The insulin resistance in women with hyperandrogenism is partially reversed by antiandrogen treatment: evidence that androgens impair insulin action in women.

Abstract

To assess whether androgen excess per se might impair insulin action, insulin sensitivity was measured by a two-step (20 and 80 mU/m2.min) hyperinsulinemic euglycemic clamp combined with indirect calorimetry and tracer glucose infusion in 43 women (13 obese and 30 nonobese) with normal glucose tolerance and clinical evidence of increased androgen action (hirsutism and/or polycystic ovary syndrome) as well as 12 age- and body mass index-matched healthy controls. Hyperandrogenic women were studied basally and after 3-4 months of antiandrogen treatment with 3 different drugs: spironolactone (n = 23), flutamide (n = 10), or the GnRH agonist buserelin (n = 10). Six women given spironolactone were also reexamined after 1 yr of therapy. At baseline, insulin-mediated glucose uptake was lower in hyperandrogenic women than in controls (by ANOVA, F = 14.3; P < 0.001). Insulin resistance was observed in both ovarian and nonovarian hyperandrogenism, as distinguished by acute GnRH agonist testing. After antiandrogen therapy, insulin action on glucose metabolism significantly increased for both the patients as a whole (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 I yr of treatment. Increases in both oxidative and nonoxidative glucose metabolism accounted for the improvement in substrate disposal induced by antiandrogen drugs. The increase in the effectiveness of insulin was greater in the lean subjects, 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 infusion 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 which antiandrogen was used. These data strongly suggest that in women, androgen excess per se contributes to impairment of insulin action.

Diagnosis of Polycystic Ovary Syndrome

“…(62) This is further confirmed by a study on female to male transsexuals that administration of testosterone induces insulin resistance in healthy female subjects. (63) Clinically, a number of antiandrogens including cyproterone acetate, flutamide, spironolacton, and finasteride have been used to treat hyperan-drogenism in women with or without PCOS.…”

“…(54) Although treatment with antiandrogens may improve the lipid profile in PCOS women with hyperandrogenism, (72) the peripheral insulin resistance associated with hyperandrogenism can only be partially reversed. (62) Based on these observations, various insulin-sensitizing agents including metformin and troglitazone have been tried to reduce the insulin resistance and in turn lower the extent of hyperandrogenism in women with PCOS.…”

Obesity and the polycystic ovary syndrome

“…As previously reported, several studies have demonstrated that antiandrogens, as well as reducing androgen levels, may significantly improve insulin resistance and hyperinsulinemia in either obese and non-obese PCOS women. These effects have been observed regardless of the type of drug used, the results observed being substantially similar for spironolactone, 55 flutamide, 54,108 finasteride 54,55 or GnRH agonists. 108 On the other hand, there are no studies investigating the effect of pure antiandrogens on body compartments and fat distribution in these women.…”

Diverse impacts of aging on insulin resistance in lean and obese women with polycystic ovary syndrome: evidence from 1345 women with the syndrome

“…The gradual decrease in IR through time may be partly attributed to androgen decline with aging. Indeed, a chicken-and-egg situation exists between IR and hyperandrogenemia in PCOS, and several in vitro and in vivo studies have demonstrated an improvement in IR through androgen reduction (37,38,39). Additionally, in either pre-or postmenopausal normal women, a direct relationship between androgen levels and IR or DM risk has been determined (40,41).…”