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ABSTRACT
The adrenal cortex secretes glucocorticoids (GC), mineralocorticoids (MC) and androgens. GC maintain homeostasis, MC
regulate fluid and electrolyte balance and adrenal androgens contribute to development of secondary sexual characteristics.
Pharmacologic GC therapy is frequently indicated in the pediatric age group. Besides having many important side effects,
prolonged high dose systemic GC therapy has a suppressive effect on endogenous steroid production. Therefore, GC
therapy should be withdrawn gradually and stopped based on assessment of hypothalamo-pituitary-adrenal (HPA) axis
recovery. Patients with HPA axis suppression require physiological replacement of GC along with enhancement of doses
during periods of stress. Due to its immunosuppressive effects, issues about safety and efficacy of live virus vaccines in
patients receiving systemic high dose GC therapy must be borne in mind. [Indian J Pediatr 2008; 75 (10) : 1039-1044]
E-mail: vbhatia@sgpgi.ac.in
Key words: Corticosteroid; Hypothalamo-pituitary-adrenal axis; Replacement dose; Stress dose
Endogenous steroidogenesis
The substrate for steroid production is cholesterol. It is
mobilised from the outer to the inner mitochondrial
membrane (by the steroidogenic acute regulatory (StAR)
protein), where it is converted to pregnenolone (Figure
1). ACTH regulation of StAR protein is the rate limiting
step in adrenal steroidogenesis.
1039
Pharmacodynamics
Systemically used GC are classified as short acting,
intermediate acting and long acting (Table 1) based on
their duration of ACTH suppression. They also differ in
their relative GC versus MC potency (Table 2) (1, 2).
However one must remember that even those CS which
have low MC activity (eg. hydrocortisone) may have MC
effects when used in high doses. The relative potency of
CS differ due to their affinity for the receptor. However,
observed potency is determined by both intrinsic
biologic potency and duration of action. There is little
correlation between circulating half life (t1/2) and its
potency. Similarly little correlation exist between t1/2
and its duration of action (1).
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Actions of corticosteroids
1. Glucocorticoids
a. Carbohydrate metabolism: GC increase
gluconeogenesis and conserve glucose for use by
essential tissues like brain and red blood cells, at
the expense of less essential tissues like muscle,
during the times of stress or starvation.
b. Protein metabolism: Overall effect is catabolic so
TABLE 1. Classification of Glucocorticoids Based on Duration
of Action
Short acting
(bioligical half
life 8-12 hr)
Intermediate acting
(biological half
life 12-36 hr)
Long acting
(biological half
life 36-72 hr
Triamcinolone
Betamethasone
Dexamethasone
Cortisol (hydrocortisone
Cortisone
Prednisolone, Prednisone
Methylprednisolone
Hydrocortisone
Cortisone
Prednisolone
Prednisone
Methylprednisolone
Dexamethasone
Fludrocortisone
1
0.8
4
4
5
25
10
1
0.8
0.8
0.8
0.5
0
125
Growth
inhibitory
1
0.8
5
5
7.5
80
-
*Anti-inflammatory potency
2. Mineralocorticoids
MC primarily act on the distal tubules and collecting
ducts of kidneys, beside their actions on gut, salivary
and sweat glands, where they stimulate reabsorption of
sodium and excretion of potassium and hydrogen ions,
thus maintaining electrolyte balance. Hyperaldos-
3. Adrenal androgens
Physiologic development of pubic and axillary hair and
odour during normal puberty is regulated by adrenal
androgens. Increased adrenal androgen production
results in virilisation in girls and peripheral precocious
puberty in boys.
Physiological replacement of CS
Prolonged GC therapy suppresses the HPA axis.
During the period which the axis takes to recover (which
may be as long as 12-18 months), the adrenal gland will not
be able to make GC in sufficient amounts needed for daily
physiology. Furthermore, it will not be able to increase GC
production to the levels required during stress, the required
release being anywhere from three times (for moderate stress)
to ten times (for severe stress) the daily production rate. This
adjustment has to be done through exogenous GC
replacement and patient education, until the patient has
been documented to have HPA axis recovery.
Glucocorticoids
The physiological secretory rate of cortisol in the intact
system is approximately 6 mg/m 2/day (3, 4, 5). The
usual maintainance GC dose is adjusted above this
estimated secretory rate as the bioavailability of cortisol
is reduced by gastric acids and first pass metabolism in
liver. Thus 8-10 mg/m 2/day of oral hydrocortisone
(HC) is a reasonable initial starting dose, though
patients with primary adrenal insufficiency may
require slightly higher doses of 10-12 mg/m2/day (6, 7,
8, 9). Later on, the dose may be individualised to avert
signs and symptoms of adrenal insufficiency on the
one hand while avoiding growth retardation and
cushingoid features on the other.
2-4 weeks
>4 weeks
Decrease*
dose slowly
stepwise
over 1-2 or
more months
to physiologic
dose#
8 am
cortisol
<3
g/dL
> 20
g/dL
3-20
g/dL
Continue physiological
replacement
Do ACTH
stimulation
test
Stop treatment
Continue
Reasses
physiologic
HPA axis
replacement
3 monthly
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Mineralocorticoids
Fludrocortisone is the synthetic MC used in all patients
with primary adrenal insufficiency and classic
congenital adrenal hyperplasia (CAH). Dosage
requirements in early infancy range from 0.05-0.3 mg/
day and remain the same or decrease to 0.05-0.2 mg/
day with age (6, 8, 9, 11). Infants need simultaneous
sodium chloride supplementation at 1-3 gm/day (17-51
mEq Na+/day), distributed in several feedings, as milk
alone does not contain adequate amounts of sodium. As
explained above, MC replacement is not required in
children with secondary adrenal insufficiency. By the
same analogy, the child recovering from prolonged
steroid therapy, who has ACTH deficiency, does not
need MC replacement.
