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Flutamide Decreases Cortisol Clearance in Patients with Congenital Adrenal Hyperplasia

Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development (E.C., M.F.K., D.P.M.), The Warren Grant Magnuson Clinical Center (D.P.M.), and Clinical Center Pharmacy Department (K.A.C., M.R.M., A.R.), National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Evangelia Charmandari, M.D., Pediatric and Reproductive Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Drive, Building 10, Suite 9D42, Bethesda, Maryland 20892-1583.

Abstract

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency is characterized by a defect in cortisol and aldosterone secretion and adrenal hyperandrogenism. Current treatment is to provide adequate glucocorticoid and mineralocorticoid substitution to prevent adrenal crises and to suppress excess adrenal androgen secretion. Satisfactory adrenocortical suppression often requires supraphysiological doses of hydrocortisone, which may produce an unacceptable degree of hypercortisolism. A new four-drug treatment regimen of flutamide, testolactone, reduced hydrocortisone dose, and 9-fludrocortisone has been shown to achieve normal growth and development after 2 yr of therapy and may, therefore, represent a potential alternative approach to the treatment of children with classic congenital adrenal hyperplasia.

We investigated the effect of flutamide and testolactone, and flutamide alone, on cortisol clearance by performing clearance studies twice in 13 children (6 males and 7 females; age range, 7.0–14.5 yr) with classic 21-hydroxylase deficiency. All studies were conducted at least 3 months after institution of the four-drug treatment regimen. In eight patients (group 1), the first cortisol clearance study was performed on the four-drug regimen, and the second study was performed after a 48-h washout period off flutamide and testolactone. In five patients (group 2), the first study was conducted 1 wk after discontinuation of testolactone and while patients were receiving flutamide, hydrocortisone and 9-fludrocortisone, and the second study was performed after a 48-h washout period off flutamide. Oral hydrocortisone was held on the day of the clearance studies, and all patients received a continuous infusion of hydrocortisone (0.6 mg/m²·h) from 1800 h to 0200 h, with cortisol concentrations measured once hourly. In addition, an in vitro study was conducted to exclude the possibility of an analytical interference of flutamide, 2-hydroxyflutamide, and testolactone with the serum cortisol immunoassay.

Total body cortisol clearance was significantly lower during treatment with the four-drug regimen than during treatment with hydrocortisone and 9-fludrocortisone (153.5 ± 26.8 vs.355.4 ± 65.8 ml/min; P = 0.001). Similar results were obtained comparing flutamide, hydrocortisone, and 9-fludrocortisone therapy to hydrocortisone and 9-fludrocortisone therapy (155.8 ± 26.5 vs. 281.8 ± 96.2 ml/min; P = 0.037). The in vitro study indicated that an interference with the serum cortisol immunoassay was unlikely.

These findings indicate that the addition of flutamide and testolactone to the treatment regimen of hydrocortisone and 9-fludrocortisone decreases cortisol clearance in patients with classic 21-hydroxylase deficiency, and this effect seems to be due to flutamide. Glucocorticoid replacement doses should be reduced when flutamide is added to the treatment regimen of patients receiving hydrocortisone.

This article has been cited by other articles:

				M. Hero, O. A. Janne, K. Nanto-Salonen, L. Dunkel, and T. Raivio Circulating Antiandrogenic Activity in Children with Congenital Adrenal Hyperplasia during Peroral Flutamide Treatment J. Clin. Endocrinol. Metab., September 1, 2005; 90(9): 5141 - 5145. [Abstract] [Full Text] [PDF]