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E n d o c r i n e C a r e
Alina German, Suheir Suraiya, Yardena Tenenbaum-Rakover, Ilana Koren, Giora Pillar,
and Ze’ev Hochberg
Pediatric Endocrinology (A.G., Z.H.) and Sleep Laboratory (S.S., G.P.), Rambam Medical Center, Haifa 31096, Israel; Pediatric Endocrine
Unit (A.G., I.K.), Clalit Health Maintenance Organization, Haifa 35013, Israel; Ha’Emek Medical Center (Y.T.-R.), Afula 18101, Israel;
and the Faculty of Medicine, Technion–Israel Institute of Technology (Y.T.-R., G.P., Z.H.), Haifa 32000, Israel
Objective: Our objective was to evaluate evening vs. morning high-HC dose with respect to disease
control, sleep pattern, and daytime activity in children with CAH.
Design: An open-label, cross-over, randomized trial of 15 children with classical CAH was per-
formed. Patients were randomized to receive 50% of the daily HC in the morning or evening for
2 wk; the other two doses included 25% of the daily dose each.
Conclusions: With respect to disease control, sleep quality and daytime activity were not affected
by treatment schedules. We recommend the high-morning dose schedule in replacement therapy
of children with CAH. (J Clin Endocrinol Metab 93: 4707– 4710, 2008)
0021-972X/08/$15.00/0 Abbreviations: CAH, Congenital adrenal hyperplasia; CV, coefficient of variation; DHEAS,
Printed in U.S.A. dehydroepiandrosterone sulfate; HC, hydrocortisone; 17OHP, 17-hydroxyprogesterone;
HPA, hypothalamic-pituitary-adrenal axis; SWS, slow-wave sleep.
Copyright © 2008 by The Endocrine Society
doi: 10.1210/jc.2008-0519 Received March 4, 2008. Accepted August 28, 2008.
First Published Online September 9, 2008
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4708 German et al. Sleep in CAH J Clin Endocrinol Metab, December 2008, 93(12):4707– 4710
Hormones of the HPA axis possibly play a significant role in TABLE 1. Clinical characteristic of the study’s 15 patients with
determining entry into and duration of different sleep and CAH
activity stages. In normal individuals the HPA axis is most
active in the second half of the night, with as much as 70% of No. of males/females 9/6
the total nighttime cortisol secretion occurring during that Age (yr) 10 (7.5; 14.5)
No. of prepubertal/pubertal patients 9/6
time, positively correlating with rapid eye movement sleep BMI (kg/m²) 19.7 (14.8; 23.4)
duration (4), whereas declining plasma cortisol levels are as- No. of 21-hydroxylase/11-hydroxylase deficiency 14/1
sociated with brain lateralization, slow-wave sleep (SWS), or HC dose (mg/m2䡠d) 14 (13.5; 15.3)
No. of initial HC dose (morning/evening) 9/6
deep sleep (2, 5). Fludrocortisone dose (g/m2䡠d) 130 (72; 145.8)
The present study was designed to evaluate evening vs. morn-
Data shown are median (first; third quartiles). BMI, Body mass index.
ing administration of a higher hydrocortisone (HC) dose with
respect to disease control, sleep pattern, and daytime activity in
children with CAH in an open-label, randomized, cross-over Assays
design. This was evaluated with a sleep log as well as a wrist 17OHP was measured using the Coat-A-Count RIA (Coat-A-
actigraph, which was shown to provide a reasonably accurate Count; Siemens Healthcare Diagnostics, Los Angeles, CA) with a
estimation of sleep and wakefulness (6). sensitivity of 0.212 nmol/liter. The within-assay coefficients of vari-
ation (CVs) were 6.7 and 3.5% at serum concentrations 0.3 and 6.5
ng/ml, respectively, and the between-assay CVs were 11 and 8.5% at
serum concentrations of 0.35 and 6.1 ng/ml, respectively. Andro-
stenedione serum levels were measured using a Diagnostic Systems
Patients and Methods Laboratories RIA kit (Webster, TX) with a sensitivity of 0.069 nmol/
liter. Intraassay CVs were 4.3 and 5.9% at serum concentrations of
Study design 0.69 and 6.9 ng/ml, respectively, and interassay CVs of 6.3 and 7.0%
This was an open-label, cross-over, randomized trial, designed to at serum concentrations of 0.63 and 6.51 ng/ml, respectively. The
compare disease control, sleep quality, and daytime activity with a high- DHEAS level was measured using Siemens Healthcare Diagnostics
morning or high-evening HC dose in children with CAH. Patients were RIA (Immune 2000 analyzer system chemiluminescent enzyme im-
randomized in two groups for their initial treatment schedule: a high- munoassay), with a sensitivity of 0.08 mol/liter. The within-assay
morning dose, when 50% of the daily HC was taken in the morning; and CVs were 9.8 and 4.3% at serum concentrations of 52 and 659 g/dl,
a high-evening dose, when 50% was taken at bedtime. The other two respectively. Testosterone levels were measured using Chemilumines-
doses included 25% of the daily dose each. The schedule was standard- cent immunoassay (Advia Centaur analyzer chemiluminescent immu-
ized to 0700 – 0800, 1300 –1400, and 2100 –2200 h according to pa- noassay; Bayer Health Care, LLC, Fernwald, Germany), with a sen-
tients’ age. Duration of the study was 4 wk: 2 wk for each treatment sitivity of 0.35 nmol/liter. Intraassay CVs were 6.2 and 2.3% at serum
schedule. Patients received standard replacement therapy with an oral concentrations 3.31 and 35.03 nmol/liter, respectively, and interassay
HC dose that was identical to each subject’s prestudy therapy, ranging CVs of 4.4 and 1.4% at serum concentrations of 3.31 and 35.03
from 13.5–15.3 mg/m2 given three times daily; 9␣-fludrocortisone was nmol/liter, respectively.
