OBJECTIVES. Studies of adults have shown that thrice-daily hydrocortisone dosing results in more physiologic cortisol profiles than twice-daily dosing. There are no data on thrice-daily dosing and only limited data on twice-daily dosing in children despite the possible adverse effects of glucocorticoid underreplacement or overreplacement.
METHODS. Using 24-hour cortisol and glucose profiles, along with computerized cognitive testing, our aim was to assess prescribed hydrocortisone regimens in children and adolescents with hypopituitarism.
RESULTS. Twenty patients with adrenocorticotrophic hormone deficiency participated. The hydrocortisone dosing regimen was thrice daily in 9 patients and twice daily in 11 patients (mean total daily dose: 8.3 ± 2.6 and 7.6 ± 2.1 mg/m2 per day, respectively). Those on twice-daily dosing had more waking hours (between 8:00 am and 8:00 pm) below the reference range than those on thrice-daily dosing (5.5 vs 2.1) and more daytime prolonged hypocortisolemia, defined as plasma cortisol level of <50 nmol/L for ≥4 hours (64% vs 0%). Morning doses >4 mg/m2 caused larger postdose peaks than <4 mg/m2 (151 vs 47 nmol/L, above the 97.5th percentile). However, there was no difference in the length of time taken to reach nadir below the 2.5th percentile (5.2 vs 4.8 hours). This was true for evening doses of >2.5 mg/m2 and < 2.5 mg/m2. No hypoglycemia or hyperglycemia was detected in association with low or high cortisol levels. On predose and postdose cognitive testing (34 paired tests), no significant change in reaction speed was detected (453.3 vs 438.8 milliseconds) or in subgroup analysis of those who had symptoms of lethargy, predose cortisol levels of <50 nmol/L, or prolonged hypocortisolemia.
CONCLUSIONS. Thrice-daily dosing resulted in less frequent and prolonged hypocortisolemia than twice-daily regimens, but we were unable to relate either regimen to acute clinical end points of glycemia, lethargy, or cognitive function.
The current management of adrenocorticotrophic hormone (ACTH) deficiency involves daily hydrocortisone replacement plus increased doses during physiologic stress. The optimum hydrocortisone dose and replacement regimen remains unclear in ACTH deficiency, whether considered to be complete or partial. Estimates of daily cortisol production rates have been revised downward from 12 to 15 mg/m2 per day1 to 6 to 8 mg/m2 per day2–4 in recent times. Therefore, given the high oral bioavailability of hydrocortisone (≥95%),5,6 a dose of 6 to 8 mg/m2 per day should be the aim of therapy, provided the patient has no hypoglycemia or symptoms of cortisol deficiency.
The short-term and medium-term risks of glucocorticoid underreplacement or overreplacement are particularly important in children and adolescents. In addition, longer-term health into adulthood needs to be considered. Adults with hypopituitarism have an increased incidence of asymptomatic premature atherosclerosis7 and excess mortality because of cardiovascular disease.8,9 Although untreated growth hormone deficiency has been the most commonly implicated etiologic factor, the effect of other hormone replacement regimens should be considered. Short-term studies in adults attempting to relate hydrocortisone dose to a tissue effect have found increased bone turnover markers in hydrocortisone overreplaced patients10 and changes in carbohydrate metabolism on “conventional” (ie, 30 mg per day, higher than currently recommended)11 but not on lower-dose hydrocortisone regimens (20 mg per day).12
Two studies have assessed hydrocortisone replacement in children with ACTH deficiency.13,14 Twice-daily (BD) hydrocortisone regimens resulted in supraphysiological postdose cortisol peaks and low predose nadirs despite a relatively high mean daily hydrocortisone dose (12.3 mg/m2 per day) in 44 patients with craniopharyngioma.13 In another study, although more satisfactory cortisol levels were described using limited filter paper sampling on BD therapy (mean dose: 8.9 mg/m2 per day), overnight data and glucose levels were not collected.14
The rationale for choosing thrice-daily (TDS) rather than BD regimens was because of the study by Groves et al,15 which showed that TDS regimens prevented afternoon hypocortisolemia and may improve well-being in adrenally insufficient adults. There are no pediatric studies in hypopituitarism of TDS hydrocortisone regimens despite its common usage, nor have cortisol profiles been reported with either BD or TDS regimens using lower hydrocortisone doses.
