Low-dose pioglitazone and low-dose flutamide added to metformin and oestro-progestagens for hyperinsulinaemic women with androgen excess: add-on benefits disclosed by a randomized double-placebo study over 24 months

Context and aim Metformin plus oestro-progestagen is a combination treatment for non-obese women with hyperinsulinaemic androgen excess. We explored whether low-dose pioglitazone (Pio) and flutamide (Flu) has readily detectable add-on effects. Design patients, intervention Randomized, double-placebo pilot study over 24 months; 38 women with hyperinsulinaemic androgen excess (mean age 20 years; BMI 23 center dot 7 kg/m(2)); all women received metformin and an oestro-progestagen for 24 months, and add-on Flu (62 center dot 5 mg/day; 21/28 days) for 18 months. A first randomization was performed at start of the study, for Pio (7 center dot 5 mg/day; 21/28 days) vs. Pio-placebo, with a cross-over of Pio subgroups at 18 month. A second randomization was performed at 18 months, for Flu vs. Flu-placebo until 24 months. Main outcomes Intima media thickness (IMT); body composition by absorptiometry; abdominal fat partitioning by magnetic resonance; circulating glucose, insulin, IGF-I, androgens, LDL : HDL ratio, RBP4, vaspin. Results Add-on effects of Pio included a gain of lean mass (mirrored by a loss of fat) and an accelerated lowering of IMT (P < 0 center dot 001). Add-on effects of flutamide included a further reduction of androgen excess. Between 0 and 18 months, women lost a quarter of their visceral fat (P < 0 center dot 001; independently of Pio); beyond 18 months, a rebound of visceral fat occurred in women who had stopped Pio and Flu. Between 0 and 24 months, insulin sensitivity increased, as did circulating RBP-4 and vaspin (all P = 0 center dot 001). Conclusion Low-dose Pio and Flu further improve long-term markers - such as IMT, lean mass and visceral fat - when jointly added to a treatment of metformin plus an oestro-progestagen in non-obese women with hyperinsulinaemic androgen excess.