Adrenal Suppression

Adrenal suppression
Straight to the point of care
Last updated: Apr 12, 2022

Table of Contents
Overview 3
Summary 3
Definition 3
Theory 4
Epidemiology 4
Aetiology 4
Pathophysiology 5
Case history 5
Diagnosis 6
Approach 6
History and exam 10
Risk factors 12
Investigations 14
Differentials 17
Management 19
Approach 19
Treatment algorithm overview 21
Treatment algorithm 22
Primary prevention 28
Secondary prevention 28
Patient discussions 28
Follow up 29
Monitoring 29
Complications 29
Prognosis 29
Guidelines 30
Diagnostic guidelines 30
Treatment guidelines 31
References 32
Images 39
Disclaimer 41
Adrenal suppression Overview
Summary
Adrenal suppression is the inadequate adrenal production of cortisol due to suppression of the hypothalamic-
pituitary-adrenal axis.
OVERVIEW
It may present clinically as adrenal insufficiency in instances of rapid tapering or cessation of exogenous
glucocorticoids or withdrawal from endogenous glucocorticoid excess (e.g., following treatment of Cushing's
disease or an adrenal tumour causing Cushing's syndrome).
The adrenocorticotropic hormone stimulation test is generally the most useful test to detect adrenal
suppression.
Preventive measures include minimising corticosteroid dose and duration when possible.
Treatment consists of augmented corticosteroid therapy plus supportive care for any intercurrent stress or
overt signs of adrenal insufficiency.
Definition
Adrenal suppression refers to decreased cortisol production as a result of negative feedback on the
hypothalamic-pituitary-adrenal axis, caused by excess glucocorticoids.[1] The consequence is decreased
production of both corticotropin-releasing hormone from the hypothalamus and adrenocorticotropic hormone
from the pituitary gland, leading to a decrease in serum cortisol levels.[1]
This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Apr 12, 2022.
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3
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Adrenal suppression Theory
Epidemiology
Adrenal suppression is most commonly encountered in patient populations where an underlying disease
is treated with exogenous glucocorticoids (e.g., chronic obstructive pulmonary disease, asthma, arthritis,
THEORY
or certain malignancies such as leukaemia).[3] [4] The prevalence or incidence of adrenal suppressin in
these different subpopulations is not often reported but may be more common than generally believed. The
percentage of patients who develop adrenal insufficiency after the use of corticosteroids varies with the
mode of delivery and underlying disease (e.g., 6.8% of asthma patients with inhaled corticosteroids only;
60% of patients with haematological malignancies and systemic corticosteroids).[3] In one review of
symptomatic adrenal suppression among children in Canada, the estimated annual incidence was 0.35 per
100,000 children aged 0-18 years.[2] The review acknowledged that incidence rates in at-risk groups, such
as those treated with corticosteroids, would be much higher.[2] Almost 80% of the children with symptomatic
adrenal suppression had received inhaled corticosteroid.[2] In one study of children taking medium doses,
or less, of inhaled corticosteroids for the treatment of asthma, the prevalence of hypothalamic-pituitary-
adrenal axis suppression was 9.3%.[5] In children receiving pharmacological doses of glucocorticoids for
inflammatory bowel disease, up to 20% exhibited prolonged adrenal suppression, even after a slow taper.[6]
Aetiology
Exogenous glucocorticoids are cited as the most frequent cause of adrenal suppression, probably because
the diseases for which they are often used (e.g., asthma, chronic obstructive pulmonary disease, and
arthritis) are fairly common.[3] [7] Systemically administered glucocorticoids are well-known causes of
adrenal suppression.[1] [3] [4] [7] [8] Less commonly recognised is that local administration of glucocorticoids
(such as intra-articular, epidural, inhaled, intranasal, or topical routes) can also cause adrenal suppression.[9]
[10] [11] [12] [13] [14] [15] Medications that act on the glucocorticoid receptor, such as megestrol and
medroxyprogesterone, are also reported causes.[1] [16] [17] In addition, as CYP3A4 is the primary pathway
for the metabolism of most prescribed glucocorticoids, concomitant medications that are CYP3A4 inhibitors
will increase exposure to glucocorticoids.[1] For example, the antiretroviral drug ritonavir is a CYP3A4
inhibitor, and is known to increase plasma concentrations of prednisone metabolites (prednisolone).[1] Other
strong CYP3A4 inhibitors include antifungals such as itraconazole and ketoconazole, and cancer treatments
such as ceritinib and idelalisib.[1] More recently, the anaesthetic induction agent etomidate was recognised
as a drug that can interfere with adrenal steroid synthesis and was noted to increase the risk of adrenal
insufficiency and mortality in patients with sepsis.[18]
Excess glucocorticoid secretion from an adrenal adenoma or carcinoma causing Cushing's syndrome can
cause suppression of the contralateral adrenal gland, with adrenal insufficiency resulting if the autonomous
adenoma or carcinoma is removed without glucocorticoid supplementation.[19] [20] In addition, after
removal of a pituitary tumour in Cushing's disease (Cushing's syndrome secondary to an adrenocorticotropic
hormone [ACTH]-secreting pituitary tumour), the remaining ACTH-secreting cells in the pituitary gland
may be sluggish in their recovery, resulting in a period of adrenal suppression necessitating glucocorticoid
supplementation.
Susceptibility to corticosteroid-induced adrenal suppression may be linked to a specific genetic variation in

