THE INSULIN-RESISTANCE IN WOMEN WITH HYPERANDROGENISM IS PARTIALLY REVERSED BY ANTIANDROGEN TREATMENT - EVIDENCE THAT ANDROGENS IMPAIR INSULIN ACTION IN WOMEN

To assess whether androgen excess per se might impair insulin action, insulin sensitivity was measured by a two-step 120 and 80 mU/m(2) . mi n) hyperinsulinemic euglycemic clamp combined with indirect calorimetr y and tracer glucose infusion in 43 women (13 obese and 30 nonobese) w ith normal glucose tolerance and clinical evidence of increased androg en action (hirsutism and/or polycystic ovary syndrome) as well as 12 a ge- and body mass index-matched healthy controls. Hyperandrogenic wome n were studied basally and after 3-4 months of antiandrogen treatment with 3 different drugs: spironolactone (n = 23), flutamide (n = 10), o r the GnRH agonist buserelin (n = 10). Six women given spironolactone were also reexamined after 1 yr of therapy. At baseline, insulin-media ted glucose uptake was lower in hyperandrogenic women than in controls (by ANOVA, F = 14.3; P < 0.001). Insulin resistance was observed in b oth ovarian and nonovarian hyperandrogenism, as distinguished by acute GnRH agonist testing. After antiandrogen therapy, insulin action on g lucose metabolism significantly increased for both the patients as a w hole (F = 7.4; P < 0.01) and each treatment group separately. However, insulin action remained lower than in controls and showed no further improvement in patients reevaluated after 1 yr of treatment. Increases in both oxidative and nonoxidative glucose metabolism accounted for t he improvement in substrate disposal induced by antiandrogen drugs. Th e increase in the effectiveness of insulin was greater in the lean sub jects, whereas the change was small and not statistically significant in the obese women. Response to treatment was more pronounced in women with nonovarian hyperandrogenism, particularly at the low insulin inf usion rate. Endogenous glucose production in hyperandrogenic patients was similar to that in healthy women and was unaffected by therapy. In conclusion, antiandrogen treatment partially reversed the peripheral insulin resistance associated with hyperandrogenism regardless of whic h antiandrogen was used. These data strongly suggest that in women, an drogen excess per se contributes to impairment of insulin action.