Safety of Medications and Hormones Used in

Pediatric Endocrinology Adrenal

Graeme R. Frank1, MD, Phyllis W. Speiser1, MD, Kurt J. Griffin2, PhD, MD,
Constantine A. Stratakis2, MD, D(med)Sci
1
Schneider Children’s Hospital, New Hyde Park, NY, and New York University School of Medicine;
2
Section on Genetics and Endocrinology, Developmental Endocrinology Branch NICHD, NIH, Bethesda, MD

Corresponding author: Dr. Phyllis W. Speiser, Division of Pediatric Endocrinology, Schneider Children’s Hospital,
Room 139 269-01 76th Ave. New Hyde Park, NY 11040, Phone: 718-470-3290, Fax: 718-470-9173, Email: pspeiser@LIJ.edu

primary infectious or gastrointestinal disorders. In older

Abstract

G
lucocorticoids have been prescribed for several
decades in treating adrenal insufficiency of various
etiologies. These drugs are also heavily used in treating
non-endocrine disease. This article will focus on adverse side
effects encountered in the chronic use of different types of
glucocorticoids in children and young adults with endocrine
causes of adrenal insufficiency. Dosing guidelines are
discussed with a view toward minimizing the common
co-morbidities of growth suppression, excess weight gain,
and osteopenia, among others. This article also discusses the
use of several inhibitors of adrenal steroid biosynthesis and
one glucocorticoid receptor antagonist for the medical
treatment of Cushing syndrome.
Ref: Ped. Endocrinol. Rev. 2004;1(Suppl 4):????
Key words: glucocorticoids, corticosteroids, cortisol,
coptisone, cushing syndrome
Adrenal Insufficiency
Background
The adrenal glands, with a combined weight of 10-15 g in the
healthy adult, are composed of a cortex and a medulla. The
adrenal cortex is the principal site for both cortisol and
aldosterone synthesis, as well as a secondary source for sex
hormone synthesis. The adrenal medulla is responsible for
catecholamine synthesis, and both epinephrine and
norepinephrine are important in nervous system regulation. For
purposes of this discussion, adrenal insufficiency will refer only
to adrenocortical defects.
Indications
Adrenal insufficiency is important to recognize because of its
potentially life-threatening implications. Symptoms and signs
of this disorder are varied and nonspecific. In infancy, these
include lethargy, vomiting, poor appetite, and
failure-to-thrive. Clinicians may mistake these problems for
formula intolerance or inadequate lactation, or, alternatively,
children, chronic fatigue, headache, gastrointestinal
symptoms, salt-craving, and hyperpigmentation may be noted.
Patients may undergo extensive evaluation before a diagnosis is
made. Glucocorticoids and mineralocorticoids are highly
effective in treating adrenocortical insufficiency. Table 1 lists
various causes of adrenal insufficiency.
Mechanism of Action
Glucocorticoids, such as cortisol, are essential for survival,
mediating a myriad of developmental and physiological
processes. Cortisol production is regulated mainly by
adrenocorticotropic hormone (ACTH), which, in turn, is
regulated by corticotropin-releasing hormone (CRH). There are
numerous additional factors contributing to the activity of the
hypothalamic-pituitary-adrenal (HPA) axis. Glucocorticoids
exert their physiological actions via one of two types of nuclear
steroid hormone receptors: the glucocorticoid receptor and the
mineralocorticoid receptor. Cortisol is far more abundantly
produced than is aldosterone, the native ligand for the
mineralocorticoid receptor. Thus, there must be a mechanism
for preventing cortisol from activating the mineralocorticoid
receptor. In healthy people, cortisol is rapidly oxidized to
inactive cortisone in regions of high mineralocorticoid receptor
concentration, preventing hormonal hypertension. This
conversion is performed by the 11β-hydroxysteroid
dehydrogenase type 2 enzyme.
Among the important actions of cortisol are stimulation of
gluconeogenesis and glycogenolysis, the overall effect of which
is to raise and maintain blood glucose levels, especially during
stress (1). Thus, glucocorticoid deficiency may cause
hypoglycemia, often a vital clue to the diagnosis of adrenal
insufficiency.
Glucocorticoids also increase cardiac output and enhance
vascular sensitivity to pressor hormones (2). Hence,
glucocorticoid deficiency reduces cardiac output and may
predispose the patient to heart failure and shock. Patients with
adrenal insufficiency may have low blood pressure and rapid
pulse, intensified by postural changes.
The cardiovascular instability associated with glucocorticoid
deficiency is exacerbated by concomitant aldosterone
deficiency. Aldosterone production is regulated mainly by the

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renin-angiotensin system, and by ambient potassium levels.
Aldosterone deficiency results in sodium loss via the kidney,
colon, and sweat glands(3). Hypotension, salt-craving, and
hyponatremia, coupled with hyperkalemia, are signs of
mineralocorticoid deficiency.
Table 2 shows the most commonly used glucocorticoids, their
relative potencies, equivalent doses, and mineralocorticoid
actions.
Dose Range and Rationale
Glucocorticoids
Children with mild secondary adrenal insufficiency (i.e.
partial pituitary ACTH deficiency) may require glucocorticoids
only when stressed. Children with primary adrenal insufficiency
(Addison disease) require doses of hydrocortisone that
approximate physiological secretion. The normal cortisol
production rate is approximately 7-9 mg/m2/day (4,5), and a
typical dose in a younger child with Addison disease would be
10 mg or less of oral hydrocortisone per day. The therapeutic
endpoints are normal growth, weight gain, blood pressure,
exercise tolerance, and, in children old enough to articulate,
their own sense of well-being.
In contrast, patients affected with congenital adrenal
hyperplasia (CAH) often require larger doses of glucocorticoids.
The goal of therapy for CAH is not only cortisol replacement,
but also suppression of excess production of adrenal sex
hormone precursors. Thus, the additional therapeutic goals are
to maintain the serum 17-hydroxyprogesterone level between
100 and 1,000 ng/dL, and to simultaneously ensure that
testosterone and androstenedione levels are within a range
appropriate for gender, age, and pubertal status. Epiphyseal
maturation is assessed by annual radiographs of the hand and
wrist, and provides an additional, albeit crude, measure of

Table 1: Causes of Adrenal Insufficiency

Disease Mode of inheritance Most common gene defect
Primary
Polyglandular autoimmune syndrome autosomal recessive AIRE
Adrenal hemorrhage - -
Congenital adrenal hyperplasia autosomal recessive CYP21A2 (21a-hydroxylase)
Adrenoleukodystrophy X-linked ABCD1 (ATPase binding cassette protein)
Adrenal hypoplasia congenita X-linked DAX1
Wolman disease autosomal recessive LIPA (Lysosomal acid lipase)
Secondary
Hypopituitarism - Various inherited defects, e.g,, PROP1, HESX1, TPIT
Withdrawal of glucocorticoid therapy - -
End-organ unresponsiveness
ACTH resistance (type 1 GC deficiency) autosomal recessive MC2R (ACTH receptor)
Cortisol resistance autosomal dominant NR3C1 (glucocorticoid receptor)
Pseudohypoaldosteronism autosomal recessive type 1 EnaC (sodium channel)
autosomal recessive type 2 WNK4 (protein kinase)
autosomal dominant MR (mineralocorticoid receptor)
GC = glucocorticoid

Table 2: Potency of Commonly Used Glucocorticoids

STEROID ANTI-INFLAMMATORY GROWTH-RETARDING SALT-RETAINING PLASMA BIOLOGICAL
GLUCOCORTICOID GLUCOCORTICOID MINERALOCORTICOID HALF-LIFE HALF-LIFE
EFFECT EFFECT EFFECT (min) (h)
Cortisol 1.0 1.0 1.0 80-120 8
Cortisone 0.8 0.8 0.8 80-120 8
Prednisone 3.5-4 5* 0.8 200 16-32
Prednisolone 4 - 0.8 120-300 16-32
Methylprednisolone 5 7.5 0.5 - -
Dexamethasone 30 80 0 150->300 36-54
Adapted with permission from: Miller,WL. The adrenal cortex. In: Rudolph CD, Rudolph AM eds. Rudolph’s Pediatrics, 21st edition, McGraw-Hill 2003
* Newer data suggest that the growth retarding effect of prednisolone (and by extension prednisone) is significantly greater, on the order of 15 (21)