the PDGFD gene locus.[21] However, universal testing is not currently recommended.
4 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: Apr 12, 2022.
Adrenal suppression Theory
Pathophysiology
Exposure to excess glucocorticoids, whether exogenously administered or endogenously produced, results
in negative feedback on the hypothalamic-pituitary-adrenal axis.[1] The result is decreased production of
THEORY
corticotropin-releasing hormone from the hypothalamus and adrenocorticotropic hormone from the pituitary
gland, leading to a decrease in blood cortisol levels.[1] Suppression may persist even after the inciting
medication or excess glucocorticoid condition ceases. In the case of excess glucocorticoid administration,
patients may have signs and symptoms of Cushing's syndrome. When the inciting medication or condition is
suddenly removed, especially in the setting of stress, symptoms of adrenal insufficiency may occur because
the adrenal(s) are unable to produce sufficient cortisol.
There are no studies directly comparing adult versus paediatric corticosteroid-induced adrenal suppression,
but the pathophysiology is the same in both populations. The risk is greater with higher doses and longer
durations of therapy.[2]
Case history
Case history #1
A 55-year-old man is seen urgently at the clinic for weakness, nausea, and vomiting. He has a history
of chronic obstructive pulmonary disease, with previous admissions to the hospital for exacerbations
necessitating systemic glucocorticoids, including twice in the past month alone. During these admissions
he recalls receiving intravenous glucocorticoids that are later switched to an oral formulation. He was
last discharged 3 weeks ago, but his take-home oral glucocorticoid doses were higher and the tapering
schedule longer than usual for him. He felt that his breathing had improved but that he was gaining
weight, so he stopped taking the pills 1 week ago. On examination, his blood pressure is 86/58 mmHg, his
pulse rate is 103 beats/minute, and he has moon facies.
Other presentations
Patients may or may not appear cushingoid. When the inciting medication or condition is suddenly
removed, secondary adrenal insufficiency occurs. Signs and symptoms of corticosteroid-induced adrenal
suppression may be subtle or overt. Symptoms range from vague fatigue and nausea to those of adrenal
crisis (e.g., hypotension).
The non-specific symptoms of adrenal suppression in children are similar to those seen in adults;
however, children may also exhibit growth failure and hypoglycaemia.[2]
5
Adrenal suppression Diagnosis
Approach
The key to diagnosis of iatrogenic adrenal suppression is eliciting exposure to exogenous glucocorticoids or
other offending agents.
Patients receiving supraphysiological doses of oral glucocorticoids for corticosteroid-responsive illnesses and
having a cushingoid appearance (centripetal obesity with a round or moon facies, dorsocervical fat pads,
and striae) should prompt recognition of possible hypothalamic-pituitary-adrenal (HPA) axis suppression.
However, HPA axis suppression has been described after only 4 to 5 days of corticosteroid therapy and as a
consequence of local glucocorticoid administration.[24] [25] In patients receiving intra-articular glucocorticoid
injections, recovery of the HPA axis can take 1 to 4 weeks depending on the dose and frequency of
injections.[9] Although some patients appear cushingoid and some have obvious symptoms of adrenal
insufficiency when the inciting corticosteroid agent is rapidly tapered or stopped, HPA axis suppression may
be subtle. Not all patients appear cushingoid, and a high index of suspicion is necessary.
Patients with adrenal suppression are at risk of adrenal crisis if glucocorticoid treatment is suddenly ceased
or if it is not increased during periods of increased stress (e.g., febrile illness, trauma, or surgery). Patients
with a history compatible with adrenal suppression and presenting with features of adrenal crisis (i.e.,
hypotension, circulatory failure) should be treated urgently. Tests may be taken as baseline, but diagnostic
tests should not delay treatment.[32]
History and symptoms

