Aromatase Inhibition Reduces Insulin Sensitivity in Healthy Men

Context: Deficiency of aromatase, the enzyme that catalyzes the conversion of androgens to estrogens, is associated with insulin resistance in humans and mice. Objective: We hypothesized that pharmacological aromatase inhibition results in peripheral insulin resistance in humans. Design: This was a double-blind, randomized, controlled, crossover study. Setting: The study was conducted at a clinical research facility. Participants: Seventeen healthy male volunteers (18-50 y) participated in the study. Intervention:The intervention included oral anastrozole (1 mg daily) and placebo, each for 6 weeks with a 2-week washout period. Main Outcome Measure: Glucose disposal and rates of lipolysis were measured during a stepwise hyperinsulinemic euglycemic clamp. Data are mean (SEM). Results: Anastrozole therapy resulted in significant estradiol suppression (59.9 +/- 3.6 vs 102.0 +/- 5.7 pmol/L, P = <.001) and a more modest elevation of total T (25.8 +/- 1.2 vs 21.4 +/- 0.7 nmol/L, P = .003). Glucose infusion rate, during the low-dose insulin infusion, was lower after anastrozole administration (12.16 +/- 1.33 vs 14.15 +/- 1.55 mu mol/kg.min, P = .024). No differences in hepatic glucose production or rate of lipolysis were observed. Conclusion: Aromatase inhibition reduces insulin sensitivity, with respect to peripheral glucose disposal, in healthy men. Local generation and action of estradiol, at the level of skeletal muscle, is likely to be an important determinant of insulin sensitivity.