Stress dosing
With stress, cortisol secretion increases. Consequently,
all patients with primary or secondary adrenal
insufficiency and CAH must be educated about the
need for increasing their GC dose during stress to avoid
an adrenal crisis, which can be fatal. They should
always carry medical identification and information
concerning therapy for stress. Care givers should have
an emergency supply of I/M HC.
There is controversy about the definition of stress
and the need to increase GC doses. Mild stresses like
immunisation, uncomplicated viral illness and upper
respiratory tract infections may not require a stress dose
steroid regimen, if the patient otherwise feels well. GC
doses should be increased during fever 38 o C,
vomiting, diarrhea, decreased oral intake, lethargy,
surgery, trauma, dental work and large burns (6, 8, 9). It
has been reported that for short term high intensity
exercise in adolescents with CAH, an additional
1042
CONCLUSION
Prolonged glucocorticoid therapy affects endogenous
CS production and has a suppressive effect on
hypothalamo-pituitary-adrenal (HPA) axis. If the
treatment duration was less than 2 weeks, GC can be
stopped abruptly. If given for > 4 weeks, GC should be
tapered to physiological dose over about 1 to 2 or more
months, and then discontinued after assessment of
adrenal functions has shown recovery. Until the HPA
axis recovers and endogenous production normalises,
GC replacement in physiological dose of 8-10 mg/m2/
day of oral hydrocortisone is required. Enhanced doses
(from 2 3 to 10 times the daily replacement) are
required during stress such as fever, infection, surgery
and trauma. HPA axis recovery is tested by 8 am
cortisol and ACTH stimulated cortisol.
REFERENCES
1. Axelrod L. Glucocorticoid therapy. In DeGroot LJ, Jemeson
JL, de Kretser D, Grossman AB, Marshall JC, Melmed S et al
eds. Endocrinology, 5 th ed. Philadelphia: Elsevier Saunders;
2006; 2329-2342.
2. Schimmer BP, Parker KL. Adrenocorticotropic hormone;
Adrenocortical steroids and their synthetic analogs;
inhibitors of the synthesis and actions of Adrenocortical
hormones. In Brunton LL, Silazo J, Parker KL, eds. Goodman
and Gilmans The Pharmacological basis of Therapeutics, 11th ed.
USA; The McGraw-Hill Companies, 2006; 1587-1612.
3. Kerrigan JR, Veldhuis JD, Leyo SA, Iranmanesh A, Rogol
AD. Estimation of daily cortisol production and clearance
rates in normal pubertal males by deconvolution analysis. J
Clin Endocrinol Metab 1993; 76: 1505-1510.
4. Esteban NV, Loughlin T, Yergey AL, Zawadzki JK, Booth
JD, Winterer JC et al. Daily cortisol production rate in man
determined by stable isotope dilution/mass spectrometry.
J Clin Endocrinol Metab 1991; 72: 39-45.
5. Linder BL, Esteban NV, Yergey AL, Winterer JC, Loriaux
DL, Cassorla F. Cortisol production rate in childhood and
adolescence. J Pediatr 1990; 117 : 892-896.
6. Shulman DI, Palmert MR, Kemp SF; Lawson Wilkins Drug
and Therapeutics Committee. Adrenal insufficiency: still a
cause of morbidity and death in childhood. Pediatrics 2007;
119 : e484-494. Epub 2007 Jan 22.
7. Lukert BP. Editorial: glucocorticoid replacementhow
much is enough? J Clin Endocrinol Metab 2006; 91 : 793-794.
8. Clayton PE, Miller WL, Oberfield SE, Ritzn EM, Sippell
WG, Speiser PW; ESPE/ LWPES CAH Working Group.
Consensus statement on 21-hydroxylase deficiency from the
European Society for Paediatric Endocrinology and the
Lawson Wilkins Pediatric Endocrine Society. Horm Res 2002;
58 : 188-195.
1043
1044
Mar 23.
14. Einaudi S, Bertorello N, Masera N, Farinasso L, Barisone E,
Rizzari C et al. Adrenal axis function after high-dose steroid
therapy for childhood acute lymphoblastic leukemia.
Pediatr Blood Cancer 2008; 50 : 537-541.
15. Felner EI, Thompson MT, Ratliff AF, White PC, Dickson
BA. Time course of recovery of adrenal function in children
treated for leukemia. J Pediatr 2000; 137 : 21-24.
16. Shah RC, Shah NK, Kukreja S. Immunization in Special
Circumstances. In Shah RC, Shah NK, Kukreja S eds. IAP
Guide Book on Immunization, 4 th ed. Mumbai: Indian
Academy of Pediatrics; 2007; 52-58.
17. Centers for Disease Control and Prevention. Recommendations of the Advisory Committee on Immunization
Practices (ACIP): Use of vaccines and immune globulins in
persons with altered immunocompetence. MMWR 1993; 42
(No.RR-4): {inclusive page numbers}.