| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Other Original Articles |
Department of Pediatrics, Kuopio University Hospital, FIN-70211 Kuopio, Finland
Address all correspondence and requests for reprints to: Raimo Voutilainen, M.D., Department of Pediatrics, Kuopio University Hospital, P.O. Box 1777, FIN-70211 Kuopio, Finland. E-mail: raimo.voutilainen{at}uku.fi
Abstract
ACTH regulates adrenal androgen production, which may thus be reduced during glucocorticosteroid therapy. Dehydroepiandrosterone sulfate is the most abundant androgen secreted by the adrenals. We wished to evaluate whether serum levels of dehydroepiandrosterone sulfate can be used as an indicator of adrenal suppression during inhaled steroid treatment in children. Sixty school-aged children with newly diagnosed asthma were randomly divided into budesonide (n = 30) and fluticasone propionate (n = 30) groups. Fifteen cromone-treated children served as a control group. The budesonide dose was 800 µg/d during the first 2 months and 400 µg/d thereafter. The respective fluticasone propionate doses were 500 and 200 µg/d. Serum dehydroepiandrosterone sulfate concentrations were measured before and after 2 and 4 months of treatment.
In the budesonide group, serum dehydroepiandrosterone sulfate decreased from the baseline by a mean of 21% (95% confidence interval, 13–29%; P < 0.001) after 2 months of high dose treatment and by 16% (95% confidence interval, 8–25%; P < 0.001) after 4 months of treatment. In the fluticasone propionate group, the respective figures were 10% (95% confidence interval, 4–16%; P < 0.01) and 6% (95% confidence interval, 16% decrease–3% increase; P = NS). A low dose ACTH test indicated adrenocortical suppression at 4 months in 14 (23%) steroid-treated children. In these children, dehydroepiandrosterone sulfate decreased by a mean of 21% (95% confidence interval, 14–28%), whereas in those 46 steroid-treated children with normal ACTH test results, dehydroepiandrosterone sulfate decreased by 8% (95% confidence interval, 0–16%; P < 0.05 between these groups). In the control group, dehydroepiandrosterone sulfate levels tended to increase (by a mean of 26%), reflecting the normal physiological change at this age.
In conclusion, inhaled steroid treatment suppresses dehydroepiandrosterone sulfate production in a dose-dependent manner. Monitoring of serum dehydroepiandrosterone sulfate concentrations can be used as a practical method to follow adrenocortical function and to detect its suppression during inhaled steroid treatment in children.
SERUM DEHYDROEPIANDROSTERONE sulfate (DHEA-S) is quantitatively the most abundant androgen secreted by the adrenals. After the first months of life, its serum concentrations are relatively low throughout childhood, rising to the adult level at puberty (1, 2, 3). The vascular pool of DHEA-S is large, and this steroid has a half-life of 10–20 h. This is substantially longer than the half-life of cortisol, which is less than 2 h (4). Thus, the diurnal changes in serum DHEA-S concentrations are minor compared with those in cortisol, which has fluctuating concentrations depending on exogenous stress and the time of the day. In addition, there is evidence that adrenal androgen secretion is more sensitive than cortisol production to the suppressive effect of exogenous glucocorticosteroids (5). In postmenopausal women, high inhaled steroid doses suppressed DHEA-S levels (6). Likewise, in asthmatics admitted to the hospital for severe bronchospasm, serum DHEA-S levels were decreased if the subjects had used inhaled or oral steroids (7).
We reported recently that a significant number of asthmatic children treated with inhaled steroids develop biochemical evidence of adrenocortical suppression on the basis of low dose ACTH test (8). In the present study we measured serum DHEA-S concentrations in samples previously collected from children with newly diagnosed asthma during inhaled steroid and cromone treatment. Our aim was to evaluate the applicability of serum DHEA-S as an indicator of adrenal suppression. We compared the changes in DHEA-S concentrations with the results of a low dose ACTH test, which is currently considered a sensitive method to reveal mild adrenal suppression (8, 9, 10, 11).
Subjects and Methods
Seventy-five children with newly diagnosed asthma were enrolled in the study. Adrenocortical function, evaluated by a low dose ACTH test, and growth characteristics for the same patient group have been reported previously (8). Sixty children were randomized to the budesonide (BUD; n = 30) and fluticasone propionate (FP; n = 30) groups, and 15 children, treated initially with cromones (CROM), formed the control group. The budesonide dose was 800 µg/d during the first 2 months and 400 µg/d thereafter, delivered by a powder inhaler (Turbuhaler, Astra, Sodertalje, Sweden). The respective fluticasone doses were 500 and 200 µg/d, also administered by powder inhaler (Diskus, Glaxo, Ware, Hertfordshire, UK). Treatment compliance was assessed by home-monitoring diaries in which the subjects recorded the medication doses used. According to our stepwise treatment policy (12), those children responding well to the initial inhaled steroid treatment [forced expiratory volume in 1 sec (FEV1) or peak expiratory flow (PEF) improved, and having no asthma symptoms; 18 in the BUD group and 19 in the FP group] were taken off steroids and put on cromones after 4 months of steroid treatment. The remaining children (12 in the original BUD group and 11 in the FP group), who did not respond as well, continued on steroids after 4 months. In the CROM group, the children received either cromolyn (30–60 mg/d) or nedocromil (12 mg/d) throughout the 4-month observation period. None of the children had used inhaled or oral steroids during the preceding year. The study was approved by the research ethics committee of Kuopio University Hospital, and the parents of the children gave informed written consent for the study.