Children with hypopituitarism and their parents often report lethargy and difficulty concentrating, especially in the afternoon. To date, no studies have attempted to quantify the cognitive changes associated with acute fluctuations in plasma cortisol and symptomatology in children and adolescents with hypopituitarism.
Clinical assessment of hydrocortisone replacement is generally based on assessment of well-being, questioning regarding symptoms of glucocorticoid deficiency, physical examination for signs of overreplacement, and dose adjustments based on current body surface area in the growing child. Because cortisol profiles are invasive and labor intensive, detailed assessments of glucocorticoid replacement regimens are not routinely performed in pediatric practice. Using 24-hour cortisol and glucose profiles along with computerized cognitive testing, our aim was to assess the currently prescribed hydrocortisone regimens in children and adolescents with hypopituitarism and to refine prescribing recommendations (including administration times and dose distribution). We hypothesized that TDS dosing was more physiological than BD dosing.
SUBJECTS AND METHODS
The study population consisted of 20 children and adolescents (aged 2.9–18.5 years) with hypopituitarism who were attending The Children's Hospital at Westmead Endocrine Clinic. Any patient diagnosed previously with ACTH deficiency was eligible for the study. Patients who had required stress dose steroids in the previous 3 months were excluded. Other pituitary hormone deficiencies were satisfactorily replaced with thyroxine (n = 18), biosynthetic human growth hormone (GH; n = 11), intranasal desmopressin acetate (n = 7), oral desmopressin acetate (n = 4), oral estradiol valerate (2 girls), and oral testosterone undecanoate (3 boys). No patient had hyperprolactinemia. Five GH-deficient patients who were growing satisfactorily without GH therapy or had achieved near final height were not receiving GH therapy.
To assess the hydrocortisone regimens in the patients with hypopituitarism, plasma cortisol and glucose profiles were assessed over a 24-hour period. Clinical symptoms of hypocortisolemia and cognitive function prehydrocortisone and posthydrocortisone dose were also assessed.
Data from 22 healthy siblings aged 5.1 to 18.5 years were used to define normal 24-hour plasma cortisol profiles. The characteristics of the study subjects and control subjects are detailed in Table 1.
The study was approved by the Ethics Committee of The Children's Hospital at Westmead. All of the participants and their parents gave informed consent/assent after receiving a detailed verbal explanation and written information about the study.
Patients were admitted at 7:00 am to the Endocrine Testing Unit at The Children's Hospital at Westmead. Local anesthetic cream was applied to the cannulation site at 7:00 am, and intravenous cannulation was performed at 7:30 am. Venous blood samples for plasma cortisol and glucose were collected into lithium heparin tubes via the previously placed intravenous cannula to minimize any distress from venipuncture. Blood samples were collected immediately before each dose of hydrocortisone to capture the plasma cortisol nadir, 1 hour after hydrocortisone to capture the plasma cortisol peak, and at other defined time points throughout the 24-hour period. Samples were refrigerated immediately and plasma separated by centrifugation within 6 hours. Plasma was stored at −80°C until batch analysis. The hydrocortisone-administration and blood-sampling times are detailed in Table 2. Subjects fasted from supper (9:00 pm) until just after their 8:00 am blood sample the next morning. No other restrictions were placed on the patients or control subjects between sampling times. They were encouraged to follow their normal diet throughout the day.
Anthropometric measurements were obtained when subjects were without shoes and in light clothing. Height was measured by using a wall-mounted Harpeneden stadiometer (Holtain Ltd, Crymych, United Kingdom) and was accurate to 0.1 cm. Weight was measured by electronic scales and was accurate to 0.1 kg.
