Randomized studies have disclosed that ethinylestradiol-drospirenone and flutamide-metformin have divergent effects on the body adiposity and adipokines of adolescents and young women with hyperinsulinemic androgen excess. We have now tested in 41 patients from those original studies whether the divergent effects on body adiposity could be mediated by divergent levels of follistatin, an adipokine that promotes subcutaneous adipogenesis. Circulating follistatin was measured, at study start and after 9 months, with an enzyme-linked immunosorbent assay. Treatment with ethinylestradiol-drospirenone was accompanied by a more adipose body composition and by a nearly 4-fold rise of follistatinemia (P<0.0001). In contrast, treatment with low-dose flutamide-metformin did not increase body adiposity and did not alter follistatinemia detectably. Finally, combined treatment with ethinylestradiol-drospirenone and flutamide-metformin was accompanied by an intermediate (2- to 3-fold) rise of follistatinemia (P<0.005). In conclusion, the principle that ethinylestradiol-drospirenone and flutamide-metformin exert diverging effects on adipokines is herewith broadened to include circulating follistatin. Hyperfollistatinemia may be among the mechanisms whereby oral contraceptives aggravate the body adiposity of adolescents and young women with hyperinsulinemic androgen excess.