given once a day with the morning HC tablets, and median plasma renin
activity level was 3.3 ng/ml䡠24 h (range 2.87–3.55). The protocol was
approved by the Rambam Medical Center Ethics committee, conducted Actigraphy
in accordance with the Declaration of Helsinki, and a written, informed Sleep quality and daytime activity were identified by continuous ac-
consent was signed by a parent. tigraph monitoring. The actigraph (Individual Monitoring Systems, Inc.,
Baltimore, MD) is a small watch-like device weighing 10 g that records
movement accelerations. It is worn all day and night (24 h except show-
Patients ers) on the wrist of the nondominant hand. Using a validated accurate
There were 18 children (10 males and eight females; median age 10 algorithm to translate the presence of movement accelerations and score
yr, range 6 –17) with normal circadian rhythm and classical CAH due awake or sleep (9, 10), the actigraph data were processed and scored for
to 21-hydroxylase deficiency (n ⫽ 14) or 11-hydroxylase deficiency the following variables: time in bed (the time from lights off until lights
(n ⫽ 1) with reasonable disease control 关as determined by mean 17- on); total sleep time (the actual time the child really slept); total wake time
hydroxyprogesterone (17OHP) levels in the previous year ⬍30 nmol/ (wake after sleep onset, i.e. the time the child spent awake between falling
liter兴 enrolled in the study. Five children had received a high-morning asleep and lights on); sleep onset latency (the time from reported lights
dose, six a high-evening dose, and four received three equal daily off till the time of falling asleep); sleep efficiency (the total sleep time as
doses. Three patients from the high-evening dose group were excluded a percentage of time in bed); arousal number; and activity index (intensity
during the study for compliance reasons, and, therefore, the group of movement acceleration during a given time).
sizes are not balanced. Exclusion criteria included known sleep, be-
havioral, or movement disturbances. Patients’ clinical characteristics
are presented in Table 1. Statistical analyses
The primary endpoints for the study were sleep and activity variables:
the changes in activity index and the number of arousals per night. The
Clinical and laboratory assessment sample size was selected to allow for 80% power to detect a difference
Assessment of disease control was done by measuring before the of 20 U activity and two nocturnal arousals per night between the two
morning dose 0800-h levels of 17OHP, testosterone, androstenedione, groups with SD at an ␣-level of 0.05.
and dehydroepiandrosterone sulfate (DHEAS) on the last day of each Comparison of endocrine results used the nonparametric Wilcoxon
treatment schedule. Reference values were retrieved from Ref. 7. Sleep signed-ranks paired test, and sleep results, with their normal distribution,
and daytime activity were assessed by a 7-d actigraph, monitoring total used the Student’s t test. Therefore, results are given as median and
sleep time, number of arousals, sleep efficiency, sleep latency, and day- quartiles for biochemical parameters, and mean ⫾ SD for sleep
time movements on the second week of each treatment schedule (8). parameters.
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J Clin Endocrinol Metab, December 2008, 93(12):4707– 4710 jcem.endojournals.org 4709
Results Discussion
Normal
Morning Evening childhood
dose dose ranges
Arousal no./night 4.7 ⫾ 2.8 4.4 ⫾ 1.7 0–6
Total sleep time (min/night) 462 ⫾ 50 531 ⫾ 46 360 – 600
Sleep efficiency (%) 85.8 ⫾ 7.6 87 ⫾ 6.4 92–100
Activity index 24 h 113 ⫾ 25 109 ⫾ 20
Sleep onset latency (min) 23 ⫾ 18 24 ⫾ 17 0 –20
Values are shown as mean ⫾ SD. No reference ranges are determined for
24-h activity index. All differences are insignificant. Activity index, Intensity
of movement acceleration during a given time; Sleep efficiency, total sleep
time as a percentage of time in bed; Sleep onset latency, time from reported FIG. 1. Comparison of 24-h activity index during high-morning (open bars) or
lights off till the time of falling asleep; Total sleep time, actual time the child high-evening (solid bars) HC dose treatment. Daytime 24-h activity was divided
really slept. into eight 3-h periods. Error bars represent SD values.
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4710 German et al. Sleep in CAH J Clin Endocrinol Metab, December 2008, 93(12):4707– 4710
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