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Flutamide-Metformin Plus Ethinylestradiol-Drospirenone for Lipolysis and Antiatherogenesis in Young Women with Ovarian Hyperandrogenism: The Key Role of Early, Low-Dose Flutamide

Endocrinology Unit (L.I.), Hormonal Laboratory (C.V.), and Department of Gynecology (S.C.), Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain 08950; and Department of Pediatrics (F.d.Z.), University of Leuven, B-3000 Leuven, Belgium

Address all correspondence and requests for reprints to: Lourdes Ibáñez, M.D., Ph.D., Endocrinology Unit, Hospital Sant Joan de Déu, University of Barcelona, Passeig de Sant Joan de Déu, 2, 08950 Esplugues, Barcelona, Spain. E-mail: libanez{at}hsjdbcn.org.

A low-dose combination of flutamide-metformin and ethinylestradiol-drospirenone was recently found to reduce the excess of total and abdominal fat, to diminish the deficit in lean mass, and to attenuate the dysadipocytokinemia of young women with ovarian hyperandrogenism, a variant of polycystic ovary syndrome. We questioned the need to give flutamide, an androgen receptor blocker, together with an oral contraceptive that contains drospirenone, a progestin claimed to have antiandrogen properties.

The additive effects of low-dose flutamide (62.5 mg/d) were assessed over 3 months in young patients with hyperinsulinemic ovarian hyperandrogenism (n = 40; age, 17 yr; body mass index, 22 kg/m²); all participants started on metformin (850 mg/d) and a fourth-generation contraceptive (ethinylestradiol 30 µg plus drospirenone 3 mg, 21 d/month), and they were randomized to receive flutamide in addition (n = 20) or not (n = 20).

Fasting blood glucose, serum insulin, lipid profile, testosterone, adiponectin, and IL-6 were determined at baseline and after 3 months, together with body composition (by dual x-ray absorptiometry) and with Doppler assessment of ovarian arterial resistance. At start, the pulsatility and resistance indices of ovarian arteries were elevated.

By comparison of 3-month changes between randomized subgroups, the addition of low-dose flutamide was found to have consistently (more) normalizing effects on low-density lipoprotein cholesterol, IL-6, and adiponectin, lean body mass, total and abdominal fat mass, and arterial flow in the ovaries.

In conclusion, low-dose flutamide is herewith identified as a pivotal component within a first contraceptive combination therapy that has been shown to attenuate the hypoadiponectinemia, ovarian vascular hyperresistance, lean mass deficit, and central adiposity of young women with polycystic ovary syndrome. Finally, these data challenge any claim that drospirenone, as currently used in a contraceptive, is a clinically significant antiandrogen.

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