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 ????

hormone balance. Desirable glucocorticoid dosing ranges from patients who are status-post pituitary surgery (11). Patients
10-15 mg/m2/day of hydrocortisone equivalents in CAH. When who have been subjected to pituitary surgery should be
epiphyseal closure is imminent, longer-acting and more potent covered with stress doses of glucocorticoids during and
glucocorticoids (e.g., prednisolone or dexamethasone) can be immediately following surgery. Several months after steroid
substituted for hydrocortisone (6). Although some clinicians tapering has been completed, such patients should be tested to
have used these drugs successfully in young children (7), there determine whether the HPA axis is intact.
is cause for concern regarding more prevalent adverse side
Mineralocorticoids
effects, i.e. iatrogenic Cushing syndrome.
Adrenal insufficiency often extends to aldosterone deficiency.
One of the most common causes of adrenal insufficiency is
An average starting dose of oral fludrocortisone is 0.1 mg per
iatrogenic resulting from lack of awareness of the need to day. The dose is titrated according to plasma renin activity,
taper glucocorticoids after long-term use. Short courses of and may be as high as 0.4 mg per day. Sodium chloride
glucocorticoids (e.g., asthma treatment consisting of ~20 supplements may also be required, particularly in infants who
mg/day of prednisone over 5 days) do not require tapering (8). ingest very little sodium with their liquid diets and in older
However, administration of hydrocortisone, prednisone, or individuals living in hot climates, or during summer months
dexamethasone in supraphysiological doses (e.g., prednisone when bodily sodium losses are high due to perspiration.
≥ 10 mg daily) for periods of greater than 2-3 weeks require In CAH, even patients who have adequate aldosterone
gradual tapering to allow the HPA axis time to recover from production may benefit from fludrocortisone treatment, as
suppression. There is no absolute algorithm for steroid such an approach aids in suppressing ACTH overproduction and
tapering, but this should be individualized as each patient reduces the cortisol replacement dose.
tolerates reduction of treatment. The taper schedule will
depend on the total dosage, dose schedule, duration of Side Effects
treatment, and underlying disease being treated. Usually, a
Supraphysiological doses of glucocorticoids are commonly
high therapeutic dose (e.g., 10 mg/kg/day of hydrocortisone, 2
used in a variety of clinical conditions such as in the treatment
mg/kg/day of prednisone, or 0.5 mg/kg/day of
of inflammatory diseases, autoimmune conditions, and certain
dexamethasone) may be reduced in a serial, step-wise fashion
malignancies, and to prevent rejection of transplanted organs.
over a period of about one week to a level typically used in These high doses of glucocorticoids are associated with
treating adrenal insufficiency in periods of crisis or stress. multiple adverse effects (Table 3). In contrast, physiological
Further tapering may then proceed during the next week, until replacement doses of glucocorticoid used to treat adrenal
a maintenance level is achieved (7-9 mg/m 2 /day
hydrocortisone equivalents, or a maximum
Table 3: Side Effects of Glucocorticoids
daily dose of 10 mg in a child). Final tapering
leading to discontinuation of therapy should Short-term use Long-term use
then proceed slowly, so that the duration of Cutaneous Cushing syndrome
tapering approximates the total length of Acne, ecchymosis, hirsutism, striae Growth suppression
treatment, up to 6-9 months (8). Intercurrent Weight gain Adrenal insufficiency
febrile illness or surgical procedures demand a Metabolic Gastrointestinal
temporary increase in the glucocorticoid dose Hypokalemia Peptic ulcer
for several days for up to a year after chronic Glucose intolerance Hepatic steatosis
glucocorticoid therapy (9). Documentation of Myopathy Ophthalmological
an intact HPA axis should be obtained before Pancreatitis Glaucoma
subjecting to surgery a patient who has a Psychiatric Subcapsular cataract
known history of prior high-dose, long-term Mood alteration, hyperactivity Hyperlipidemia
glucocorticoid treatment. This may be done by Insomnia, psychosis Osteoporosis
documenting an 0800 serum cortisol level Neurological
>10 µg/dL, or by performing a Cosyntropin benign intracranial hypertension, seizures
(synthetic ACTH) challenge. If such Hypertension
documentation cannot be obtained in time, it Hematological
is safest to treat with supplemental stress Increased leukocyte count, transient monocytopenia
glucocorticoid coverage in the perioperative Eosinophilopenia, increased erythropoiesis
period for any patient within one year of Thrombocytosis
withdrawal of previous therapy (10). Immunological
Adrenal insufficiency is a common cause of Decreased delayed hypersensitivity skin reaction, anergy
mortality in the post-operative period for