Methods
The children in the BUD and FP groups were examined before any steroid treatment and after 2, 4, and 6 months of treatment. The children in the CROM group were examined at the beginning and after 4 months of treatment. An asthma nurse measured the children’s weights and heights (Harpenden stadiometer, Holtain Ltd., Crymych, UK) at all visits. The heights were expressed as SD scores. Ventilatory functions were followed by measuring FEV1 (Medicro 905, Medicro Ltd., Kuopio, Finland). At all visits blood samples for serum DHEA-S determination were stored at -70 C, and analyzed after collection simultaneously by Coat-A-Count DHEA-SO4 RIA (Diagnostic Products, Los Angeles, CA). The sensitivity of the assay was 0.03 µmol/liter, and the intraassay coefficient of variation was 3.8% for low and 5.3% for high values. The interassay coefficient of variation was 6.3% and 11% for low and high values, respectively. A low dose ACTH test (0.5 µg/1.73 m2) was performed at the beginning of the study and at 4 months, at the same time as the blood sample for DHEA-S was withdrawn. The serum samples for cortisol determinations (Cortisol 125I RIA Kit, Orion Diagnostica, Espoo, Finland) were withdrawn 30 and 60 min after ACTH injection. The ACTH test result was considered abnormal if the stimulated cortisol was below 330 nmol/liter after ACTH injection. This criterion was calculated from the baseline (before maintenance medication) measurements; a stimulated cortisol concentration more than 2 SD below the mean was considered abnormal (8).
Statistical analysis
The data were analyzed by the Statistical Package for the Social
Sciences, version 9.0 (SPSS, Inc., Chicago, IL). In
statistical analyses, the t test was used for continuous
variables, and the 
2 test was used for
noncontinuous variables.
Results
At the beginning of the study the groups did not differ in age,
height, FEV1, or serum DHEA-S
concentrations (Table 1
). The
children in the CROM group were slightly lighter than those in the
steroid groups. There were more males in the FP group than in the CROM
group. During the 4-month treatment period FEV1
improved significantly (P < 0.01) and equally well in
the steroid groups. At 4 months it was, on the average, 101% [95%
confidence interval (CI), 95–106%] of the predicted in the BUD group
and 99% (95% CI, 94–102%) of the predicted in the FP group. In the
CROM group, FEV1 did not change; at 4 months it
was, on the average, 91% (95% CI, 84–98%) of the predicted
value.
|
. In the BUD group
DHEA-S decreased from the baseline by 21% (95% CI,
13–29%) after 2 months (P < 0.001) and by 16% (95%
CI, 8–25%) after 4 months of treatment (P < 0.001).
In the FP group, the respective figures were 10% (95% CI, 4–16%;
P < 0.01) and 6% (95% CI, 16% decrease–3%
increase; P = NS). In the CROM group, in contrast, the
DHEA-S values tended to increase (mean change, +26%; 95%
CI, -11 to 63%; P = NS). The CROM group differed
significantly from both the BUD (P < 0.01) and FP
(P < 0.05) groups. The difference between the BUD and
FP groups was significant at 2 months, but not at 4 months.
|
).
The serum DHEA-S concentrations in the preadrenarchal
(defined here as basal DHEA-S <1 µmol/liter) and
postadrenarchal (basal DHEA-S 
1 µmol/liter) children
are presented separately in Table 2. The decreases in serum
DHEA-S concentrations were significant at 2 months (after
higher steroid doses) in both pre- and postadrenarchal children, but
after the reduction of the dose were significant only in the
postadrenarchal children.
|
).
|
Both inhaled BUD and FP evoked significant and dose-dependent decreases in serum DHEA-S concentrations. The decreases caused by double doses of BUD were greater than those caused by FP. In contrast, during cromone treatment the DHEA-S concentrations tended to increase, which can be explained by normal age-dependent change. The changes induced by steroids were reversible; the values returned to the baseline level when the inhaled steroid doses were reduced or the steroid medication was stopped.
