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BACKGROUND The endocrine hallmark of polycystic ovary syndrome (PCOS) is hyperinsulinaemic hyperandrogenism; another facet of PCOS is low-grade inflammation. METHODS In adolescents and young women with hyperinsulinaemic hyperandrogenism (n = 118; mean age 16 years, body mass index 22 kg/m(2)), we analysed whether the PCOS-associated rise in leukocyte count is already detectable at young age and, if so, whether such elevation is lowered by metformin, flutamide-metformin, oral contraception (OC), or their combination. RESULTS Leukocyte count (x 1000/mm(3)) in patients was high versus controls (7.5 +/- 0.1 versus 6.4 +/- 0.1; P < 0.001) due to a rise in neutrophils (4.2 +/- 0.1 versus 3.0 +/- 0.1; P < 0.001). Randomized studies at mean ages of 12.5 years (n = 24) and 15.2 years (n = 33) demonstrated normalizing effects of metformin (850 mg/day; P < 0.001) and, respectively, metformin plus flutamide (62.5 mg/day) on neutrophil counts; in young women (18.3 years; n = 41), the neutrophil count rose further on OC monotherapy (P = 0.003), but normalized on the same OC plus flutamide-metformin (P < 0.001 versus OC alone). CONCLUSIONS (i) A high leukocyte count is already present in girls with hyperinsulinaemic hyperandrogenism, and this is due to a raised neutrophil count; (ii) this hyperneutrophilia is attenuated by metformin or flutamide-metformin, and is amplified by OC monotherapy; (iii) if these treatments are combined, the normalizing effect of flutamide-metformin overcomes the OC effect on neutrophil count.

Flutamide is a nonsteroidal antiandrogenic agent that to date has been used chiefly in treating prostate cancer. Hepatotoxicity, although rare, is a potentially fatal side effect that has been documented with doses of 750 to 1500 mg daily. Minor hepatotoxicity has been associated with doses as low as 250 mg daily. This study examined the risk of hepatotoxicity when flutamide was given in ultralow doses for up to 3 years and for periods as long as 54 months. Participants were 190 hyperandrogenic girls and young women, 150 of whom had established and 40 incipient polycystic ovary syndrome (PCOS); none were obese. Flutamide was given alone or in combination with metformin, an insulin sensitizer, and/or an estro-progestagen oral contraceptive containing gestodene or drospirenone. Doses of flutamide ranged from 62.5 to 250 mg daily. Circulating levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) served as markers of hepatic toxicity. All participants had normal levels of ALT and AST at baseline, and concentrations were unchanged during flutamide treatment-both 3 months after the start of treatment and at the last assessment, which took place after a mean of 19 months on treatment. Treatment times ranged up to 54 months. No subject had an AST or ALT level of 45 U/L or higher at any time. These findings suggest that flutamide is a safe treatment when used in low dosage to treat hyperandrogenic, nonobese girls and young women having actual or impending PCOS. It remains possible that hepatic toxicity may, in rare instances, develop in patients taking ultralow doses of flutamide. Nevertheless, the investigators anticipate that such doses may become a part of treating hyperandrogenic girls and young women with PCOS. They do recommend that transaminase levels be monitored during flutamide treatment.