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insufficiency are generally free from side effects. However, in
children with adrenal insufficiency secondary to CAH, the goal
of therapy is not only to provide physiological replacement of
glucocorticoid, but also to suppress excessive adrenal androgen
production. Therefore, doses of glucocorticoids are mildly
supra-physiological and, not surprisingly, adverse effects are
more frequently encountered.
Linear Growth
In supra-physiological doses, glucocorticoids interfere with
the growth hormone (GH)-IGF-I axis at the level of the
hypothalamus, pituitary and target organs. In addition,
glucocorticoids have a direct growth-inhibiting effect at the
level of the growth plate (12). Furthermore, in CAH patients,
inadequate glucocorticoid therapy leads to androgen excess
that causes accelerated epiphyseal maturation and loss of
growth potential. Therefore, it is not surprising that most
patients with CAH do not achieve their adult target heights.
Although numerous studies have reported short adult stature as
an inevitable consequence of CAH, with the final height SDS
averaging –2.0, a recent meta-analysis of 18 studies found a
mean final height SDS of –1.37 (13). The same authors reported
their own study involving 65 patients and demonstrated that,
with earlier diagnosis and good compliance, final adult stature
frequently falls within 0.5-1 SD of target height (13).
Growth during infancy: In salt-wasting CAH, loss of final adult
height potential might be the result of excessive doses of
glucocorticoids in the first one to two years of life. Van der
Kamp et al investigated 34 patients with salt-wasting and 26
non-salt-wasting patients. In the first three months of life, the
mean length SDS decreased to –1.50. This early growth failure
was probably secondary to the high average dose of
hydrocortisone (40 mg/m2/day) administered. It should be
noted that this dose is approximately five times the
physiological secretion rate in neonates (14). In this study, final
height corrected for target height was approximately -1.26 SDS
in both males and females, but patients treated with salt
supplements during the first year had a better final height
outcome (-0.83 SDS) (15). Similar findings were demonstrated
in a recent Finnish study (16). In 56 subjects with
21-hydroxylase deficiency diagnosed in infancy, the mean
length decreased from +0.8 SDS at birth to –1.0 by one year of
age. The doses of hydrocortisone were greatest during the first
year, up to 37.3 mg/m 2 /day (16). Finally, Manoli et al
demonstrated that, in patients with salt-wasting CAH, height at
two years was negatively correlated to the hydrocortisone dose
in the birth to two-year period (r = -0.79, p = 0.011) and final
height was positively correlated with height at two years
(r = 0.688, p = 0.019) (17).
These data suggest that growth retardation in the first one to
two years of life might have a detrimental effect and,
therefore, treatment with lower doses of glucocorticoids might
be beneficial for final adult height. Furthermore, since growth
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during the first year is not very sensitive to androgens, the
elevated levels of androgens that will likely accompany
treatment with lower doses of glucocorticoids will likely not
have a negative effect on growth (18,19).
Growth during childhood: The dose of glucocorticoid is also
important during childhood. In a randomized controlled trial
investigating the effect of 15 or 25 mg/m 2 /day of oral
hydrocortisone (average and upper limit of generally
recommended doses) in 26 children (18 girls) aged 3.6 months –
15 years (median age 45.3 months), growth velocity was
significantly decreased during treatment with 25 mg/m 2/day
compared to 15 mg/m2/day. Although a dose-dependent effect
upon serum 17-hydroxyprogesterone, testosterone, and
androstenedione was found, increased levels were found in
more that half the determinations made during the 25
mg/m2/day dosing period (20). The authors concluded that a
dose of 25 mg/m2/day of hydrocortisone is harmful to growth
velocity and that normalization of the 17-hydroxyprogesterone
and androgen levels should be avoided.
Choice of glucocorticoid: Generally, in children,
hydrocortisone has been favored over longer-acting
glucocorticoids (prednisone and dexamethasone) based on the
assumption that these longer-acting glucocorticoids are more
growth-suppressive. Recently, however, these assumptions
have been challenged. Rivkees and Crawford (7) examined the
growth of 17 boys and 9 girls with CAH treated with carefully
titrated doses of dexamethasone. Males were treated for a
mean of 7.3±1.1 years, during which time the change in bone
age was 7.0±1.3 years and the change in height age was
9.1±1.1 years. Females were treated for 6.8±1.3 years, over
which time the change in bone age was 6.5±1.0 years and
change in height age 6.3±0.8 years. When the daily doses of
hydrocortisone and dexamethasone were compared,
dexamethasone was 70-fold more potent than hydrocortisone.
This relative potency of dexamethasone contrasts markedly
with the manufacturer’s claim that dexamethasone is only
approximately 30-fold more potent than hydrocortisone. This
apparent marked under-reporting of the potency is probably
responsible for overtreatment and consequent growth failure in
dexamethasone-treated children. Similarly, the dose potency
of prednisolone relative to hydrocortisone has recently been
brought into question. When liquid hydrocortisone was
discontinued, Punthakee et al switched young children with
adrenal insufficiency to liquid prednisolone to facilitate precise
dosing. Initial dosing that relied on the assumed relative
potency of prednisolone to hydrocortisone of 5:1 resulted in
marked growth failure. With respect to growth, the authors
suggest a relative potency of 15:1 (21).
Glucocorticoid metabolism: The bioavailability of
glucocorticoids is determined by the isomers of
11 β-hydroxysteroid dehydrogenase that catalyze the
interconversion of cortisol and cortisone, as well as
prednisolone and prednisone. Polymorphisms in this enzyme, as
well as polymorphisms in hepatic cytochrome P450 enzymes
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responsible for xenobiotic and drug metabolism, result in
individual variations in drug metabolism and, therefore, doses
should be customized for each patient. Given the higher
potency and longer duration of action of prednisolone and
dexamethasone, it is easier to ‘overdose’ children using these
glucocorticoids. As a result, the joint Lawson Wilkins Pediatric
Endocrinology/European Society for Pediatric Endocrinology
(LWPES/ESPE) CAH Working Group Consensus Statement
considers hydrocortisone to be the preferred glucocorticoid
during infancy and childhood, and considers the longer-acting
glucocorticoids a therapeutic option at or near the completion
of linear growth (6).
Obesity
Overtreatment with glucocorticoids will both stunt growth
and increase adiposity. However, weight gain is commonly seen
even in children whose CAH is well-controlled. Cornean et al
studied the height and change in BMI, and triceps and
subscapular skinfolds in 22 prepubertal children with
well-controlled CAH at one, five, and 10 years. In these
children, initial doses of hydrocortisone (15-25 mg/m2/day) and
fludrocortisone (150 mcg/m 2/day) were adjusted to body
surface area, growth rate and changes in skeletal maturation
(22). Maintaining a 50th percentile height velocity without
acceleration of skeletal age was taken as evidence of good
control. Despite good control, BMI SDS increased significantly
throughout childhood. The increase in BMI was due to increased
body weight (fat mass) since the height SDS remained constant.
It was noted that the adiposity rebound (beginning of the
post-infancy rise in the BMI) took place about 3 years earlier
that in the normal population. Early rebound is known to
increase the rate of overweight in adulthood.
In this study, only peripheral fat (skinfolds) were evaluated.
However, in glucocorticoid excess, adult patients generally
develop florid (though reversible) central adiposity from
visceral fat accumulation. It is well known that central
adiposity has more severe consequences than peripheral
adiposity in terms of increased cardiovascular morbidity (23).
Bone mineral density (BMD)
Bone is a dynamic tissue that undergoes constant remodeling.
Bone resorption is mediated by the osteoclast, a
multinucleated cell derived from the peripheral
mononuclear/macrophage lineage that decalcifies bone and
creates a resorption pit. This bone resorption is later followed
by bone formation, the process whereby osteoblasts, derived
from pluripotential mesenchymal cells, secrete osteoid into the
resorption pit. The osteoid then calcifies into bone.
Glucocorticoids are thought to induce osteoporosis by a
number of mechanisms that include: a. suppressing osteoblast
formation, activity and survival (24); b. increasing osteoclast
maturation and activity (25,26); c. inhibiting apoptosis in of
mature osteoclasts (27); and d. decreasing calcium absorption
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from the gut (28). Of these, inhibition of osteoblastic bone
formation is thought to be the most important. There is
marked individual susceptibility to the skeletal effects of
glucocorticoids and this is likely related to the expression of
11β-hydroxysteroid dehydrogenase type 1 activity (this reaction
favors the formation of cortisol) in the osteoblast (29).
Given the negative effects of glucocorticoids on BMD, and the
fact that the doses of glucocorticoids used in the past were
much higher than physiological replacement doses (30), a
number of investigators have evaluated BMD in children and
young adults with CAH. It should be emphasized that BMD in
patients with CAH should be evaluated in relation to the
metabolic control of the patients since excess androgen
exposure in under treated or poorly controlled subjects may
increase bone density, while overtreatment will result in
decreased BMD. In addition, since glucocorticoids preferentially
affect trabecular bone (31), the lumbar spine would be the site
most likely affected. Some studies have demonstrated reduced
BMD. Cameron et al, for example, evaluated BMD in 21
Australian patients (aged 8-32 years) with CAH and compared
them to a control group. Only in males was the mean spinal
BMAD (bone mineral apparent density), assessed by dual energy
x-ray absorptiometry (DEXA) and adjusted for skeletal size,
lower that that of male controls (32). In addition, Paganini et
al evaluated 50 patients (aged 1-28 years) with CAH, 41 with
classic CAH (27 salt-wasters and 14 simple virilizers) and 9 with
non-classical CAH. The duration of therapy was shorter and the
doses of glucocorticoids were significantly lower in the
non-classical group compared to those with classical CAH.
Patients with classical CAH had reduced volumetric BMD
(measured by DEXA and adjusted for vertebral volume)
compared to those with non-classical CAH (33).
Not all studies have demonstrated reduced BMD in patients
with CAH. Some have shown no influence on areal BMD
(measured by DEXA) in children with CAH (34,35), while others
demonstrated increased regional areal BMD (measured by
DEXA) (36). Possible explanations for the disparate findings
include differences in disease expression (proportion of
patients with salt-wasting CAH, as these patients are diagnosed
and treated from an earlier age), different doses of
glucocorticoid used, and methodology used to assess bone
density. DEXA provides only a two-dimensional measurement of
BMD. It calculates the bone mineral content (grams) and
divides it by the area of the bone (cm2). In contrast, true BMD
should include not only length and width of bone, but also the
depth, to yield a three-dimensional volumetric BMD. Failure to
adjust for the volume of bone results in underestimates of BMD
in short children and overestimates of BMD in tall children.
In adult patients with CAH, both the dose and preparation of
glucocorticoid has been shown to influence BMD. In 32 adult
patients with CAH, both mean BMD at the femoral neck and
lumbar spine were less than in controls. Both current and
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long-term mean glucocorticoid doses showed significant
negative correlations with BMD. Patients on hydrocortisone
were less often overtreated and had better BMD Z-score means
than patients substituted with prednisone, prednisolone, or
dexamethasone (37).
Blood Pressure
While hypertension is commonly found in Cushing syndrome,
it is less frequently encountered in patients receiving
exogenously administered glucocorticoid therapy. This may be
attributable in part to efficient conversion of hydrocortisone
(cortisol) and prednisolone (but not dexamethasone) to
inactive cortisone and prednisone, respectively, by the enzyme
11β-hydroxysteroid dehydrogenase type 2. These conversions
protect the mineralocorticoid receptor from exposure
to high-affinity glucocorticoid ligands, thereby
preventing hypertension. While the exact mechanism of
glucocorticoid-induced hypertension is not clear, it is thought
to be secondary to enhanced vascular reactivity to pressor
hormones (38). Although little is known about the prevalence
of raised blood pressure in children with CAH, some new data
suggest that these children have elevated blood pressure and
absence of the physiological nocturnal dip (39). Thirty-eight
children with CAH underwent 24-hour ambulatory blood
pressure monitoring. Both the mean daytime systolic and
diastolic blood pressure SDS were significantly greater than
those of the reference population and 58% of patients had
systolic and 24% had diastolic hypertension. Eighty-four percent
had absence of the physiological nocturnal dip in systolic blood
pressure. BMI SDS was higher than in the reference population
and related to systolic blood pressure SDS. The combination of
elevated blood pressure, absence of the nocturnal dip in blood
pressure, and the association of obesity (22) and insulin
resistance (40) may place patients with CAH at risk for
developing metabolic syndrome (syndrome X)-related
atherosclerotic cardiovascular disease in later life. At present,
routine anti-hypertensive treatment and insulin-sensitizing
agents are not recommended for CAH patients.
Conclusion
Most of the adverse effects of glucocorticoids in children
treated for adrenal insufficiency occur as a result of the
supra-physiological doses that are administered. Failure to
taper therapy after chronic high-dose glucocorticoid
administration is a frequent cause of morbidity in
glucocorticoid-treated individuals with non-endocrine disease.
Furthermore, one must recognize the need for increased dose
level and frequency during acute illness. While it is now
well-established that the physiological secretion rate of
cortisol in children and adults is approximately 7-9 mg/m2/day
(4,5) (significantly less than previously thought), it should be
recognized that there is marked individual variability in
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intestinal absorption and metabolism of orally administered
glucocorticoids. Therefore, no “correct dose” of glucocorticoid
replacement exists. Titration of the dose of glucocorticoid
should be carefully performed using growth rate and weight
gain. Determination of bone age and measurement of serum
adrenocortical hormone levels are helpful in patients with CAH.
Following these guidelines should not only optimize linear
growth, but also minimize the potential adverse effects of
glucocorticoids on BMD, weight gain, and blood pressure.
Glucocorticoid Excess
Background
Cushing syndrome in childhood is most often caused by
supraphysiological doses of exogenous glucocorticoids (41,42).
While this is often an expected side effect of high-dose
glucocorticoid therapy, it has also been described with the
routine use of nasal or topical steroid preparations (43,44). In
children, endogenous Cushing syndrome is rare (45). When it
occurs, it is most often due to a corticotropin (ACTH)-secreting
pituitary tumor (“Cushing disease”) (46), but it may also be
due to an ectopic ACTH-secreting tumor (47), or
ACTH-independent adrenal hyperplasia, which is almost
invariably bilateral (48-50). Glucocorticoid excess (GCE) causes
hyperphagia, weight gain, poor linear growth, hypertension,
and osteopenia. Although less prominent when seen in adults,
striae can develop in children (51).
Indications
Correction of GCE is important at any age to prevent short-
and long-term complications: weight gain, hypertension,
hyperglycemia, osteopenia, muscle weakness,
immunosuppression, and changes in mood and thought (46). In
children, GCE has an additional inhibitory effect on linear
growth. After prolonged GCE is corrected, some catch-up
growth may occur, but this is often incomplete (52). Iatrogenic
GCE can sometimes be minimized by using regimens
incorporating other classes of medications that allow the
glucocorticoid dose to be reduced. For endogenous Cushing
syndrome, it is preferable to treat definitively the underlying
condition, e.g., surgical excision of an adenoma (46). Medical
treatment may be necessary, either as a temporizing strategy
prior to surgery, or as a long-term therapy for an inoperable
tumor (53).
Mechanism of Action
Agents typically used to treat GCE belong to two classes:
those that inhibit enzymes involved in steroid biosynthesis
(e.g., aminoglutethimide, ketoconazole, mitotane,
metyrapone, and etomidate; Figure), and one that is a
glucocorticoid antagonist (mifepristone). Aminoglutethimide
primarily inhibits cholesterol (20,22) desmolase (P450scc,
encoded by CYP11A1), but may also down regulate the ACTH
77
 ????

