Indian Journal of Pediatrics, Volume 75October, 2008 1039

Correspondence and Reprint requests : Vijayalakshmi Bhatia,

Department of Endocrinology SGPGIMS, Lucknow-226 014,
India. Phone: +91-522-2668700x2380, Fax: +91-522-2668017
[Received August 19, 2008; Accepted August 19, 2008]
Symposium on Steroid Therapy
Corticosteroid Physiology and Principles of Therapy
Priyanka Gupta and Vijayalakshmi Bhatia
Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow,India
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therapy should be withdrawn gradually and stopped based on assessment of hypothalamo-pituitary-adrenal (HPA) axis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
Corticosteroids (CS) are an important class of naturally
occurring and synthetic steroid hormones that affect
virtually every aspect of human physiology. They are a
common part of our prescriptions, sometimes in
physiological doses and sometimes for pharmacological
therapy. CS therapy affects endogenous CS production
and has a suppressive effect on hypothalamo-pituitary-
adrenal (HPA) axis. This chapter deals with principles
of endogenous steroidogenesis and CS therapy
including actions of CS, agents used in CS therapy,
dosing and withdrawal regimes, stress dosing and
immunisation related issues.
The adrenal cortex and HPA axis
The adrenal cortex consists of three zones. The zona
glomerulosa, located immediately beneath the capsule,
synthesizes aldosterone, the most potent
mineralocorticoid (MC) in humans. The zona fasciculata
(middle zone) produces cortisol (hydrocortisone), the
principle circulating glucocorticoid (GC). Adrenal
androgens are secreted by both zona fasciculata and zona
reticularis (innermost zone).
GC secretion is regulated by adrenocorticotrophic
hormone (ACTH), produced in the anterior pituitary
and released in secretory bursts throughout the day
and night. ACTH production is in turn driven by
corticotrophin releasing hormone (CRH) from the
hypothalamus. Pulses of ACTH occur every 30-120
minutes. Varying amplitude of ACTH pulses leads to
the normal diurnal rhythm of cortisol production.
Plasma cortisol is highest in the early morning, low in
the afternoon and evening, and lowest 1 or 2 hours after
sleep begins. Cortisol has a negative feedback on ACTH
and CRH production. Thus when GC production is
impaired as in Addison disease, ACTH is elevated.
Similarly, excess GC (either endogenous or exogenous)
suppresses ACTH.
In contrast to the ACTH driven GC pathway, MC
synthesis is regulated mainly by the renin-angiotensin
system and by potassium levels in blood, with ACTH
having only a short term effect. This is the reason why
patients with primary adrenal insufficiency require
both GC and MC for treatment, whereas
hypopituitarism patients with ACTH deficiency require
only GC and no MC replacement.
The mechanism of regulation of adrenal androgens
is not completely understood. Adrenarche, the onset of
adrenal secretion of dehydroepiandrosterone and
androstenedione, is a maturational process and
usually sets in prior to the onset of puberty.
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.
P. Gupta and V. Bhatia
1040 Indian Journal of Pediatrics, Volume 75October, 2008
Structure and mechanism of action
Glucocorticoid (GC) activity is determined by a
hydroxyl group at carbon-11 of the steroid molecule.
Cortisone and prednisone are 11-keto compounds,
lacking GC activity. They are converted in the liver to
cortisol and prednisolone respectively, the
corresponding 11- hydroxyl compounds. All GC
preparations marketed for topical or local use (like
intra-articular) are 11- hydroxyl compounds,
obviating the need for biotransformation.
1
The actions of all CS are mediated by interaction of
hormone with CS receptor, which regulates gene
transcription. CS continue to act inside the cell even
after their disappearance from the circulation, as the
events initiated and the products of these events (such
as specific proteins) may be present even after
disappearance of CS from the circulation.
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).
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
Fig. 1. Endogenous Steroidogenesis
TABLE 1. Classification of Glucocorticoids Based on Duration
of Action
Short acting Intermediate acting Long acting
(bioligical half (biological half (biological half
life 8-12 hr) life 12-36 hr) life 36-72 hr
Cortisol (hydrocortisone Triamcinolone Betamethasone
Cortisone Dexamethasone
Prednisolone, Prednisone
Methylprednisolone
TABLE 2. Relative Potency of Commonly Used Corticosteroids.
