclusion In men with type 2 diabetes, low testosterone is associated with adiposity, glycaemic control, and increased adipose aromatase expression. Relative estrogen excess may contribute to hypothalamic‐pituitary‐testicular axis suppression and represents a novel target for diagnostic and therapeutic strategies.