Total cortisol concentration in venous plasma was evaluated using an Immulite 1000 cortisol chemiluminescence immunoassay (Diagnostic Products Corp, Los Angeles, CA). The mean interassay and intraassay coefficients of variation for the cortisol assay were 6.0% and 4.1%, respectively. The lower detection limit for the cortisol assay was 10 nmol/L (coefficient of variation: 11%; plasma cortisol conversion factor: 1 μg/dL = 27.625 nmol/L). Reference ranges for plasma cortisol levels were derived by using the 2.5th and 97.5th percentiles of control-subject cortisol values at each time point. Glucose was measured on a VITROS Fusion using dry-slide chemistry (Ortho-Clinical Diagnostics, Raritan, NJ).
Other Data Collected
Patient- and parent/carer-reported symptoms of lethargy, weakness, concentration difficulties, or other symptoms at any time point throughout the day were recorded. Patients were asked which of these symptoms (if any) they attributed to their hydrocortisone dose, timing, or cortisol levels.
In ACTH-deficient patients ≥8 years old, cognitive function was assessed immediately before and 1 to 2 hours after each dose of hydrocortisone. A computerized cognitive test battery from CogState (CogState Ltd, Carlton South, Victoria, Australia) was administered in a quiet room. The test battery consisted of 4 tasks in the form of card games on a laptop computer and assessed psychomotor reaction time, memory (1 card learning task), and executive function (strategy learning task and choice/decision-making task). Each patient had 1 practice attempt (first administration) before commencing the study test (second administration). The tests were chosen because they are quick and easy to administer (12 minutes to complete test battery), have no significant practice effect after the second administration, have been validated in children as young as 8 years old,16 and have sensitivity to detect impairment of motor ability, memory, attention, and concentration. For each task, psychomotor reaction time was measured in milliseconds. In addition, the number of correct responses was recorded and expressed as a percentage of the total number of trials for each task.
An independent sample t test was used to compare baseline characteristics and total daily dose (TDD) of hydrocortisone between different treatment groups. Characteristics of the cortisol profiles on BD and TDS hydrocortisone regimens were compared (hours below or above the reference range). For this analysis, the following definitions were used: waking hours = 8:00 am to 8:00 pm, sleeping hours = 8:00 pm to 8:00 am, prolonged hypocortisolemia = plasma cortisol level of <50 nmol/L for ≥4 hours, complete ACTH deficiency = 8:00 am cortisol level of <100 nmol/L, partial ACTH deficiency = 8:00 am cortisol level of ≥100 nmol/L, and hypoglycemia = blood glucose level of <3.5 mmol/L. For nonnormally distributed data, Mann-Whitney U test was used to compare the treatment regimens. One sample Student's t test was used to compare predose and postdose cognitive function. A nonparametric, 1-sample Kolmogorov-Smirnov test was used for analysis of nonnormally distributed data. Spearman's rank-order correlation coefficient was used to assess the relationship between cortisol dose, cortisol peak, time to nadir, and cortisol area under the curve (AUC).
Twenty ACTH-deficient patients participated (11 girls, 7 with congenital hypopituitarism). The oral hydrocortisone dosing regimen was BD in 11 and TDS in 9 patients. The mean TDD of hydrocortisone on BD regimens was 7.6 ± 2.1 mg/m2 per day and on TDS regimens was 8.3 ± 2.6 mg/m2 per day. See Table 1 for baseline characteristics of the control group and patient group by treatment regimen.
Comparison of Regimens
Hydrocortisone replacement regimens resulted in cortisol profiles outside the control range in all 20 of the patients taking oral hydrocortisone (see Fig 1). Comparing the BD and TDS regimens, the TDD of hydrocortisone, total number of hours above the reference range, and sleeping hours (8:00 pm to 8:00 am) below the reference range were similar (see Table 3). However, those on the BD dose had more waking hours (8:00 am to 8:00 pm) below the reference range than those on the TDS dose (5.5 vs 2.1; P = .006). Nocturnal prolonged hypocortisolemia (plasma cortisol level of <50 nmol/L for ≥4 hours) was common on both regimens. Daytime prolonged hypocortisolemia was more common on BD than TDS regimens (see Table 3).
