Flutamide-metformin for post-menarcheal girls with preclinical ovarian androgen excess:: evidence for differential response by androgen receptor genotype
Por:
Ong KK, de Zegher F, López-Bermejo A, Dunger DB and Ibañez-Toda L
Publicada:
1 nov 2007
Resumen:
yyObjective: Addition of androgen receptor (AR) blockade (flutamide) to insulin-sensitising therapy (metformin) may confer synergistic benefits in girls with hyperinsulinaemic androgen excess. We hypothesised that girls with shorter AR gene CAG repeat allefes, and thus greater receptor sensitivity, might benefit more from the addition of low-dose flutamide. Design: Open randomised crossover study. Methods: In this study, 32 post-menarcheal girls (mean age 12.1 years) with a history of low birth weight and precocious pubarche were subgrouped by CAG genotype ('short': CAG mean length :! 2 0, n = 14; 'long': CAG > 20, it = 18). Within each subgroup, girls were 1: 1 randomised to metformin alone (850 mg/day) or in combination with flutamide (62.5 mg/day) for 12 months. To allow comparisons with no treatment, long-CAG girls randomised to flutamide-metformin, and short-CAG girls randomised to metformin alone were observed for 12 months before treatment. Body composition by absorptiometry, fasting lipid profiles and levels of insulin, glucose and androgens were measured during the first 12 months on each treatment. Results: In all girls,]. 2 months flutamide-metformin lowered body fat and improved lipid profiles when compared with no treatment. Compared with metformin alone, flutamide-metformin achieved greater reductions in the percentage of body fat and abdominal fat mass in the short-CAG subgroup (P= 0.001 to P<0.0001). In contrast, in the long-CAG subgroup, flutamide-metformin produced no further improvements when compared with metformin alone. Conclusions: In young post-menarcheal girls with preclinical androgen excess, low-dose flutamidemetformin improved body composition and key endocrine-metabolic abnormalities. However, only those girls with genetic markers of greater AR sensitivity may benefit from the addition of flutamide above metformin alone.
Filiaciones:
Ong KK:
Medical Research Council Epidemiology Unit, Cambridge CB0 2QQ, UK
de Zegher F:
Medical Research Council Epidemiology Unit, Cambridge CB0 2QQ, UK
López-Bermejo A:
Medical Research Council Epidemiology Unit, Cambridge CB0 2QQ, UK
Dunger DB:
Medical Research Council Epidemiology Unit, Cambridge CB0 2QQ, UK
Ibañez-Toda L:
Medical Research Council Epidemiology Unit, Cambridge CB0 2QQ, UK
MRC, Epidemiol Unit, Cambridge CB0 2QQ, England
MRC, Dept Pediat, Cambridge CB0 2QQ, England
Univ Leuven, Dept Woman & Child, B-3000 Louvain, Belgium
Dr Josep Trueta Hosp, Diabet Endocrinol & Nutr Unit, Girona 17007, Spain
Univ Barcelona, Hosp Sant Joan De Deu, Endocrinol Unit, Barcelona 08950, Spain
MRC, Epidemiol Unit, Cambridge CB0 2QQ, England
MRC, Dept Pediat, Cambridge CB0 2QQ, England
Univ Leuven, Dept Woman & Child, B-3000 Louvain, Belgium
Dr Josep Trueta Hosp, Diabet Endocrinol & Nutr Unit, Girona 17007, Spain
Univ Barcelona, Hosp Sant Joan De Deu, Endocrinol Unit, Barcelona 08950, Spain
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