Preparation Potency relative to hydrocortisone
Glucocorticoid* Mineralocorticoid Growth
inhibitory
Hydrocortisone 1 1 1
Cortisone 0. 8 0. 8 0. 8
Prednisolone 4 0. 8 5
Prednisone 4 0. 8 5
Methylprednisolone 5 0. 5 7. 5
Dexamethasone 25 0 80
Fludrocortisone 10 125 -
*Anti-inflammatory potency
Corticosteroid Physiology and Principles of Therapy
Indian Journal of Pediatrics, Volume 75October, 2008 1041
that there is negative nitrogen balance with muscle
wasting, osteoporosis, growth slowing, skin
atrophy, increased capillary fragility, bruising
and striae. Healing of wounds is delayed.
c. Fat deposition: It is increased on shoulders, face
and abdomen.
d. Maintainance of blood pressure: GC enhances the
vascular reactivity to other vasoactive substances
such as nor-epinephrine and angiotensin-II.
e. Anti-vitamin D action: They decrease calcium
absorption from the gut and increase urinary
calcium excretion, thus are useful in treatment of
hypercalcemia in sarcoidosis and vitamin D
intoxication.
f. Fluid and electrolyte balance: GC exert their effect
on tubular function and glomerular filtration rate.
They play a permissive role in renal free water
excretion.
g. Renal excretion of urate is increased.
h. Anti-inflammatory and immunosuppressive
effects: GC decrease recruitment and function of
inflammatory cells and vascular permeability at
the site of inflammation. They also inhibit
prostaglandin and leucotriene synthesis by
inhibiting the release of arachidonic acid from the
phospholipids. By these mechanisms, GC protect
the organism from the damage caused by its own
defense reactions and the products of these
reactions during stress. Consequently, the use of
GC as anti-inflammatory and immuno-
suppressive agents represent the application of
physiological effects to the treatment of diseases.
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-
teronism causes positive sodium balance with
consequent expansion of extracellular volume, normal/
slight increase in plasma sodium concentration,
hypokalemia and alkalosis. In contrast, MC deficiency
leads to sodium wasting, contraction of extracellular
volume, hyponatremia, hyperkalemia and acidosis.
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/m
2
/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.
TABLE 3. Guideline for Glucocorticoid Withdrawal After Prolonged Therapy
<2 weeks No need to taper; can stop abruptly
2-4 weeks Taper over 1-2 weeks
>4 weeks Decrease* 8 am < 3 Continue physiological Reassess HPA axis 3
dose slowly cortisol g/dL replacement montly
stepwise > 20 Stop treatment
over 1-2 or g/dL
more months 3-20 Do ACTH Normal Stop treatment
to physiologic g/dL stimulation Abnormal Continue Reasses
dose
#
test physiologic HPA axis
replacement 3 monthly
*Increase the dose, if the underlying disease flares up
#Physiological dose: 10 mg/m
2
per day of hydrocortisone or 2.5 mg/m
2
per day prednisolone HPA: hypothalamopituitary
adrenal
P. Gupta and V. Bhatia
1042 Indian Journal of Pediatrics, Volume 75October, 2008
HC is preferred in infancy and childhood because of its
relatively low growth suppressing effects. Long lasting
GC (prednisolone and dexamethasone) may be an
option at/or near the completion of linear growth.
However, cost may be an important concern for our
patients. An equivalent dose of tablet hydrocortisone
(Hisone) is approximately 30 times costlier than
prednisolone (Wysolone). A hydrocortisone dose of 10
mg/m
2
/day corresponds to 2.5 mg/m
2
/day of
prednisolone and 0.25 mg/m
2
/day of dexamethasone
(Table 2). HC is given in 3 divided doses at 6-8 am, 2
pm and 8 pm, prednisolone is given in two divided
doses at 6-8 am and 4 pm, whereas dexamethasone is
given in once daily dose at 6-8 am (6, 8, 10). These
schedules are designed to mimic the normal diurnal
rhythm of cortisol production, wherein the serum
cortisol approaches very low levels by midnight.
One must monitor blood pressure, weight and
height beside other clinical and laboratory variables,
during treatment with CS.
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
morning dose of HC did not alter blood glucose, lactate,
free fatty acids, or epinephrine levels compared with
placebo. Thus exercise, although a physical stressor,
does not require increased dosing (12). In their
consensus statement on CAH, the Lawson Wilkins
Pediatric Endocrine Society and European Society for
Pediatric Endocrinology did not recommend increasing
the GC dose during psychological and emotional stress
(3).
For stress dosing, HC is the preferred agent due to its
MC activity (6). For patients able to take orally, it should
be 2-3 times the maintainance dose (6, 8, 9). Trauma
patients or those unable to take oral steroids require
parenteral (I/M or I/V) HC. At home, this can be
initiated by I/M hydrocortisone sodium succinate in a
dose of 50 mg/m
2
. This will provide coverage for 6-8
hours. The more severe stresses such as major surgery
and sepsis should be treated aggressively with doses up
to 100 mg/m
2
/day divided every 6 hourly intravenously
(6). Blood glucose should be monitored, and I/V sodium
and glucose replacements given as needed. In the
postoperative period, dose of hydrocortisone may be
tapered on a daily basis depending on the patients
condition and the level of stress, most of the patients
reaching physiological dosage by 7
th
postoperative day.
