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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2006-1554
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 6 2125-2129
Copyright © 2007 by The Endocrine Society

Basal and Cosyntropin-Stimulated Plasma Cortisol Concentrations, as Measured by High-Performance Liquid Chromatography, in Children Aged 5 Months to Younger than 6 Years

George P. Chrousos, Liza O’Dowd, Tom Uryniak, Brandon Simpson, Frank Casty and Mitchell Goldman

First Department of Pediatrics (G.P.C.), Athens University Medical School, 115 27 Athens, Greece; and AstraZeneca LP (L.O., T.U., B.S., F.C., M.G.), Wilmington, Delaware 19850

Address all correspondence and requests for reprints to: George P. Chrousos, M.D., F.A.A.P., M.A.C.P., M.A.C.E., Professor and Chairman, First Department of Pediatrics, Athens University Medical School, Aghia Sophia Children’s Hospital, 115 27 Athens, Greece. E-mail: chrousge{at}med.uoa.gr.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: Topical corticosteroids are the recommended first-line treatment for all severities of persistent asthma and moderate to severe allergic rhinitis. Potential adrenal suppression resulting from corticosteroid administration necessitates monitoring of children participating in clinical studies. Measurement of pretreatment cortisol concentrations is necessary to assess effects on adrenal function.

Objective: Plasma cortisol concentrations are assay dependent; normal reference range values must be obtained for each assay. Our objective is to provide these values for children as determined by HPLC.

Design and Patients: Two multicenter, randomized, double-blind, placebo-controlled studies evaluating basal and cosyntropin-stimulated morning plasma cortisol concentrations for patients aged 5 to younger than 12 months with asthma and patients aged 2 to younger than 6 yr with allergic rhinitis using HPLC were conducted.

Main Outcome Measures: Main planned outcomes of these studies are reported elsewhere. This manuscript reports plasma cortisol concentration reference range values.

Results: In general, mean basal plasma cortisol concentrations (n = 177) (mean ± SD, nmol/liter) were similar among the 5 to younger than 9 months, 9 to younger than 12 months, 2 to younger than 3 yr, 3 to younger than 4 yr, 4 to younger than 5 yr, and 5 to younger than 6 yr age groups (218 ± 149, 281 ± 144, 257 ± 105, 231 ± 83, 298 ± 118, and 237 ± 65, respectively) and increased to comparable levels 60 min after cosyntropin stimulation (n = 178; 622 ± 176, 638 ± 176, 697 ± 99, 655 ± 103, 662 ± 113, and 610 ± 68, respectively). However, patients younger than 12 months had wider ranges of basal and stimulated values.

Conclusions: Basal and cosyntropin-stimulated morning plasma cortisol concentrations of children aged 5 to younger than 12 months and 2 to younger than 6 yr were consistently measurable, with the large majority similar among the age groups examined, and comparable with those reported elsewhere for adults.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
TOPICAL CORTICOSTEROIDS ARE the recommended first-line treatment for all severities of persistent asthma and moderate to severe allergic rhinitis (AR) (1, 2, 3, 4, 5). Because of concern regarding hypothalamic-pituitary-adrenal (HPA) axis suppression after topical corticosteroid treatment in young children with asthma and AR, assessment of HPA axis function may be indicated in this patient population.

Cortisol is produced through the coordinated activity of the HPA axis throughout the day on a diurnal cycle that peaks in the early morning (6). Morning plasma cortisol concentration has been used as an index of adrenal function because it reflects peak endogenous activity of the HPA axis (6). ACTH (1–39) is secreted by the pituitary gland to stimulate cortisol production by the adrenal cortices (6). Cosyntropin (ACTH 1–24) is a fully active synthetic peptide, consisting of the first 24 amino acids of ACTH (6). Stimulation with cosyntropin along with measurement of the resultant cortisol concentration is a widely used method to evaluate HPA axis function in patients at risk of secondary adrenal insufficiency due to administration of exogenous corticosteroids (6, 7, 8).

