Treatment of hirsutism, hyperandrogenism, oligomenorrhea, dyslipidemia, and hyperinsulinism in nonobese, adolescent girls: Effect of flutamide

Functional ovarian hyperandrogenism, a Variant of polycystic ovary syndrome , is often associated with hyperinsulinism and dyslipidemia. The mechanisms interlinking this triad are poorly understood; both hyperandrogenism and h yperinsulinism have been proposed as factors involved in the pathogenesis o f the dyslipidemia. Precocious pubarche (PP) in girls is a risk factor for subsequent anovulation, ovarian and adrenal, hyperandrogenism, hyperinsulin ism and dyslipidemia. Flutamide, a nonsteroidal antiandrogen, is known to be effective in reducin g hirsutism in patients with ovarian hyperandrogenism. However, the effects of flutamide on the endocrine-metabolic correlates of hyperandrogenism are uncertain. We assessed the effects of low dose flutamide treatment (250 mg daily for 18 months) on hormonal and metabolic variables in 18 nonobese ad olescent girls (age, 16.8 +/- 0.3 yr) with functional ovarian hyperandrogen ism (diagnosis by GnRH agonist test) after PP. Flutamide treatment was accompanied by a marked decrease in the hirsutism s core, free androgen index, and testosterone, andro-stenedione, and dehydroe piandrosterone levels and by an increase in sex hormone-binding globulin co ncentrations. However, there were no substantial changes in the pattern of menstrual cycles, gonadotropin, estradiol, or dehydroepiandrosterone sulfat e concentrations, and there was no detectable effect on the 17-hydroxyproge sterone response to GnRH agonist. Serum triglycerides, total cholesterol, a nd low-density lipoprotein cholesterol levels decreased markedly during flu tamide therapy, whereas high-density lipoprotein cholesterol, fasting glyce mia/insulinemia, and the insulin response to a glucose load remained unchan ged. Flutamide was well tolerated. In conclusion, low dose flutamide treatment was found to be an effective an d safe approach to reduce hirsutism and circulating androgen, low-density l ipoprotein cholesterol, and triglyceride levels in girls with functional ov arian hyperandrogenism after PP. However, flutamide failed to increase high -density lipoprotein cholesterol levels or decrease hyperinsulinemia, i.e. to affect two major risk factors for subsequent cardiovascular disease.