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Oral Hydrocortisone Administration in Children with Classic 21-Hydroxylase Deficiency Leads to More Synchronous Joint GH and Cortisol Secretion

London Center for Pediatric Endocrinology (E.C., C.G.D.B., P.C.H.), University College London, London, W1T 3AA, United Kingdom; Guilford (S.M.P.), Connecticut 06437; Diabetes Research Laboratories (D.R.M.), Radcliffe Infirmary, Oxford OX2 6HE, United Kingdom; and Clinical Pharmacology (A.J.), St. Bartholomew’s School of Medicine and Dentistry, London EC1M 6BQ, United Kingdom

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 humans, GH and cortisol are secreted in a pulsatile fashion and a mutual bidirectional interaction between the GH/IGF-I axis and hypothalamic-pituitary-adrenal axis has been established. Classic congenital adrenal hyperplasia (CAH) is characterized by a defect in the synthesis of glucocorticoids and often mineralocorticoids, and adrenal hyperandrogenism. Substitution therapy is given to prevent adrenal crises and to suppress the abnormal secretion of androgens and steroid precursors from the adrenal cortex. However, treatment with twice or three times daily oral hydrocortisone does not mimic physiological adrenal rhythms and may influence the activity of the GH/IGF-I axis. We investigated the pattern of GH and cortisol secretion and the synchrony of joint GH-cortisol secretory dynamics in 15 children with classic 21-hydroxylase deficiency (5 males and 10 females; median age 9.5 yr, range 6.1–11.0 yr) and 28 short normal children (23 males and 5 females; median age 7.7 yr, range 4.9–9.3 yr). All subjects were prepubertal. Serum GH and cortisol concentrations were determined at 20-min intervals for 24 h. The irregularity of GH and cortisol secretion was assessed using approximate entropy (ApEn), a scale- and model-independent statistic. The synchrony of joint GH-cortisol secretion was quantified using the cross-ApEn statistic. Cross-correlation analysis of GH and cortisol secretory patterns was computed at various time lags covering the 24-h period. Children with CAH had significantly lower mean 24-h serum cortisol concentrations (6.4 ± 2.2 vs. 10.4 ± 2.6 µg/dl, P < 0.001), ApEn (GH) (0.64 ± 0.13 vs. 0.74 ± 0.17, P = 0.04), ApEn (cortisol) (0.54 ± 0.13 vs. 1.08 ± 0.18, P < 0.001) and cross-ApEn values of paired GH-cortisol secretion (0.78 ± 0.19 vs. 1.05 ± 0.12, P < 0.001) than normal children. There was no difference in mean 24-h GH concentrations between the two groups (4.5 ± 2.9 vs. 4.5 ± 1.9 mU/liter). In children with CAH, a significant positive correlation between GH and cortisol was noted at lag time 0 min (r = 0.299, P < 0.01), peaking at 20 min (r = 0.406, P < 0.0001), whereas in normal children, a significant negative correlation between the two hormones was noted at lag time 0 min (r = -0.312, P < 0.01). The above findings suggest that children with classic CAH have a more regular pattern of GH secretion and a more synchronous joint GH-cortisol secretory dynamics than their normal counterparts. These differences reflect bidirectional interactions between the GH/IGF-I axis and hypothalamic-pituitary-adrenal axis in humans, and are likely to evolve as a result of the exogenous administration of hydrocortisone at fixed doses and at specific time intervals, which leads to a more regular pattern in circulating cortisol concentrations, independent of variations in CRH and ACTH concentrations.

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