Although normal reference ranges have been established for serum cortisol levels in children aged 5 d to 18 yr using a fluorescence polarization immunoassay (9) and for adults using a RIA (10) and HPLC (Quest Diagnostics, Inc., Van Nuys, CA), normal basal and cosyntropin-stimulated cortisol concentrations determined by HPLC have not been defined for young children. Previous studies that compared different assays head to head have shown that plasma cortisol concentrations obtained by HPLC are significantly lower than values obtained using an RIA or fluorescence polarization immunoassay (11, 12). Presumably HPLC is able to separate and quantify plasma cortisol when other steroids and their metabolites, which can cross-react with reagents in the immunoassays, are present in the sample (13). However, the plasma cortisol values obtained using one assay should not be directly compared with those obtained by a different assay because plasma cortisol concentrations are assay dependent. Therefore, normal reference range values must be obtained for each assay used.

Information about basal and cosyntropin-stimulated morning plasma cortisol concentrations for young children will be useful for the evaluation of HPA axis function in young children in both clinical trials and clinical practice. The objective of this analysis was to provide age-stratified basal and cosyntropin-stimulated morning plasma cortisol concentrations, determined by HPLC, for children aged 5 months to younger than 6 yr.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Study design

Pretreatment, postrandomization, plasma cortisol concentrations were determined in patients randomized to receive placebo or active treatment in two multicenter, randomized, double-blind, placebo-controlled studies designed to evaluate HPA axis function in children after treatment with inhaled or intranasal budesonide [AstraZeneca studies SD-004-0732 (study 1) and SD-005-0697 (study 2)]. Study 1, a 12-wk study conducted at 34 centers in the United States, included children aged 5 to younger than 12 months with asthma who were treated with budesonide inhalation suspension (Pulmicort Respules; AstraZeneca LP, Wilmington, DE; two doses: 0.5 and 1.0 mg) or matching placebo. Study 2, a 6-wk study conducted at 11 centers in the United States, included children aged 2 to younger than 6 yr with AR who were treated with budesonide aqueous nasal spray (Rhinocort Aqua; AstraZeneca LP; 64 µg once daily) or matching placebo. Posttreatment data analysis and results are not discussed in this manuscript; they are reported elsewhere (14, 15). Only pretreatment (baseline) plasma cortisol data are evaluated in this study.

Both studies were conducted in accordance with guidelines in the Declaration of Helsinki. Investigators at each center received formal approval from an independent ethics committee or institutional review board and obtained written informed consent from the legal guardians of each patient before enrollment.

Patient population

Patients randomized into study 1 were males or females aged 5 to younger than 12 months, who had been diagnosed with asthma or, as judged by the investigator, had demonstrated signs and symptoms of mild to moderate persistent asthma (two or more episodes of persistent or recurrent wheezing) and who might benefit from inhaled antiinflammatory therapy. Patients were excluded from participation in the study for the following reasons: diagnosis of severe asthma; history of assisted ventilation; evidence of separate severe, chronic lung disease; severe gastroesophageal reflux disease; diagnosis of severe combined immunodeficiency disease; HIV positivity; hospitalization for a pulmonary disease or respiratory infection within the previous 4 wk; treatment with systemic corticosteroids within the previous 4 wk; suspected endocrine abnormality; or having been born at less than 32 wk of gestation.

Patients randomized into study 2 were males or females aged 2 to younger than 6 yr, who had a documented history of AR verified by a positive skin prick test for perennial or seasonal allergens present in their environment or a documented history of 4 wk or more of continuous chronic symptoms of AR with nasal secretions positive for eosinophils immediately before the screening visit. Patients’ heights and weights were within the fifth to 95th percentile. In addition, patients were considered candidates for intranasal corticosteroid therapy based on a history of either inadequate symptom control with antihistamines, decongestants, or immunotherapy or prior success with intranasal corticosteroid treatment. Patients were excluded from participation in the study for the following reasons: abnormalities or conditions of the nose that might cause significant nasal obstruction (e.g. sinusitis, septal deviation, or nasal polyposis); significant disease (e.g. diabetes mellitus) or unstable medical condition; systemic corticosteroid use within 90 d of screening; use of inhaled corticosteroids, intranasal corticosteroids, or moderate- to high-potency topical corticosteroids (greater than topical corticosteroid potency class V or VI) within 30 d of screening; or use of medications that could interfere with the interpretation of the data or a patient’s participation in the study.

Measurements

In study 1, the basal cortisol sample was obtained before or at 0830 h. Basal and stimulated plasma cortisol concentrations were determined from blood samples obtained via indwelling cannulae before and 60 min after iv infusion of cosyntropin (125 µg). Blood samples (2 ml) were collected in heparinized tubes and immediately centrifuged, and the resulting plasma was transferred to a cryovial and frozen.