receptor (54); it also inhibits aromatase (P450arom,

encoded by CYP19A1). Ketoconazole inhibits several
P450 enzymes including P450scc ,
17α-hydroxylase/17,20-lyase (P450c17, encoded by
CYP17A1), and 11β-hydroxylase (P450c11, encoded by
CYP11B1) (55-57). Mitotane (o, p’-DDD) inhibits P450
scc, 3β-hydroxysteroid dehydrogenase (encoded by
HSD3B2), and 11- and 18-hydroxylases (P450c11 and
P450c18, encoded by the highly homologous CYP11B2);
it also has an adrenotoxic effect at higher doses, which
has been reported to cause permanent adrenocortical
insufficiency (58,59). Metyrapone is a specific inhibitor
of 11β-hydroxylase. Etomidate inhibits 11β-hydroxylase
and, to a lesser extent, cholesterol (20,22) desmolase
(60). Mifeprestone (RU 486) is a competitive antagonist
of steroid hormone receptors for glucocorticoids,
progestins, and androgens61.

Dose Range and Rationale

In general, these agents are often started at lower
doses, and then titrated upwards to achieve and
maintain effectiveness. With the exception of
etomidate, these are all oral agents.
Aminoglutethimide
Aminoglutethimide is not as effective a monotherapy
as are the agents discussed below, but it can be a
useful adjunct to treatment with other inhibitors of
steroidogenesis (62). It is FDA-approved for this use in
adults only. Adult doses can start at 0.5 g/day and
increase gradually to 2 g/day. The safety of
aminoglutethimide in children has not been
established. In one report, a 16-year-old received 1 g/d Figure: Sites of Action of Inhibitors of Steroid Synthesis
(53). DOC = deoxycorticosterone
Ketoconazole
Mitotane
In the United States, ketoconazole is approved by the FDA as
Mitotane is FDA-approved for treatment of adrenocortical
an antifungal agent in adults and in children over 2 years of
age. Its use to treat GCE is “off label,” but is well-accepted. carcinoma in adults and children; treatment of GCE is, again,
Ketoconazole is useful as a monotherapy for GCE, with adult an “off-label” use. Mitotane is effective as monotherapy and
doses typically between 400 and 1200 mg/day (63,64). Doses of has often been used in conjunction with radiation (67-70). Up
200-600 mg/day have been used in children (53). The pediatric to 30% may achieve permanent remission of GCE following
dose for antifungal use is 3.3-6.6 mg/kg/day (65). In the discontinuation of mitotane (70). Doses in pediatric patients
absence of more extensive studies in children with GCE, it have been in the range of 3 g/day or 5-12 g/m2/day (53,71,72).
would be reasonable to start in this range, and titrate up, as Metyrapone
needed, to control cortisol levels. Over time, increasing doses Metyrapone is also useful as monotherapy (73,74), although it
may be required, especially in Cushing disease: as cortisol
is not approved in the US as treatment for GCE, and is no
levels fall, negative feedback on pituitary corticotrophs is
longer available there. In adults, metyrapone therapy is
decreased, and corticotropin production is increased as a result
initiated at 0.5 g/d divided bid-qid, and may be increased
of the altered pituitary set-point (66). Absorption of
ketoconazole is dependent on an acidic environment. gradually to a maximum dose of 6 g/d (75). Although few
Therefore, it cannot be used in patients taking proton-pump studies have been reported in children, doses used have ranged
inhibitors or in achlohydric patients (65). from 0.75 to 3 g/day (53,76).

Pediatric Endocrinology Reviews (PER) ● Volume 2 ● Supplement 1 ● September 2004 78

 ????

