OBJECTIVE: Increased serum ferritin levels, indicating increased body iron stores, have been found in overweight and obese women with polycystic ovary syndrome (PCOS). This finding might result from reduced menstrual losses secondary to oligo- or amenorrhea or from hyperinsulinism secondary to insulin resistance, because insulin favors the intestinal absorption and the tissue deposition of iron. To explore which of these mechanisms is responsible for the increase in body iron stores in women with PCOS, we have monitored the changes in serum ferritin levels during treatment with an antiandrogenic oral contraceptive or an insulin sensitizer. RESEARCH DESIGN AND METHODS: Thirty-four consecutive PCOS patients were randomized to an oral contraceptive containing 35 microg ethinyl-estradiol plus 2 mg cyproterone acetate (Diane(35) Diario) or metformin (850 mg twice daily), and their serum ferritin levels were evaluated at baseline and after 12 and 24 weeks of treatment. RESULTS: Despite the fact that treatment with Diane(35) Diario restored regular menstrual cycles in all the patients, whereas metformin only did so in 50% of them, serum ferritin levels decreased at 12 and 24 weeks of treatment only with metformin, in association with a marked increase in insulin sensitivity. On the contrary, no changes in ferritin and insulin sensitivity were observed with Diane(35) Diario. CONCLUSIONS: Our present results suggest that insulin resistance and hyperinsulinism, and not the reduced menstrual losses secondary to from oligo- or amenorrhea, are responsible of the increased ferritin levels and body iron stores found in overweight and obese women with PCOS.