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

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.

Cross-sectional study.

One hundred eighty men with type 2 diabetes and 92 healthy men in the reference cohort.

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.

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.

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.