Etomidate glucocorticoid production more completely, followed by

Etomidate is an ultra-short-acting nonbarbiturate imidazole provision of exogenous replacement glucocorticoids. In the
hypnotic. At sub-hypnotic doses, it inhibits adrenal steroid latter case, drug interactions must be considered.
biosynthesis (77). It is the only parenteral agent available to Aminoglutethimide
treat GCE, and can be useful when a patient is unable to take Patients taking aminoglutethimide may experience
oral medications. As an anesthetic, it is approved for adults drowsiness, pruritus, nausea, vomiting, and myalgia (85). A
and children over 10 years of age. Adult doses of 2.5 mg/h or rash accompanied by fever may be a transient effect in the
0.1 mg/kg/h have been shown to decrease cortisol and ACTH first few weeks therapy in up to 35% (86-88). Hypothyroidism is
responses in patients with Cushing
syndrome (77,78) There is a report
of a patient with GCE treated with Table 4: Drug Interactions with Ketoconazole
a continuous infusion of etomidate Increased Concentration/Effect of Drug Increased Side Effects
for eight weeks (79). More Amlodipine Fluticasone: -> HPA suppression
recently, a patient with an ectopic Amprenavir HMG-Co-A reductase inhibitors
ACTH-secreting tumor was Coumadin, Warfarin, Anisindione, Phenindione Atorvastatin, cervistatin, simvastatin
maintained for over five months Aripiprazole -> increased risk of myopathy
with short, daily infusions of a Astemizole (-> Prolonged QT interval)
propylene glycol preparation of Benzodiazepines Decreased Concentration of Ketoconazole
etomidate (80). No dosing Budesonide Due to Decreased Gastric Acidity
information is available for Carbamazepine Aluminum compounds
etomidate in pediatric patients Cilostazol Calcium compounds
with GCE. Cisapride Magnesium compounds
Mifepristone Cyclosporine Bicarbonate compounds
Mifepristone has been effective Delavirdine Cimetidine
in reversing the symptoms of Donepezil Esomeprazole
Cushing syndrome at doses of 5-25 Eletriptan Omeprazole
mg/kg/day (81-83). In most cases, Ergot derivatives Famotidine
mifepristone was started at the Felodipine Lansoprazole
lower end of this dose range and Fentanyl Ranitidine
titrated upward to achieve Fexofenadine
adequate control of cortisol levels. Gransietron Other Mechanisms
There is one pediatric case Imatinib Nevirapine
reported in which a 27-month-old Imipramine Phenytoin
girl with elevated cortisol of Indinavir Rifampin
unknown etiology was treated for Loratadine Sucralfate
nine 9 weeks with mifepristone at Methylprednisone
a dose of 5 to 20 mg/kg/day. She Mifepristone Increased Concentration/Effect of
had resolution of cushingoid Nelfinavir Ketoconazole
symptoms and subsequent Nifedipine Amprenavir
remission, even after terminating Prednisolone Isoniazid
treatment (84). Mifepristone has Prednisone Octreotide
not been approved as a therapy for Progesterone Ritonavir
GCE in the US. Quinidine
Saquinavir
Adverse Effects Sibutramine
Effective use of any of these Sirolimus
agents may lead to adrenal Sildenafil
insufficiency. Treatment regimens Tacrolimus
should be monitored closely and Terfenadine (-> Prolonged QT interval)
titrated to maintain relatively Tolbutamide
normal levels of serum cortisol. Tretinoin
Alternatively, therapy may be Vardenafil
targeted to inhibit endogenous

Pediatric Endocrinology Reviews (PER) ● Volume 2 ● Supplement 1 ● September 2004 79


frequent resulting from blockage of tyrosine iodination by
aminoglutethimide (89). Hematopoetic suppression may occur.
Aminoglutethimide has a variable effect on levels of exogenous
glucocorticoids; it decreases the half-life of dexamethasone,
but not of hydrocortisone (90). Increased clearance has also
been reported for digitoxin, medroxyprogesterone, and
tamoxifen (85).
Ketoconazole
Nausea and vomiting are frequent, occurring in up to 50% of
treated subjects. These effects are dose-dependent and are
minimized by taking ketoconazole with meals (91).
Gynecomastia is experienced by up to 21% of males taking a
daily dose of 600 mg (91). Transient fatigue, myalgia, and
photophobia may occur (92). Two patients were reported to
develop hypothyroidism while taking ketoconazole (93), but
subsequent studies have not supported this link (94). More
serious effects include hemolytic anemia and
thrombocytopenia, which occur in fewer than 1% of patients.
Liver failure is reported to occur in approximately 1 in 10,000
patients. Early detection is imperative, as it may be reversible.
(65). Routine measurement of serum liver enzymes is,
therefore, recommended. There is one case of fatal liver
failure reported in a 14-year-old girl with Cushing disease after
unsuccessful pituitary surgery (95). Ketoconazole inhibits
cytochrome P450 enzymes responsible for metabolizing
numerous other drugs (Table 4), which may require dosage
adjustments to avoid toxicities (65).
Mitotane
Mitotane can cause permanent insufficiency of adrenocortical
hormones. This is more common with higher doses (≥ 4 g/d)
(96-98). A large fraction of patients treated with mitotane
experience anorexia, nausea, hyperlipoproteinemia, and
hypothyroidism (67) Approximately half may experience
depression, lethargy, and decreased memory (67,99).
Permanent brain damage has been reported with prolonged
treatment (99). Mitotane induces enhanced expression of
cytochrome P450 enzymes, which increases the clearance of
other drugs, including exogenous glucocorticoids and warfarin
(99,100). Severe and fatal infections have occurred when live
vaccines are administered to people taking mitotane. Mitotane
has an extremely long half-life (18-159 days) (99). This raises
concern for its use in fertile women who may wish to delay
pregnancy for several years following treatment.
Metyrapone
Specific inhibition of 11β-hydroxylase and increased ACTH
stimulation can lead to hypertension due to accumulation of
steroid precursors with mineralocorticoid activity (101). Acne
and hirsutism may result from accumulation of precursors with
androgen activity (102,103). Fatigue, weakness, confusion,
bone marrow depression, and nausea have also been reported
(104).
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Etomidate
Brief periods of myoclonus and tremor are frequent when
etomidate is used as an anesthetic agent, as is pain at the site
of infusion (105,106). With larger doses, the sedative effects
become more apparent.
Mifepristone
There is one case reported of a woman with inoperable
Cushing syndrome who was treated with two 6-month courses
of mifepristone, 400 mg/day (107). While her cushingoid
symptoms resolved during this treatment, she developed
massive endometrial hyperplasia; this resolved following
discontinuation of the drug. When used as an abortifacient,
mifepristone is associated with headaches, nausea, and
vomiting. It is not approved for other uses during pregnancy
(108). Patients taking mifepristone have been reported to
develop adrenal insufficiency (83,109).
Reproductive Effects
Although experimental data are scarce, any drugs that
interfere with the biosynthesis of adrenal steroids would be
expected to mimic developmental defects seen in the
congenital adrenal hyperplasia syndromes. Ambiguous genitalia
have been reported in one female baby exposed to
aminoglutethimide in utero (110). High doses of ketoconazole
are associated with fetal digit anomalies in rats (65) and there
is one case of finger agenesis reported from France (111). The
FDA assigns aminoglutethimide to pregnancy risk class D
(positive evidence of human fetal risk exists, but benefits in
certain situations may make use of the drug acceptable despite
its risks), while ketoconazole, metyrapone, mitotane, and
etomidate are class C (animal studies have shown that the drug
exerts teratogenic or embryocidal effects, and there are no
adequate, well-controlled studies in pregnant women, or: no
studies are available in either animals or pregnant women)
(65,85,99).
Conclusion
While surgical and/or radiation therapy may provide
definitive treatment of the underlying cause of Cushing
syndrome, these modalities are not always appropriate or
effective. Although no agents are FDA-approved to treat GCE in
children, a small, but growing, body of literature suggests the
above agents should be effective in this setting.
References
1. Pilkis SJ, Granner DK. Molecular physiology of the regulation of
hepatic gluconeogenesis and glycolysis. Annu Rev Physiol
1992;54:885-909
2. Kelly JJ, Mangos G, Williamson PM, Whitworth JA. Cortisol and
hypertension. Clin Exp Pharmacol Physiol Suppl 1998;25:S51-S56
3. Bonvalet JP. Regulation of sodium transport by steroid hormones.
Kidney Int Suppl 1998;65:S49-S56
4. 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
80

