This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Charmandari, E. Articles by Brook, C. G. D. Search for Related Content PubMed PubMed Citation Articles by Charmandari, E. Articles by Brook, C. G. D.

Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency: Alterations in Cortisol Pharmacokinetics at Puberty

London Centre for Paediatric Endocrinology, University College London (E.C., P.C.H., C.G.D.B.) and Department of Clinical Pharmacology, St. Bartholomew’s, and The Royal London School of Medicine and Dentistry (A.J.), London, United Kingdom W1N 8AA

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

Abstract

In congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, treatment with glucocorticoid and mineralocorticoid substitution is not always satisfactory. Suboptimal control is often observed in pubertal patients, despite adequate replacement doses and adherence to treatment. We investigated whether the pubertal process is associated with alterations in cortisol pharmacokinetics resulting in a loss of control of the hypothalamic-pituitary-adrenal axis.

We determined the pharmacokinetics of hydrocortisone administered iv as a bolus. A dose of 15 mg/m² body surface area was given to 14 prepubertal (median age, 9.4 yr; range, 6.1–10.8 yr), 20 pubertal (median, 13.5 yr; range, 10.6–16.8 yr), and 6 postpubertal (median, 18.2 yr; range, 17.2–20.3 yr) patients with salt-wasting CAH. All patients were on standard replacement therapy with hydrocortisone and 9-fludrocortisone. Serum total cortisol concentrations were measured at 10-min intervals for 6 h following iv hydrocortisone bolus and analyzed using a solid-phase RIA.

The serum total cortisol clearance curve was monoexponential. Mean clearance was significantly higher in the pubertal group (mean, 427.0 mL/min; SD, 133.4) compared with the prepubertal (mean, 248.7 mL/min; SD, 100.6) and postpubertal (mean, 292.4 mL/min; SD, 106.3) (one-way ANOVA, F = 9.8, P < 0.001) groups. This effect persisted after adjustment for body mass index. The mean volume of distribution was also significantly higher in the pubertal (mean, 49.5 L; SD, 12.2) than the prepubertal (mean, 27.1 L; SD, 8.4) patients but not in the postpubertal (mean, 40.8 L; SD, 16) (ANOVA, F = 15.2, P < 0.001) patients. The significance remained after correction for body mass index. There was no significant difference in mean half-life of total cortisol in prepubertal (mean, 80.2 min; SD, 19.4), pubertal (mean, 84.4 min; SD, 24.9), and postpubertal (mean, 96.7 min; SD, 9.9) patients. Similar differences between groups were observed when the pharmacokinetic parameters of free cortisol were examined. In addition, the half-life of free cortisol was significantly shorter in females compared with males (P = 0.04).

These data suggest that puberty is associated with alterations in cortisol pharmacokinetics resulting in increased clearance and volume of distribution with no change in half-life. These alterations probably reflect changes in the endocrine milieu at puberty and may have implications for therapy of CAH and other conditions requiring cortisol substitution in the adolescent years.

This article has been cited by other articles:

				E. CHARMANDARI and G. P CHROUSOS Metabolic Syndrome Manifestations in Classic Congenital Adrenal Hyperplasia: Do They Predispose to Atherosclerotic Cardiovascular Disease and Secondary Polycystic Ovary Syndrome? Ann. N.Y. Acad. Sci., November 1, 2006; 1083(1): 37 - 53. [Abstract] [Full Text] [PDF]

				G. Pinto, V. Tardy, C. Trivin, C. Thalassinos, S. Lortat-Jacob, C. Nihoul-Fekete, Y. Morel, and R. Brauner Follow-Up of 68 Children with Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency: Relevance of Genotype for Management J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2624 - 2633. [Abstract] [Full Text] [PDF]

				R. S. Legro, H. M. Lin, L. M. Demers, and T. Lloyd Urinary Free Cortisol Increases in Adolescent Caucasian Females during Perimenarche J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 215 - 219. [Abstract] [Full Text] [PDF]

				E. Charmandari, K. A. Calis, M. F. Keil, M. R. Mohassel, A. Remaley, and D. P. Merke Flutamide Decreases Cortisol Clearance in Patients with Congenital Adrenal Hyperplasia J. Clin. Endocrinol. Metab., July 1, 2002; 87(7): 3197 - 3200. [Abstract] [Full Text] [PDF]

				E. Charmandari Author's Response: Serum Cortisol and 17-Hydroxyprogesterone Concentrations in Children with Classic Congenital Adrenal Hyperplasia J. Clin. Endocrinol. Metab., June 1, 2002; 87(6): 2993 - 2993. [Full Text] [PDF]

				E. Charmandari, S. M. Pincus, D. R. Matthews, A. Johnston, C. G. D. Brook, and P. C. Hindmarsh Oral Hydrocortisone Administration in Children with Classic 21-Hydroxylase Deficiency Leads to More Synchronous Joint GH and Cortisol Secretion J. Clin. Endocrinol. Metab., May 1, 2002; 87(5): 2238 - 2244. [Abstract] [Full Text] [PDF]

				E Charmandari, C G D Brook, and P C Hindmarsh Why is management of patients with classical congenital adrenal hyperplasia more difficult at puberty? Arch. Dis. Child., April 1, 2002; 86(4): 266 - 269. [Abstract] [Full Text] [PDF]