In study 2, basal cortisol samples were obtained at approximately 0800 h. Basal and stimulated plasma cortisol concentrations were determined from blood samples obtained via indwelling cannulae before and 30 and 60 min after iv infusion of cosyntropin (10 µg). Blood samples (5 ml) were collected in heparinized tubes and stored on ice until centrifugation. After centrifugation, the resulting plasma sample was split into two aliquots and frozen. Frozen plasma samples in both studies were analyzed by a central laboratory (Quest Diagnostics) using HPLC.

Statistical analyses

Pretreatment, postrandomization plasma cortisol concentrations were summarized according to age group using descriptive statistics. Unless otherwise indicated, all values presented are mean ± SD.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
A total of 118 children were randomized in study 1 and 68 children in study 2. Demographics at baseline are listed in Table 1Go. Males comprised 61% of the children in study 1 and 66% in study 2. In study 1, eight patients had missing basal morning plasma cortisol concentrations and six had missing 60-min cosyntropin-stimulated morning plasma cortisol concentrations. In study 2, two patients had missing 30-min cosyntropin-stimulated morning plasma cortisol values and one patient was missing the 60-min cosyntropin-stimulated morning plasma cortisol value. All morning plasma cortisol concentrations obtained were included in the descriptive analyses.


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  		TABLE 1. Baseline demographics

 
In each study, pretreatment, postrandomization morning plasma cortisol concentrations did not differ substantially between children randomized to receive placebo and those randomized to receive active treatment (study 1 placebo group: basal 245 ± 148 nmol/liter (n = 41), stimulated 631 ± 182 nmol/liter (n = 43); study 1 active treatment group: basal 251 ± 151 nmol/liter (n = 69), stimulated 630 ± 172 nmol/liter (n = 69); study 2 placebo group: basal 248 ± 99 nmol/liter (n = 33), stimulated 645 ± 107 nmol/liter (n = 32); study 2 active treatment group: basal 263 ± 95 nmol/liter (n = 35), stimulated 666 ± 94 nmol/liter (n = 34). Therefore, pretreatment, postrandomization plasma cortisol concentrations were combined in all subsequent analyses regardless of the patient’s randomization block.

The basal morning plasma cortisol concentration was measurable and similar among all age groups examined. Individual basal morning plasma cortisol concentration values are shown according to age group in Fig. 1Go with SD values. The mean basal morning plasma cortisol concentration was 218 ± 149 nmol/liter for children aged 5 to younger than 9 months and 281 ± 144 nmol/liter for those aged 9 to younger than 12 months. In study 2, the mean basal morning plasma cortisol concentration was 257 ± 105 nmol/liter for children aged 2 to younger than 3 yr, 231 ± 83 nmol/liter for those aged 3 to younger than 4 yr, 298 ± 118 nmol/liter for those aged 4 to younger than 5 yr, and 237 ± 65 nmol/liter for those aged 5 to younger than 6 yr. Note that there is increased dispersion about the mean for patients aged 5 to younger than 12 months, compared with patients aged 2 to younger than 6 yr.


Figure 1
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  		FIG. 1. Basal plasma cortisol concentrations and cosyntropin-stimulated plasma cortisol concentrations at 60 min. Solid lines indicate mean values; broken lines indicate upper and lower SD values.