5. 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
6. Clayton PE, Miller WL, Oberfield SE, Ritzen EM, Sippell WG, Speiser
PW. 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
7. Rivkees SA, Crawford JD. Dexamethasone treatment of virilizing
congenital adrenal hyperplasia: the ability to achieve normal growth.
Pediatrics 2000;106:767-773
8. Stwerart P. The Adrenal Cortex. In: Larsen P, Kroneneberg H, Melmed
S, editors. Williams Textbook of Endocrinology. Philadelphia: W.B.
Saunders, 2002
9. Lamberts SW, Bruining HA, de Jong FH. Corticosteroid therapy in
severe illness. N Engl J Med 1997;337:1285-1292.
10. Oelkers W. Adrenal insufficiency. N Engl J Med 1996;355:1206-1212
11. Bates AS, Van't Hoff W, Jones PJ, Clayton RN. The effect of
hypopituitarism on life expectancy. J Clin Endocrinol Metab
1996;81:1169-1172
12. Hochberg Z. Mechanisms of steroid impairment of growth. Horm Res
2002;58 Suppl 1:33-38
13. Eugster EA, Dimeglio LA, Wright JC, Freidenberg GR, Seshadri R,
Pescovitz OH. Height outcome in congenital adrenal hyperplasia
caused by 21-hydroxylase deficiency: a meta-analysis. J Pediatr
2001;138:26-32
14. Metzger DL, Wright NM, Veldhuis JD, Rogol AD, Kerrigan JR.
Characterization of pulsatile secretion and clearance of plasma cortisol
in premature and term neonates using deconvolution analysis. J Clin
Endocrinol Metab 1993;77:458-463
15. van der Kamp HJ, Otten BJ, Buitenweg N, De Muinck
Keizer-Schrama SM, Oostdijk W, Jansen M, Delemarre-de Waal HA,
Vulsma T, Wit JM. Longitudinal analysis of growth and puberty in
21-hydroxylase deficiency patients. Arch Dis Child 2002;87:139-144
16. Jaaskelainen J, Voutilainen R. Growth of patients with
21-hydroxylase deficiency: an analysis of the factors influencing adult
height. Pediatr Res 1997;41:30-33
17. Manoli I, Kanaka-Gantenbein C, Voutetakis A, Maniati-Christidi M,
Dacou-Voutetakis C. Early growth, pubertal development, body mass
index and final height of patients with congenital adrenal hyperplasia:
factors influencing the outcome. Clin Endocrinol (Oxf) 2002;57:669-676
18. Thilen A, Woods KA, Perry LA, Savage MO, Wedell A, Ritzen EM.
Early growth is not increased in untreated moderately severe
21-hydroxylase deficiency. Acta Paediatr 1995;84:894-898
19. Aceto TJ, MacGillivray MH, Caprano VJ, Munschauer RW, Raiti S.
Congenital virilizing adrenal hyperplasia without acceleration of
growth or bone maturation. Jama 1966;198:1341-1343
20. Silva IN, Kater CE, Cunha CF, Viana MB. Randomised controlled trial
of growth effect of hydrocortisone in congenital adrenal hyperplasia.
Arch Dis Child 1997;77:214-218
21. Punthakee Z, Legault L, Polychronakos C. Prednisolone in the
treatment of adrenal insufficiency: A re-evaluation of relative
potency. J Pediatr 2003:402-405
22. Cornean RE, Hindmarsh PC, Brook CG. Obesity in 21-hydroxylase
deficient patients. Arch Dis Child 1998;78:261-263
23. Fontbonne A, Thibult N, Eschwege E, Ducimetiere P. Body fat
distribution and coronary heart disease mortality in subjects with
impaired glucose tolerance or diabetes mellitus: the Paris Prospective
Study, 15-year follow-up. Diabetologia 1992;35:464-468
24. Dempster DW. Bone histomorphometry in glucocorticoid-induced
osteoporosis. J Bone Miner Res 1989;4:137-141
25. Vidal NO, Brandstrom H, Jonsson KB, Ohlsson C. Osteoprotegerin
mRNA is expressed in primary human osteoblast-like cells:
down-regulation by glucocorticoids. J Endocrinol 1998;159:191-195
26. Sasaki N, Kusano E, Ando Y, Nemoto J, Iimura O, Ito C, Takeda S,
Yano K, Tsuda E, Asano Y. Changes in osteoprotegerin and markers
of bone metabolism during glucocorticoid treatment in patients with
chronic glomerulonephritis. Bone 2002;30:853-858
27. Weinstein RS, Chen JR, Powers CC, Stewart SA, Landes RD, Bellido
T, Jilka RL, Parfitt AM, Manolagas SC. Promotion of osteoclast
survival and antagonism of bisphosphonate-induced osteoclast
apoptosis by glucocorticoids. J Clin Invest 2002;109:1041-1048
Pediatric Endocrinology Reviews (PER) ● Volume 2 ● Supplement 1 ● September 2004
????
28. Hahn TJ, Halstead LR, Strates B, Imbimbo B, Baran DT. Comparison
of subacute effects of oxazacort and prednisone on mineral
metabolism in man. Calcif Tissue Int 1980;31:109-115
29. Cooper MS, Blumsohn A, Goddard PE, Bartlett WA, Shackleton CH,
Eastell R, Hewison M, Stewart PM. 11beta-hydroxysteroid
dehydrogenase type 1 activity predicts the effects of glucocorticoids
on bone. J Clin Endocrinol Metab 2003;88:3874-3877
30. Miller WL. Clinical review 54: Genetics, diagnosis, and management of
21-hydroxylase deficiency. J Clin Endocrinol Metab 1994;78:241-246
31. Chiodini I, Carnevale V, Torlontano M, Fusilli S, Guglielmi G, Pileri
M, Modoni S, Di Giorgio A, Liuzzi A, Minisola S, Cammisa M,
Trischitta V, Scillitani A. Alterations of bone turnover and bone mass
at different skeletal sites due to pure glucocorticoid excess: study in
eumenorrheic patients with Cushing's syndrome. J Clin Endocrinol
Metab 1998;83:1863-1867
32. Cameron FJ, Kaymakci B, Byrt EA, Ebeling PR, Warne GL, Wark JD.
Bone mineral density and body composition in congenital adrenal
hyperplasia. J Clin Endocrinol Metab 1995;80:2238-2243
33. Paganini C, Radetti G, Livieri C, Braga V, Migliavacca D, Adami S.
Height, bone mineral density and bone markers in congenital adrenal
hyperplasia. Horm Res 2000;54:164-168
34. Girgis R, Winter JS. The effects of glucocorticoid replacement
therapy on growth, bone mineral density, and bone turnover markers
in children with congenital adrenal hyperplasia. J Clin Endocrinol
Metab 1997;82:3926-3929
35. Gussinye M, Carrascosa A, Potau N, Enrubia M, Vicens-Calvet E,
Ibanez L, Yeste D. Bone mineral density in prepubertal and in
adolescent and young adult patients with the salt-wasting form of
congenital adrenal hyperplasia. Pediatrics 1997;100:671-674
36. Speiser P, New M, Gertner J. Increased bone mineral density in
congenital adrenal hyperplasia. Pediatr Res 1993;33:S81
37. Jaaskelainen J, Voutilainen R. Bone mineral density in relation to
glucocorticoid substitution therapy in adult patients with
21-hydroxylase deficiency. Clin Endocrinol (Oxf) 1996;45:707-713
38. Whitworth JA. Studies on the mechanisms of glucocorticoid
hypertension in humans. Blood Press 1994;3:24-32
39. Roche E, Charmandari E, Dattani M, Hindmarsh P. Blood pressure in
children and adolescents with congenital adrenal hyperplasia
(21-hydroxylase deficiency): a preliminary report. Clin Endocrinol (Oxf)
2003;58:589-596
40. Charmandari E, Weise M, Bornstein SR, Eisenhofer G, Keil MF,
Chrousos GP, Merke DP. Children with classic congenital adrenal
hyperplasia have elevated serum leptin concentrations and insulin
resistance: potential clinical implications. J Clin Endocrinol Metab
2002;87:2114-2120
41. Ermis B, Ors R, Tastekin A, Ozkan B. Cushing's syndrome secondary
to topical corticosteroid abuse. Clin Endocrinol (Oxf) 2003;58:795-796.
42. Agadi S. Iatrogenic Cushing's syndrome: a different story. Lancet
2003;361:1059
43. Perry RJ, Findlay CA, Donaldson MD. Cushing's syndrome, growth
impairment, and occult adrenal suppression associated with intranasal
steroids. Arch Dis Child 2002;87:45-48
44. Chen F, Kearney T, Robinson S, Daley-Yates PT, Waldron S,
Churchill DR. Cushing's syndrome and severe adrenal suppression in
patients treated with ritonavir and inhaled nasal fluticasone. Sex
Transm Infect 1999;75:274
45. Robyn JA, Koch CA, Montalto J, Yong A, Warne GL, Batch JA.
Cushing's syndrome in childhood and adolescence. J Paediatr Child
Health 1997;33:522-527
46. Magiakou MA, Mastorakos G, Oldfield EH, Gomez MT, Doppman JL,
Cutler GB, Jr, Nieman LK, Chrousos GP. Cushing's syndrome in
children and adolescents. Presentation, diagnosis, and therapy. N Engl
J Med 1994;331:629-636
47. Normann T, Havnen J, Mjolnerod O. Cushing's syndrome in an infant
associated with neuroblastoma in two ectopic adrenal glands. J Pediatr
Surg 1971;6:169-175
48. Kirk JM, Brain CE, Carson DJ, Hyde JC, Grant DB. Cushing's
syndrome caused by nodular adrenal hyperplasia in children with
McCune-Albright syndrome. J Pediatr 1999;134:789-792
81

