Context & Objective: One of the treatments for hyperinsulinemic hyperandrogenism in non-obese women is combined androgen-receptor blockade (with flutamide; Flu), insulin-sensitization (with metformin; Met) plus an estro-progestagen contraceptive. We tested whether adding low-dose pioglitazone (Pio 7.5 mg/d) confers more benefit.

Setting: University Hospital.

Study Population and Design: This double-blind study enrolled 38 young women with hyperinsulinemic hyperandrogenism [mean body mass index (BMI) 24 Kg/m²], all of whom started on Flu (62.5 mg/d), Met (850 mg/d) plus a transdermal estro-progestagen, each for 21/28 d over 6 mo. Patients were randomly assigned to receive, in addition, placebo (n=19) or Pio (n=19; 7.5 mg/d), for the same 21/28 d over 6 mo.

Main Outcomes: BMI, waist-to-hip ratio (WHR), hirsutism score, fasting endocrine-metabolic markers, body composition, abdominal fat (visceral versus subcutaneous), and carotid intima media thickness (IMT) at study start and after 6 mo.

Results: PioFluMet reduced IMT more than FluMet, and lowered glucose, IGF-I and C-reactive protein more, as well as the ratio of LDL-to-HDL cholesterol and the ratio of Neutrophils-to-Lymphocytes. PioFluMet treatment was followed by a leaner body composition and a loss of visceral fat (both p<0.001). In the total group, the changes included not only decreases in WHR, hirsutism score and testosterone (all P<0.001), but also minor drops in ALT, AST, -GT and LDH (all P<0.005), indicating absence of hepatotoxicity; BMI remained unchanged. Clinical side-effects were not detected.

Conclusion: In this proof-of-concept study, addition of Pio to FluMet plus an estro-progestagen led to improvements in the endocrine-metabolic condition, in low-grade inflammation, in total and visceral adiposity, and in markers of cardiovascular health.