Cortisol AUC was >97.5th percentile for control subjects in 3 patients and <2.5th percentile in 7 patients. There was no significant difference in mean AUC for those on BD and those on TDS hydrocortisone (3050.7 vs 3716.2 nmol/hour per L; P = .40; see Table 3). Excluding 4 patients (1 on TDS dose and 3 on BD dose) with partial ACTH deficiency, hydrocortisone TDD per square meter correlated with AUC (r = 0.77; P < .005).
All of the patients receiving oral hydrocortisone had 1-hour postdose plasma cortisol peaks >97.5th percentile at some point during the 24-hour sampling period. There was a modest correlation between hydrocortisone dose and plasma cortisol peak, with wide variability in peak cortisol levels for similar doses (see Fig 2A). Morning doses >4 mg/m2 caused larger peaks than those <4 mg/m2 (151 vs 47 nmol/L above the 97.5th percentile; P = .022). However, there was no difference in the length of time taken to reach nadir below the 2.5th percentile (5.2 vs 4.8 hours; P = .5). There was no significant correlation between morning dose and time to reach nadir (see Fig 2C). Similarly, night time doses >2.5 mg/m2 resulted in larger cortisol peaks than doses <2.5 mg/m2 (365 vs 148 nmol/L above the 97.5th percentile; P = .05) but did not prevent early morning cortisol nadirs when compared with doses <2.5 mg/m2 (7.1 vs 6.6 hours to fall below the 2.5th percentile; P = .19; see Fig 2 B and D). Cortisol levels remained above the 2.5th percentile for longer after the evening dose than after the higher morning doses (2.8 ± 1.1 mg/m2 vs 4.0 ± 1.2 mg/m2, P = .001 and 6.9 ± 0.7 hours vs 5.3 ± 1.3 hours; P < .005; see Fig 2 C and D).
No hypoglycemia (plasma glucose ≤ 3.5 mmol/L) was detected at any sampling time point. One patient was diagnosed with type 2 diabetes on the basis of the blood glucose profile. She was receiving a relatively low dose of hydrocortisone (TDD 5.7 mg/m2 per day) and had a family history of type 2 diabetes. Excluding this patient, the mean fasting blood glucose levels at 4:00 am (5.0 ± 0.5 mmol/L) and 8:00 am (4.7 ± 0.4 mmol/L) did not differ between those with plasma cortisol levels of <20or >20 or 50 nmol/L cut points (see Table 4). There were no episodes of hyperglycemia (plasma glucose level of ≥11.1 mmol/L) in association with 1-hour postdose cortisol peaks (mean blood glucose level: 5.2 ± 0.8 mmol/L at 9:00 am, 5.2 ± 0.3 mmol/L at 3:00 pm, 4.9 ± 0.4 mmol/L at 5:00 pm, and 5.4 ± 0.5 mmol/L at 9:00 pm; see Table 5).
Symptoms and Cognitive Function
Ten patients described lethargy, which they attributed to low cortisol levels prehydrocortisone dose (BD dose: 5 patients; TDS dose: 5 patients). In the morning, the mean cortisol levels in symptomatic and asymptomatic patients were 16.7 and 9.9 nmol/L (P = .34), when glucose levels were 4.5 and 5.1 mmol/L (P = .94). In the evening, cortisol levels were 62.6 nmol/L in symptomatic vs 63.8 nmol/L (P = .98) in asymptomatic patients when blood glucose levels were 5.1 and 5.3 mmol/L (P = .54).
On predose and postdose cognitive testing (34 paired tests), no significant change in reaction speed was detected in the whole group (453.3 vs 438.8 milliseconds; P = .44) or in subgroup analysis of those who had symptoms of predose lethargy, predose cortisol level of <50 nmol/L, or prolonged predose hypocortisolemia. Predose and postdose tests of attention, learning, and memory also did not differ significantly.
