Levonorgestrel and Norethindrone Alter Insulin Action on Skeletal Muscle of the Female Rat

Summary Prospective studies of women receiving oral contraceptives suggest that the progestin component may induce insulin resistance and variable deterioration of glucose tolerance. Because the tissue sites and nature of this insulin antagonism are not well-defined, we studied the effects of two parenterally administered progestins, levonorgestrel (NG) and norethindrone (NE), on insulin-regulated glucose uptake and phenylalanine release by the perfused rat hindquarter. Female rats were injected sc for 14 days with NG or NE (10 or 30 μg/kg/day). Low-dose NG and high-dose NE approximate the per kg dose received by women taking a high-dose progestin oral contraceptive. Phenylalanine release and glucose uptake (nmole/min/g) by the perfused hindquarters were calculated from the A-V difference for each. Progestin treatment (30 μg/kg/d) significantly reduced phenylalanine release from hindquarters perfused without exogenous insulin. Hindquarters from the high dose NG and low and high dose NE rats perfused with insulin (100 μU/ml) released 22% less phenylalanine than control rats perfused with the same insulin concentration (P < 0.01) but the net suppression below baseline was similar in the control and steroid-treated groups. High-dose progestin treatment did not alter glucose uptake by hindquarters perfused without exogenous insulin. Insulin (100 μU/ml) increased glucose uptake by hindquarters of control and progestin-treated rats as compared to animals in the same treatment group perfused without exogenous insulin (P < 0.01). High dose NE impaired insulin-stimulated glucose uptake 24% below values of the control group (P < 0.01). The other NE and NG doses had no effect. Under these experimental conditions, both NG and NE have anabolic effects on skeletal muscle that are not additive to the acute effects of insulin. Only NE significantly impaired insulin action on glucose uptake.