HPA axis suppression and glucocorticoid withdrawal
Systemic treatment courses as brief as 2 weeks result only in
transient suppression of endogenous cortisol production.
Topical/local GC therapy has a lower chance of HPA
axis suppression. However, long term use of high doses
of potent inhaled GC like fluticasone may lead to
impaired adrenal functions (13). In a study of children
being treated for leukemia, a 4 week course of GC
resulted in suppression of HPA axis for up to 8-10 weeks
after discontinuation (14, 15). The time course of recovery
correlated with the total duration and total previous dose
of GC. However, HPA axis suppression may persist for
as long as 12 months after withdrawal of treatment. The
recovery may be more rapid in children than adults (1).
During recovery, hypothalamo-pituitary function
recovers before adrenocortical function. Patients with
mild suppression of the HPA axis (i.e. normal basal
plasma and urine CS but impaired response to ACTH)
resumes normal HPA function more rapidly than do
those with severe depression of HPA axis (i.e. low basal
and impaired response to ACTH).
While withdrawing GC therapy, one has to balance
the risk of adverse effects of prolonged steroid use with
the risk of flare up of the underlying condition for
which GC therapy was being given. There is also a
potential risk of adrenal insufficiency with rapid
withdrawal. If the treatment duration was less than 2
weeks, GC can be stopped abruptly. In children getting
treatment for 2-4 weeks, the dose of GC may be
Corticosteroid Physiology and Principles of Therapy
Indian Journal of Pediatrics, Volume 75October, 2008 1043
decreased over 1 or 2 weeks. Step-wise tapering is
mandatory in patients on prolonged GC therapy. GC
dose is slowly decreased to physiological dose over
about 1 to 2 or more months, and then discontinued
after assessment of adrenal functions has shown
recovery (Table 3). Tests for recovery of adrenal
functions may be performed approximately every 3
months once the GC has been tapered to physiological
doses. Use of shorter acting preparations, single rather
than multiple daily doses and alternate day therapy
favour early recovery of the HPA axis. More details
about GC withdrawal are described in the
accompanying article on steroid toxicity.
Assessment of the HPA axis
Before testing for recovery, the replacement GC is
withdrawn, 24 hours before the test in the case of HC
(i.e. the dose of the previous morning may be the last
one taken) and 48 hours before with prednisolone. This
is done as these medicines will cross react in a cortisol
assay. Dexamethasone does not cross react in the
cortisol assay and thus can be used during the period
off prednisolone, if the patient resides in a remote area
far away from medical facilities and is expected not to
have recovered. Unless 8 am cortisol is clearly low (< 3-
5 g/dL) or clearly normal (>20 g/dL), an ACTH
stimulation test is indicated. This test can be performed
at any time of the day, not necessarily at 8 am. Serum
cortisol 20 g/dL 60 minutes after an I/M injection of
250 g of synthetic ACTH (Synacthen, Cortrosyn) is
regarded as normal and reflects normal response to
stress. Other tests used, such as the low dose (1 g)
ACTH test and insulin hypoglycaemia test are not
described here in detail as they are not the practical tests
for paediatricians to use and are beyond the scope of
this review.
Immunisation related issues
As recommended by the Indian Academy of Pediatrics,
children receiving CS in the dose of 2 mg/kg/day for
more than 14 days should not receive live-virus
vaccines until they are off-steroids for at least 1 month.
However physiological low dose, topical or inhaled
therapy are not contraindications (16).
Similarly, the ACIP (Advisory Committee on
Immunisation Practices, of the American Academy of
Pediatrics) writes that steroid therapy usually does not
contraindicate administration of live-virus vaccines
when such therapy is (a) short term (<2 weeks); (b) low
to moderate dose; (c) long term, alternate day treatment
with short acting preparations; (d) maintenance
physiological doses or (e) administered topically or
locally. A dose of 2 mg/kg/day or a total dose of 20
mg/day of prednisolone is considered sufficiently
immunosuppressive to raise concern about safety of
immunisation with live-virus vaccines. It may also
reduce the immune response to vaccines. Physicians
should wait for at least 3 months after discontinuation
of therapy for administration of live-virus vaccine to
patients who have received high dose systemic steroids
for greater than or equal to 2 weeks (17).
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/m
2
/
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.
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