This is the first study to report cortisol and blood glucose profiles on both BD and TDS regimens in children with hypopituitarism on the currently recommended lower daily dose of hydrocortisone.17 Our data confirm findings from adult studies that TDS dosing results in more physiological cortisol profiles than BD. Despite this, all of the regimens produced unphysiological profiles reflecting the rapid absorption and short circulating half-life of hydrocortisone. The mean total daily dose in our group was less than that used in the only other large pediatric study (7.9 vs 12.3 mg/m2 per day).13 This lower total daily dose was not associated with hypoglycemia despite the 11-hour overnight fast and the low cortisol levels for prolonged periods of time suggesting that these lower doses are unlikely to cause fasting hypoglycemia in children with hypopituitarism. A limitation of our study is that the youngest participant was 2.9 years old. Therefore, we did not study any infants or young toddlers with hypopituitarism who would be at higher risk of hypoglycemia and in whom the developing brain is more vulnerable to the effects of hypoglycemia.
To assess the study patients under relatively normal circumstances, they were asked to follow their usual dietary habits. It is possible that food intake could have masked hypoglycemia on the study day. Therefore, our study does not provide information about unusual or extreme events, such as a missed meal, a vomited meal, an intercurrent illness, or a change in routine.
From Fig 1, 4 patients with partial ACTH deficiency can be identified by their endogenous early morning cortisol rise. The results remained unchanged when these 4 patients were excluded from each analysis. However, it is possible that the small numbers of participants in this study may have prevented the detection of small differences between groups. For example, a retrospective power analysis revealed that 48 patients, 24 in each group (cortisol <50 or >50 nmol/L), would have been required to detect a fasting blood glucose difference of 0.5 mmol/L with 80% power.
Another study weakness may be that patients were studied on their prescribed dosing regimen rather than in a randomized crossover design. Regimens were chosen by the treating endocrinologist based on their personal prescribing habit. It is possible that individual patient variations in cortisol metabolism may have led to regimen changes before study entry. To address this possible bias, we reviewed each patient's medical charts for information about previous hydrocortisone regimens. Three patients currently on BD hydrocortisone had previously been on TDS doses. These 3 changed regimen (from TDS to BD dose) because of the difficulties with administering a dose during school hours. Only 1 patient was changed from BD dose to TDS hydrocortisone on the basis of afternoon fatigue and reported an improvement in symptoms. Unfortunately, it is not possible to derive from this 1 case whether a placebo effect or a true biological effect was observed. The other study patients who complained of lethargy had not had dose adjustments made in response to their symptoms. Therefore, it is unlikely that previous regimen changes caused a significant bias in this study.
The fact that many of our patients with ACTH deficiency taking oral hydrocortisone had prolonged episodes of hypocortisolemia while maintaining seemingly normal activity, normal blood glucose levels, and denying symptomatology indicates that the intracellular half-life (ie, the intracellular processes initiated by hydrocortisone) continue for much longer than circulating plasma cortisol half-life would suggest. Although this is reassuring, important clinical questions remain unanswered. For example, do more physiologic profiles translate into improvements in functioning and cognition, when is dose adjustment required, and is there a better measure of cortisolemia than total plasma cortisol (eg, free plasma cortisol or direct measurement of in vivo glucocorticoid activity)?
Historically, dose adjustments in pediatric practice have been made on the basis of symptomatology and body surface area–related dose calculations. However, because symptomatology is often vague and may not be perceived by the patient, a more objective measure of symptomatic hypocortisolemia would be beneficial. In addition, in our patients with complete ACTH deficiency, predose cortisol levels did not differ between those with symptoms and those without symptoms. Therefore, we attempted to quantify symptomatic hypocortisolemia by assessing cognitive function prehydrocortisone and posthydrocortisone dose. We were unable to find any difference in reaction speed, memory, concentration, or learning in our children with hypopituitarism. It is possible that the cognitive tests that we administered did not measure the appropriate cognitive variable, were not sensitive enough to detect the cognitive variability associated with fluctuations in cortisol, and/or subjective symptoms are unreliable indicators of symptomatic hypocortisolemia. These findings highlight the need for larger randomized studies addressing clinical and biological end points in children taking oral hydrocortisone.