49. Davies JH, Barton JS, Gregory JW, Mills C. Infantile McCune-Albright
syndrome. Pediatr Dermatol 2001;18:504-506
50. Boston BA, Mandel S, LaFranchi S, Bliziotes M. Activating mutation
in the stimulatory guanine nucleotide-binding protein in an infant with
Cushing's syndrome and nodular adrenal hyperplasia. J Clin Endocrinol
Metab 1994;79:890-893
51. Stratakis C, Mastorakos G, Mitsiades N, Mitsiades C, Chrousos G.
Skin manifestations of Cushing disease in children and adolescents
before and after the resolution of hypercortisolemia. Pediatr Dermatol
1998;15:253-258
52. Savage MO, Lienhardt A, Lebrethon MC, Johnston LB, Huebner A,
Grossman AB, Afshar F, Plowman PN, Besser GM. Cushing's disease in
childhood: presentation, investigation, treatment and long-term
outcome. Horm Res 2001;55 Suppl 1:24-30
53. Storr HL, Plowman PN, Carroll PV, Francois I, Krassas GE, Afshar F,
Besser GM, Grossman AB, Savage MO. Clinical and endocrine
responses to pituitary radiotherapy in pediatric Cushing's disease: an
effective second-line treatment. J Clin Endocrinol Metab
2003;88:34-37
54. Fassnacht M, Beuschlein F, Vay S, Mora P, Allolio B, Reincke M.
Aminoglutethimide suppresses adrenocorticotropin receptor expression
in the NCI-h295 adrenocortical tumor cell line. J Endocrinol
1998;159:35-42
55. Feldman D. Ketoconazole and other imidazole derivatives as inhibitors
of steroidogenesis. Endocr Rev 1986;7:409-420
56. Sonino N. The use of ketoconazole as an inhibitor of steroid
production. N Engl J Med 1987;317:812-818
57. Rajfer J, Sikka SC, Rivera F, Handelsman DJ. Mechanism of
inhibition of human testicular steroidogenesis by oral ketoconazole. J
Clin Endocrinol Metab 1986;63:1193-1198
58. Hart MM, Swackhamer ES, Straw JA. Studies on the site of action of
o,p'-DDD in the dog adrenal cortex. II. TPNH- and corticosteroid
precursor-stimulation of o,p'-DDD inhibited steroidogenesis. Steroids
1971;17:575-586
59. Ojima M, Saitoh M, Itoh N, Kusano Y, Fukuchi S, Naganuma H. The
effects of o,p'-DDD on adrenal steroidogenesis and hepatic steroid
metabolism. Nippon Naibunpi Gakkai Zasshi 1985;61:168-178
60. Allolio B, Dorr H, Stuttmann R, Knorr D, Engelhardt D, Winkelmann
W. Effect of a single bolus of etomidate upon eight major
corticosteroid hormones and plasma ACTH. Clin Endocrinol (Oxf)
1985;22:281-286
61. Spitz IM, Bardin CW. Mifepristone (RU 486)--a modulator of progestin
and glucocorticoid action. N Engl J Med 1993;329:404-412
62. Schteingart DE, Conn JW. Effects of aminoglutethimide upon adrenal
function and cortisol metabolism in Cushing's syndrome. J Clin
Endocrinol Metab 1967;27:1657-1666
63. Tabarin A, Navarranne A, Guerin J, Corcuff JB, Parneix M, Roger P.
Use of ketoconazole in the treatment of Cushing's disease and ectopic
ACTH syndrome. Clin Endocrinol (Oxf) 1991;34:63-69
64. Winquist EW, Laskey J, Crump M, Khamsi F, Shepherd FA.
Ketoconazole in the management of paraneoplastic Cushing's syndrome
secondary to ectopic adrenocorticotropin production. J Clin Oncol
1995;13:157-164
65. Bowers S, TW T. Ketoconazole. In: RK K, editor. Drugdex System.
Expires 6/2004 ed. Greenwood Village, CO: Thomson Micromedex,
2003
66. Engelhardt D, Jacob K, Doerr HG. Different therapeutic efficacy of
ketoconazole in patients with Cushing's syndrome. Klin Wochenschr
1989;67:241-247
67. Schteingart DE, Tsao HS, Taylor CI, McKenzie A, Victoria R,
Therrien BA. Sustained remission of Cushing's disease with mitotane
and pituitary irradiation. Ann Intern Med 1980;92:613-619
68. Orth DN, Liddle GW. Results of treatment in 108 patients with
Cushing's syndrome. N Engl J Med 1971;285:243-247
69. Zachmann M, Gitzelmann RP, Zagalak M, Prader A. Effect of
aminoglutethimide on urinary cortisol and cortisol metabolites in
adolescents with Cushing's syndrome. Clin Endocrinol (Oxf)
1977;7:63-71
70. Luton JP, Mahoudeau JA, Bouchard P, Thieblot P, Hautecouverture
M, Simon D, Laudat MH, Touitou Y, Bricaire H. Treatment of
Cushing's disease by o,p'DDD. Survey of 62 cases. N Engl J Med
1979;300:459-464.
Pediatric Endocrinology Reviews (PER) ● Volume 2 ● Supplement 1 ● September 2004
????
71. Wooten MD, King DK. Adrenal cortical carcinoma. Epidemiology and
treatment with mitotane and a review of the literature. Cancer
1993;72:3145-3155
72. Teinturier C, Pauchard MS, Brugieres L, Landais P, Chaussain JL,
Bougneres PF. Clinical and prognostic aspects of adrenocortical
neoplasms in childhood. Med Pediatr Oncol 1999;32:106-111
73. Thoren M, Adamson U, Sjoberg HE. Aminoglutethimide and
metyrapone in the management of Cushing's syndrome. Acta
Endocrinol (Copenh) 1985;109:451-457
74. Jeffcoate WJ, Rees LH, Tomlin S, Jones AE, Edwards CR, Besser
GM. Metyrapone in long-term management of Cushing's disease. Br Med
J 1977;2:215-217
75. Nieman LK. Medical therapy of Cushing's disease. Pituitary
2002;5:77-82
76. Dickstein G, Lahav M, Shen-Orr Z, Edoute Y, Barzilai D. Primary
therapy for Cushing's disease with metyrapone. JAMA
1986;255:1167-1169
77. Schulte HM, Benker G, Reinwein D, Sippell WG, Allolio B. Infusion of
low dose etomidate: correction of hypercortisolemia in patients with
Cushing's syndrome and dose-response relationship in normal subjects.
J Clin Endocrinol Metab 1990;70:1426-1430
78. Allolio B, Schulte HM, Kaulen D, Reincke M, Jaursch-Hancke C,
Winkelmann W. Nonhypnotic low-dose etomidate for rapid correction
of hypercortisolaemia in Cushing's syndrome. Klin Wochenschr
1988;66:361-364
79. Drake WM, Perry LA, Hinds CJ, Lowe DG, Reznek RH, Besser GM.
Emergency and prolonged use of intravenous etomidate to control
hypercortisolemia in a patient with Cushing's syndrome and peritonitis.
J Clin Endocrinol Metab 1998;83:3542-3544
80. Krakoff J, Koch CA, Calis KA, Alexander RH, Nieman LK. Use of a
parenteral propylene glycol-containing etomidate preparation for the
long-term management of ectopic Cushing's syndrome. J Clin
Endocrinol Metab 2001;86:4104-4108
81. Chu JW, Matthias DF, Belanoff J, Schatzberg A, Hoffman AR,
Feldman D. Successful long-term treatment of refractory Cushing's
disease with high-dose mifepristone (RU 486). J Clin Endocrinol Metab
2001;86:3568-3573
82. Nieman LK, Chrousos GP, Kellner C, Spitz IM, Nisula BC, Cutler GB,
Merriam GR, Bardin CW, Loriaux DL. Successful treatment of
Cushing's syndrome with the glucocorticoid antagonist RU 486. J Clin
Endocrinol Metab 1985;61:536-540
83. Sartor O, Cutler GB, Jr. Mifepristone: treatment of Cushing's
syndrome. Clin Obstet Gynecol 1996;39:506-510
84. Beaufrere B, de Parscau L, Chatelain P, Morel Y, Aguercif M,
Francois R. RU 486 administration in a child with Cushing's syndrome.
Lancet 1987;2:217
85. Berner B. Aminoglutethimide. In: Klasco R, editor. Drugdex System.
Expires 6/04 ed. Greenwood Village, CO: Thomson Micromedex, 2000
86. Murray RM, Pitt P, Jerums G. Medical adrenalectomy with
aminoglutethimide in the management of advanced breast cancer. Med
J Aust 1981;1:179-181
87. Wells SA, Jr, Santen RJ, Lipton A, Haagensen DE, Jr., Ruby EJ,
Harvey H, Dilley WG. Medical adrenalectomy with aminoglutethimide:
clinical studies in postmenopausal patients with metastatic breast
carcinoma. Ann Surg 1978;187:475-484
88. Stratakis CA, Chrousos GP. Capillaritis (purpura simplex) associated
with use of aminoglutethimide in Cushing's syndrome. Am J Hosp
Pharm 1994;51:2589-2591
89. Rallison ML, Kumagai LF, Tyler FH. Goitrous hypothyroidism induced
by amino-glutethimide, anticonvulsant drug. J Clin Endocrinol Metab
1967;27:265-272
90. Halpern J, Catane R, Baerwald H. A call for caution in the use of
aminoglutethimide: negative interactions with dexamethasone and
beta blocker treatment. J Med 1984;15:59-63
91. Sugar AM, Alsip SG, Galgiani JN, Graybill JR, Dismukes WE, Cloud
GA, Craven PC, Stevens DA. Pharmacology and toxicity of high-dose
ketoconazole. Antimicrob Agents Chemother 1987;31:1874-1878
92. Ross JB, Levine B, Catanzaro A, Einstein H, Schillaci R, Friedman
PJ. Ketoconazole for treatment of chronic pulmonary
coccidioidomycosis. Ann Intern Med 1982;96:440-443
82

