Effects of metformin and leuprolide acetate on insulin resistance and testosterone levels in nondiabetic postmenopausal women: a randomized, placebo-controlled trial

Objective To determine whether insulin sensitizers lower androgen levels and whether androgen suppression improves insulin resistance in nondiabetic postmenopausal women. Design Randomized, double-blind, placebo-controlled study. Setting Clinical and Translational Research Center of a university hospital. Patient(s) Thirty-five postmenopausal women aged 50–79 years with insulin resistance and higher T levels. Intervention(s) Subjects were randomized to metformin plus leuprolide acetate (LA) placebo, LA plus metformin placebo, or LA placebo plus metformin placebo in a 1:1:1 fashion during a 12-week period. Main Outcome Measure(s) Insulin sensitivity (M) assessed by euglycemic–hyperinsulinemic clamp and free T by equilibrium dialysis. Result(s) In those randomized to metformin, free T decreased by 19% compared with placebo, along with an expected improvement in M. Total T also decreased significantly, whereas sex hormone-binding globulin (SHBG) did not change. In those randomized to LA, the percent change in M was not different from placebo, despite a 48% relative decrease in free T levels. Conclusion(s) These data are the first to establish a causal link between insulin resistance and T in postmenopausal women. They confirm that treatment of insulin resistance decreases T production in this population and demonstrate that pharmacologic lowering of T does not affect insulin resistance.