Although inhaled steroids represent the drugs of choice for treatment of asthma, the possibility of systemic side-effects restricts their use, particularly in children (13). One of the crucial problems is the suppression of hypothalamic-pituitary-adrenal function. Glucocorticosteroids suppress this axis by reducing the secretion of ACTH, which, in turn, reduces the secretion of cortisol and other steroids by the adrenal glands. Clinically significant adrenal suppression has been reported in children treated with high doses of inhaled steroids (14). Determination of serum cortisol levels in the morning is a simple, but rather insensitive, way to assess adrenocortical suppression. For example, Ferguson et al. (15) did not detect any change in baseline cortisol levels during the treatment with inhaled BUD (800 µg/d) or FP (400 µg/d). Urinary cortisol measurement represents a more sensitive, but somewhat inconvenient, way to estimate cortisol secretion. In two studies 800 µg/d BUD (16) and beclomethasone (17) did not influence urinary cortisol excretion. Monitoring of 24-h serum cortisol concentrations is the most sensitive, but also the most inconvenient, way to determine cortisol secretion. When this method was used, 400 µg/d beclomethasone and BUD reduced (18), whereas 200 µg/d BUD did not reduce (19) cortisol secretion. In terms of stimulation tests, low dose ACTH tests are considered more sensitive than the standard short test to reveal mild adrenal suppression during inhaled steroid treatment (20, 21). However, in clinical practice these tests are also somewhat cumbersome, because they require an iv cannula and repeated blood samples. Thus, there is still no reliable, sensitive, and simple test to identify adrenal insufficiency during glucocorticosteroid therapy.
In the present study, DHEA-S concentrations decreased significantly more in those children with an abnormal low dose ACTH test result than in those with a normal test result, and the decreases were seen in both pre- and postadrenarchal children. This suggests that a decrease in both serum DHEA-S concentration and cortisol response in the ACTH test measure adrenal suppression caused by the same mechanism. Kreitzer and co-workers (22) did not find any decrease in DHEA-S levels in preadrenarchal children after a short, 1-wk course of prednisone, even though the decrease in postadrenarchal children was significant. Thus in a young preadrenarchal child there may also be an alternative, ACTH-independent, regulatory pathway of DHEA-S synthesis (22, 23). However, during adrenarche, ACTH becomes the most important regulator of DHEA-S secretion, and therefore even short courses of exogenous glucocorticosteroids can suppress DHEA-S production in older children (22). In addition, there is evidence that chronic, low dose glucocorticoid treatment can suppress adrenal androgen levels without long-term suppression of cortisol production, and that the capacity to secrete cortisol recovers more rapidly than the ability to secrete adrenal androgens (24, 25). Thus, the systemic effects of long-term inhaled (or low dose oral) steroid treatment might be evaluated even more reliably by measuring adrenal androgens than by measuring cortisol responses in ACTH stimulation tests. In addition, as the daily fluctuation in the DHEA-S concentration is small compared with that in cortisol (4, 26), DHEA-S can be measured at any time of the day, and one blood sample will suffice. Thus, DHEA-S measurements offer a practical way to estimate adrenal suppression during glucocorticosteroid treatment. However, as serum DHEA-S levels are rather low in young children, the DHEA-S assay used should be sensitive enough to detect small changes.
Adrenal androgen secretion starts to increase normally between 6–8 yr of age, and this may be accompanied by a transient acceleration of linear growth (27, 28). Thus, the decrease in DHEA-S values during glucocorticosteroid treatment might at least partly account for the growth delay seen in steroid-treated children. However, as found in the present study, the decrease in adrenal androgen secretion seems to be reversible in most children if inhaled steroid treatment is continued at low enough doses. Thus, it is likely that in the majority of steroid-treated children the growth suppression, when present, is transient and is most evident at the beginning of the inhaled steroid therapy (29). Decreasing compliance with inhaled steroid treatment after the first months of therapy could be another explanation for the recovery of DHEA-S secretion and growth, but we did not notice compliance problems during our 6 months follow-up period.
In conclusion, even conventional doses of inhaled steroids suppress DHEA-S production dose-dependently. A decrease in serum DHEA-S concentration may indicate a risk for systemic side-effects of long-term inhaled steroid treatment in children, and it could be used as a sign to consider alternative therapies for asthma in these children. Thus serum DHEA-S measurement can be used as a practical method to follow adrenocortical function during corticosteroid therapy in individual patients.
Acknowledgments
Footnotes
This work was supported by the Finnish Foundation of Pediatric Research, Novo Nordisk Foundation, Academy of Finland, and Kuopio University Hospital (Research Contract 5145).
Abbreviations: BUD, budesonide; CI, confidence interval; CROM, cromone-treated control group; DHEA-S, dehydroepiandrosterone sulfate; FEV1, forced expiratory volume in 1 sec; FP, fluticasone propionate.
Received December 6, 2000.
Accepted June 4, 2001.
References
sterballe
O 1991 Adrenal function in asthmatic children treated with inhaled
budesonide. Acta Paediatr Scand 80:213–217[Medline]
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
), and the rest of the children (12 in the BUD group and
11 in the FP group) were continued on steroids (
and 
). The
groups differed significantly at 2 months (
, P <
0.05). **, P < 0.01; ***,
P < 0.001 (compared with the baseline level).