 
The cosyntropin-stimulated morning plasma cortisol concentration was measurable and similar among all age groups examined, despite differences in cosyntropin doses used. It should be noted that both doses were supraphysiologic, well above the maximum of the dose-response curve (16). Individual cosyntropin-stimulated morning plasma cortisol concentration values at 60 min are shown according to age group in Fig. 1Go with SD values. In study 1, 60 min after stimulation with 125 µg cosyntropin, the mean plasma cortisol concentration increased to 622 ± 176 nmol/liter for children aged 5 to younger than 9 months and 638 ± 176 nmol/liter for children aged 9 to younger than 12 months. In study 2, 60 min after stimulation with 10 µg cosyntropin, the plasma cortisol concentration increased to 697 ± 99 nmol/liter for children aged 2 to younger than 3 yr, 655 ± 103 nmol/liter for children aged 3 to younger than 4 yr, 662 ± 113 nmol/liter for children aged 4 to younger than 5 yr, and 610 ± 68 nmol/liter for children aged 5 to younger than 6 yr. In study 2, the cortisol concentration was also determined 30 min after stimulation with 10 µg cosyntropin. The mean plasma cortisol concentration increased to 614 ± 92 nmol/liter for patients aged 2 to younger than 3 yr, 546 ± 100 nmol/liter for patients aged 3 to younger than 4 yr, 602 ± 117 nmol/liter for patients aged 4 to younger than 5 yr, and 534 ± 76 nmol/liter for patients aged 5 to younger than 6 yr. As with the baseline values, there was an increased dispersion about the mean in the 5 to younger than 12 month group of subjects, compared with the older group of 2 to younger than 6 yr. There were children aged 5 to younger than 12 months whose stimulated values were below the lowest stimulated range of children aged 2 to younger than 6 yr.

The median and range of basal and cosyntropin-stimulated morning plasma cortisol concentrations were determined according to age group. Because the data are not normally distributed, the median cortisol concentration may provide a better measure of the central tendency of the data. The median and range of basal morning cortisol concentrations were similar among all age groups examined and increased to comparable levels after cosyntropin stimulation (Table 2Go).


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  		TABLE 2. Basal and cosyntropin-stimulated morning plasma cortisol concentrations (nmol/liter)

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
In young children, normal reference range concentrations of plasma cortisol, as determined by HPLC, are not currently available. In this analysis, basal and cosyntropin-stimulated morning plasma cortisol concentrations were consistently measured for children aged 5 to younger than 12 months, and 2 to younger than 6 yr, using HPLC. Concentrations obtained were in a few cases outside the normal reference ranges of healthy adults aged 16–70 yr determined using the same HPLC assay (Quest Diagnostics) (basal: male, 141–548 nmol/liter; female, 174–538 nmol/liter; stimulated: male, 282-1096 nmol/liter; female, 348-1076 nmol/liter). The ranges measured in the study populations are basal: 5 to younger than 12 months, 57–674 nmol/liter; 2 to younger than 6 yr, 122–613 nmol/liter; stimulated: 5 to younger than 12 months, 163-1058 nmol/liter; 2 to younger than 6 yr, 385–925 nmol/liter. It is important in assessing the results of very young children to point out that both basal and stimulated concentrations were lower in some of the patients aged younger than 12 months when compared with those aged 2 yr and older. In addition, there were higher basal and stimulated values in a few patients aged younger than 12 months than seen in the older children, further increasing differences in the overall range of values when comparing the 2 studies. However, the reference ranges for the majority of children with asthma or AR, especially those children aged 2 yr and older, appear to be similar to those of normal healthy adults using this methodology. It should be noted that HPLC measurements of plasma cortisol are generally lower (about half) than values determined by immunometric methods, and this is the result of the increased specificity and accuracy of the former method that does not recognize close metabolites of cortisol.

It must be noted that the cortisol concentrations reported here were determined from samples collected from children with asthma, recurrent wheezing, and AR and therefore may not be representative of a normal, healthy population of children. It is possible that the children may have experienced stress factors (either chronic or subacute) before testing; it has been noted that children aged 7–12 yr with allergic asthma exhibit a blunted cortisol response to stress, even though basal cortisol concentrations in saliva of these patients are similar to those of controls (17). A recent study by Priftis et al. (18) has shown that approximately 10% of prepubertal children with asthma have decreased cortisol responses to low dose ACTH 1–24 (1 µg) that normalize with inhaled corticosteroid therapy.

The plasma cortisol concentrations reported here were from the postrandomization, pretreatment groups taken from two clinical studies designed to evaluate the effect of intranasal or inhaled budesonide on HPA axis function. Due to the very young age of these patients, doses lower than the 250-µg standard used for adults were chosen. Previous studies have shown that a 1-µg dose shows a maximal response at 30 min; a higher dose is needed to examine responses at 60 min (12, 19, 20). The studies also show stimulated cortisol concentrations to be comparable after stimulation with doses of cosyntropin ranging from 5 to 250 µg, suggesting that the 250-µg dose is not necessary to elicit a maximal response (12, 19, 20).