Although all of the patients who were taking oral hydrocortisone experienced supraphysiological cortisol levels, from our data we can infer that increasing the dose per square meter above certain “threshold” levels (4 mg/m2 in the morning and 2.5 mg/m2 in the afternoon and evening) only worsens the magnitude of cortisol peaks without extending the length of time taken to fall below the reference range. Presumably this reflects rapid glomerular cortisol filtration and renal excretion, which occurs after each dose, when plasma cortisol levels are high and plasma cortisol binding sites are fully saturated.
Excluding the patient with type 2 diabetes, we did not detect any hyperglycemia during the supraphysiological cortisol peaks or at any time point. Our results are in agreement with data from McConnell et al.12 They reported no increase in hepatic or peripheral insulin resistance on lower-dose replacement therapy in adults.12
The observation that, despite lower doses in the evening, cortisol levels were maintained above the 2.5th percentile for longer than after the morning dose (6.9 ± 0.7 vs 5.3 ± 1.3 hours) can be explained by decreased cortisol clearance in the evening and overnight, which has been documented previously in other adult studies.18,19 In addition, there may have been differences in hydrocortisone absorption related to dose timing and food intake, which we did not control for.
There are more obstacles to accurate prescribing of hydrocortisone than the unanswered medical questions. As with other chronic illnesses in children and adolescents, administration of medication during the day can be logistically difficult. The currently available hydrocortisone preparations (4-, 5-, 10-, and 20-mg tablets) are not ideal. Although oral hydrocortisone suspension could make small dose adjustments easier, it was withdrawn because of concerns about poor bioavailability.20 Although longer-acting synthetic glucocorticoids (such as prednisolone, methylprednisolone, and dexamethasone) could prevent nadirs, blood levels are difficult to monitor, and their more potent glucocorticoid activity may make overreplacement likely. Even if a slow release hydrocortisone preparation were available, as is currently being developed in the United Kingdom,21 it is unlikely that the body surface area adjustments necessary in pediatric prescribing would be possible.
On the basis of these data, we would recommend aiming for a total daily hydrocortisone dose of 6 to 8 mg/m2 per day, which equates to estimates of daily cortisol production and does not seem to be associated with altered glucose metabolism or cognitive changes. Caution should be taken in management of younger children (<3 years old) with ACTH deficiency who are at a higher risk of hypoglycemia. The regimen and dose splitting should be tailored to suit each individual child. Cortisol and glucose profiles may be useful in difficult-to-manage patients or those at higher risk of hypoglycemia. Additional larger studies to identify and quantify the symptomatology and cognitive defects associated with acute hypocortisolemia are required. Once identified, these may be useful tools to guide hydrocortisone dose adjustment.
This study was supported by the following research grants (to Dr Maguire): National Health and Medical Research Council, Australian Government, Medical Postgraduate Scholarship; Pfizer Pediatric Endocrine Career Development Grant; and Eli Lilly Australasian Pediatric Endocrine Group Research Grant.
- Accepted January 25, 2007.
- Address correspondence to Ann M. Maguire, MB, BCh, BAO, Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Locked Bag 4001, Sydney, New South Wales 2145, Australia. E-mail:
Financial Disclosure: Dr Falleti is employed by CogState. The other authors have indicated they have no financial relationships relevant to this article to disclose.
- ↵Kenny FM, Preeyasombat C, Migeon CJ. Cortisol production rate: II. Normal infants, children, and adults. Pediatrics.1966;37 :34– 42
- ↵Charmandari E, Johnston A, Brook CG, Hindmarsh PC. Bioavailability of oral hydrocortisone in patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency. J Endocrinol.2001;169 :65– 70
- ↵Sieratzki JS, Gompels C, Poyser K, Beaman J, Savage DC. Filter paper cortisol profiles in secondary adrenocortical insufficiency. Arch Dis Child.1995;73 :351– 353
- ↵Groves RW, Toms GC, Houghton BJ, Monson JP. Corticosteroid replacement therapy: twice or thrice daily? J R Soc Med.1988;81 :514– 516
- ↵Ross RJM. Optimization of adrenal glucocorticoid replacement therapy [abstract]. Presented at: annual meeting of the Endocrine Society; June 24–27, 2006; Boston, MA
- Copyright © 2007 by the American Academy of Pediatrics