Low Testosterone in Men With Type 2 Diabetes: The Role of Estrogen Excess and Aromatase Activity.
Level 4 - case-series / case-control
Cross-sectional observational study with a reference control group
PubMed 41565585 · doi:10.1111/cen.70098
What was done
A cross-sectional study evaluated 180 men with type 2 diabetes and a reference cohort of 92 healthy men. The researchers measured sex steroid hormones, body composition, metabolic biomarkers, subcutaneous adipose tissue aromatase (*CYP19A1*) gene expression, and *CYP19A1* genetic variants. Estradiol and testosterone T-scores were calculated based on the healthy cohort to quantify relative estrogen excess.
What was found
Total testosterone <10 nM was associated with HbA1c (p < 0.001), BMI (p = 0.007), leptin (p = 0.009), and insulin resistance (p = 0.026). Calculated free testosterone (CFT) <220 pM 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 demonstrated relative estrogen excess (Estradiol T-score minus Testosterone T-score: 1.63 [0.94, 2.76] vs. 0.06 [-0.74, 0.51] in healthy controls, p < 0.001). A common *CYP19A1* variant was linked to higher adipose aromatase expression (p = 0.044) and low CFT (p = 0.042). On multivariable analysis, BMI (p < 0.001), *CYP19A1* expression (p = 0.020), and HbA1c (p = 0.006) were independently associated with CFT.
Why it matters
This study indicates that increased adipose aromatase expression and relative estrogen excess contribute to low testosterone in men with type 2 diabetes independently of BMI and glycemic control, highlighting a potential mechanistic and therapeutic target.
Limits
The cross-sectional design cannot establish causality between aromatase activity and hypogonadism. Free testosterone was calculated rather than directly measured via equilibrium dialysis, and the total diabetic cohort was relatively small (180 men).
Cited by
- contradicts Elevated insulin directly inhibits the aromatase enzyme, impairing the conversion of testosterone into estrogens in the ovary.