93. Kitching NH. Hypothyroidism after treatment with ketoconazole. Br
Med J (Clin Res Ed) 1986;293:993-994
94. De Pedrini P, Tommaselli A, Montemurro G. No effect of
ketoconazole on thyroid function of normal subjects and hypothyroid
patients. Int J Clin Pharmacol Res 1988;8:485-488
95. Zollner E, Delport S, Bonnici F. Fatal liver failure due to
ketoconazole treatment of a girl with Cushing's syndrome. J Pediatr
Endocrinol Metab 2001;14:335-338
96. Lubitz JA, Freeman L, Okun R. Mitotane use in inoperable adrenal
cortical carcinoma. JAMA 1973;223:1109-1112
97. Gutierrez ML, Crooke ST. Mitotane (o,p'-DDD). Cancer Treat Rev
1980;7:49-55
98. Hutter AM, Jr, Kayhoe DE. Adrenal cortical carcinoma. Clinical
features of 138 patients. Am J Med 1966;41:572-580
99. Drugdex Editorial Staff. Mitotane. In: Klasco R, editor. Drugdex
System. Expires 6/04 ed. Greenwood Village, CO: Thomson
Micromedex, 2003
100. Hague RV, May W, Cullen DR. Hepatic microsomal enzyme induction
and adrenal crisis due to o,p'DDD therapy for metastatic adrenocortical
carcinoma. Clin Endocrinol (Oxf) 1989;31:51-57
101. Connell JM, Cordiner J, Davies DL, Fraser R, Frier BM, McPherson
SG. Pregnancy complicated by Cushing's syndrome: potential hazard of
metyrapone therapy. Case report. Br J Obstet Gynaecol
1985;92:1192-1195
102. Harris PL. Alopecia associated with long-term metyrapone use. Clin
Pharm 1986;5:66-68
Pediatric Endocrinology Reviews (PER) ● Volume 2 ● Supplement 1 ● September 2004
????
103. Orth DN. Metyrapone is useful only as adjunctive therapy in Cushing's
disease. Ann Intern Med 1978;89:128-130
104. Drugdex Editorial Staff. Metyrapone. In: RK K, editor. Dosing and
Therapeutic Tools Database. Expires 6/2004 ed. Greenwood Village,
CO: Thomson Micromedex, 2002
105. Doenicke A, Gabanyi D, Lemce H, Schurk-Bulich M. Haemodynamics
and myocardial function after administration of three short-acting i.v.
hypnotics, etomidate, propanidid, methohexital. Anaesthesist
1974;23:108-115
106. Morgan M, Lumley J, Whitwam JG. Etomidate, a new water-soluble
non-barbiturate intravenous induction agent. Lancet 1975;1:955-956
107. Newfield RS, Spitz IM, Isacson C, New MI. Long-term mifepristone
(RU486) therapy resulting in massive benign endometrial hyperplasia.
Clin Endocrinol (Oxf) 2001;54:399-404
108. Baker D, Lee K. Mifepristone. In: Klasco R, editor. Drugdex System.
expires 6/04 ed. Greenwood Village, CO: Thomson Micromedex, 2003
109. Laue L, Lotze MT, Chrousos GP, Barnes K, Loriaux DL, Fleisher TA.
Effect of chronic treatment with the glucocorticoid antagonist RU 486
in man: toxicity, immunological, and hormonal aspects. J Clin
Endocrinol Metab 1990;71:1474-1480
110. LeMaire WJ, Cleveland WW, Bejar RL, Marsh JM, Fishman L.
Aminoglutethimide: a possible cause of pseudohermaphroiditism in
females. Am J Dis Child 1972;124:421-423
111. Cabou C, Lacroix I, Rista C, Rolland M, Chassaing N, Calvas P,
Montastruc JL, Damase-Michel C. Finger agenesis after in utero
exposure to ketoconazole: a case report. Therapie 2003;58:172-174
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