In this study, patient cortisol values were stratified according to age but were combined without regard to the race or sex of the patient. Additional studies using HPLC are needed to determine whether morning plasma concentrations in young children vary according to race, sex, or other variables. We have no age-related explanation for the difference in the range of the cortisol values between the children aged younger than 12 months and children aged 2 yr or older both at basal and 60 min after ACTH stimulation, especially because the majority of patients were within the normal range for adults. Approximately 14% of the patients aged younger than 12 months did not reach a normal cosyntropin-stimulated plasma cortisol concentration of 500 nmol/liter or greater. It should be noted, however, that these are two different groups of children; the children aged younger than 12 months were patients with mild to moderate persistent asthma or recurrent wheezing and the patients aged 2 to younger than 6 yr were patients with AR. One possible explanation, although speculative, may be that in the younger age group, the diurnal variation of cortisol in some of these patients may be different because of unstable sleep/wake patterns related to asthma. Future studies will be required to resolve whether these are age-related or asthma-related effects.

In conclusion, the reported basal and cosyntropin-stimulated morning plasma cortisol concentrations determined by HPLC for young children should be useful in future studies that assess HPA axis function in pediatric populations. It is especially important in assessing the results of very young children to note the tendency in the present study for some patients aged younger than 12 months to have values lower than those aged 2 to younger than 6 yr. We have no explanation for the wider dispersion of the basal and cosyntropin-stimulated values in the asthmatic infants compared with the toddlers and children in the rhinitis group, and we are uncertain regarding the physiological importance of the lower values in certain infants and whether asthma may have played a role in these lower values.


   Acknowledgments
 
The authors acknowledge Stella Y. Chow, Ph.D., and John E. Fincke, Ph.D. (Tri-Med Communications) for providing medical writing support funded by AstraZeneca LP.


   Footnotes
 
This work was supported by AstraZeneca LP.

First Published Online March 13, 2007

Abbreviations: AR, Allergic rhinitis; HPA, hypothalamic-pituitary-adrenal.

Received July 17, 2006.

Accepted March 7, 2007.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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  8. Boner AL 2001 Effects of intranasal corticosteroids on the hypothalamic-pituitary-adrenal axis in children. J Allergy Clin Immunol 108:S32–S39
  9. Jonetz-Mentzel L, Wiedemann G 1993 Establishment of reference ranges for cortisol in neonates, infants, children and adolescents. Eur J Clin Chem Clin Biochem 31:525–529[Medline]
  10. Beers M, Berkow R, eds. 1999 The Merck manual of diagnosis and therapy. 19th ed. Rathway, NJ: Merck Research Laboratories
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  12. Nye EJ, Grice JE, Hockings GI, Strakosch CR, Crosbie GV, Walters MM, Jackson RV 1999 Comparison of adrenocorticotropin (ACTH) stimulation tests and insulin hypoglycemia in normal humans: low dose, standard high dose, and 8-hour ACTH-(1–24) infusion tests. J Clin Endocrinol Metab 84:3648–3655[Abstract/Free Full Text]
  13. Caldarella AM, Reardon GE, Canalis E 1982 Analysis for cortisol in serum by liquid chromatography. Clin Chem 28:538–543[Free Full Text]
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  15. Kim KT, Rabinovitch N, Uryniak T, Simpson B, O’Dowd L, Casty F 2004 Effect of budesonide aqueous nasal spray on hypothalamic-pituitary-adrenal axis function in children with allergic rhinitis. Ann Allergy Asthma Immunol 93:61–67[Medline]
  16. Demitrack MA, Dale JK, Straus SE, Laue L, Listwak SJ, Kruesi MJ, Chrousos GP, Gold PW 1991 Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. J Clin Endocrinol Metab 73:1224–1234[Abstract]
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  18. Priftis K, Papadimitriou A, Anthracopoulos B, Gatsopoulou E, Fretzayas A, Nicolaidou P, Chrousos G 2006 Adrenal function improvement in asthmatic children on inhaled steroids studied longitudinally. Neuroimmunomodulation 13:56–62[CrossRef][Medline]
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  20. Dickstein G, Shechner C, Nicholson WE, Rosner I, Shen-Orr Z, Adawi F, Lahav M 1991 Adrenocorticotropin stimulation test: effects of basal cortisol level, time of day, and suggested new sensitive low dose test. J Clin Endocrinol Metab 72:773–778[Abstract]




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