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Circulating Antiandrogenic Activity in Children with Congenital Adrenal Hyperplasia during Peroral Flutamide Treatment

Hospital for Children and Adolescents (M.H., L.D., T.R.), University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland; Biomedicum Helsinki (O.A.J., T.R.), Institute of Biomedicine/Physiology, and Department of Clinical Chemistry (O.A.J.), University of Helsinki, Helsinki, Finland; Department of Pediatrics (K.N.-S.), Turku University Central Hospital, Turku, Finland; and Department of Pediatrics (L.D.), Kuopio University Hospital, Kuopio, Finland

Address all correspondence and requests for reprints to: Taneli Raivio, M.D., Hospital for Children and Adolescents, University of Helsinki, P.O. Box 281, FIN-00029 HUS, Finland. E-mail: taneli.raivio{at}helsinki.fi.

Context: The degree of androgen receptor blockade achieved with peroral flutamide is unknown.

Objective: The aim of this study was to examine the contribution of flutamide to circulating antiandrogenic activity in children with congenital adrenal hyperplasia using a recombinant cell bioassay.

Design: We describe an open-label, prospective clinical study.

Setting: The study was conducted at the Hospital for Children and Adolescents, University of Helsinki, or the Turku University Hospital, Finland.

Participants: Seven children, age 7.2–10.5 yr, were included.

Intervention: As an experimental approach to improve control of height velocity and the rate of bone maturation, the patients received letrozole (2.5 mg/d) and flutamide (10 mg/kg·d) and were followed up at 3-month intervals for 3–12 months. Before employing the bioassay, two pools of sera (obtained before and during flutamide treatment) were supplemented with increasing amounts of testosterone, and all sera (n = 27) of individual patients were supplemented with a constant amount of exogenous testosterone.

Main Outcome Measure: The main outcome measure was circulating antiandrogenic activity.

Results: Flutamide and/or its metabolites shifted the dose-response curve of testosterone, in that only the highest testosterone concentration, corresponding to 1803 ng/dl (62.5 nM) in human serum, was measurable by the bioassay. In individual sera supplemented with testosterone, flutamide treatment suppressed androgen bioactivity from 378 ± 20 ng/dl (13.1 ± 0.7 nM) (mean ± SEM) (pretreatment) to 110 ± 20 ng/dl (3.8 ± 0.7 nM) (3 months), 83.7 ± 12 ng/dl (2.9 ± 0.4 nM) (6 months), 46.2 ± 6 ng/dl (1.6 ± 0.2 nM) (9 months), and 57.7 ± 9 ng/dl (2.0 ± 0.3 nM) (12 months) testosterone equivalents (P < 0.01).

Conclusions: A dose of flutamide less than 10 mg/kg·d appears sufficient to inhibit AR in children. The recombinant cell bioassay employed herein offers a novel means to monitor the treatment of patients receiving antiandrogens.

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