Patients receiving supraphysiological doses of glucocorticoids are at risk of adrenal suppression,
especially if these are potent and/or administered for a prolonged period.[1] [7] [33] However, non-
systemic corticosteroids may also cause adrenal suppression.[1] Patients may need prompting: for
example, asking specifically about eye drops, nasal sprays, inhalers for breathing problems, or injections
for pain.
The history should be directed to elicit the pattern of glucocorticoid use. It is important to ask about
diseases for which corticosteroids are commonly prescribed, and oral or alternate routes of administration
DIAGNOSIS
such as:
• Inhaled corticosteroids for asthma or chronic obstructive pulmonary disease[11] [12]

• Intranasal corticosteroids for allergic rhinitis[13]
• Topical corticosteroids for the treatment of dermatological conditions[14] [15]
• Intra-articular and epidural corticosteroids for rheumatological or pain disorders.[9] [10]
Equivalent doses of hydrocortisone, prednisolone, prednisone, and dexamethasone are:
Dose equivalency for glucocorticoids

Created by MC Lansang and SL Quinn
Non-prescribed sources of corticosteroids such as over-the-counter eczema treatments, skin-lightening

creams, and herbal medicines may contain corticosteroids. Other sources of prescribed corticosteroids,
such as enemas or rectal foam for inflammatory bowel disease, should also be sought. Additional
information as to the type, dose, route of administration, and length of corticosteroid treatment should
be obtained. Less commonly, patients give a history of taking medications that act on the glucocorticoid
receptor, such as megestrol or medroxyprogesterone.[1] [16] [17] Patients should also be asked about
concomitant medications that may interfere with glucocorticoid metabolism.[1] CYP3A4 is the primary
pathway for the metabolism of most prescribed glucocorticoids, and so CYP3A4 inhibitors will increase
exposure to glucocorticoids.[1] For example, the antiretroviral drug ritonavir is a CYP3A4 inhibitor, and
is known to increase plasma concentrations of prednisone metabolites (prednisolone).[1] Other strong
DIAGNOSIS
CYP3A4 inhibitors include antifungals such as itraconazole and ketoconazole, and cancer treatments
such as ceritinib and idelalisib.[1] This list is not exhaustive, and you should consult your local drug
formulary. Rarely, patients have a history of removal of a pituitary adenoma or carcinoma that caused
Cushing's syndrome.[19] [20]
Symptoms of adrenal insufficiency may be present, especially when the inciting agent is rapidly tapered
or stopped. In patients with glucocorticoid-induced adrenal suppression, interaction with medications that
induce CYP3A4 will decrease synthetic glucocorticoid levels and may also cause symptoms of adrenal
insufficiency. Examples of agents that induce CYP3A4 include carbamazepine, phenobarbital, phenytoin,
primidone, rifampicin, and nafcillin.[1] This list is not exhaustive, and you should consult your local drug
formulary. Symptoms of adrenal insufficiency are generally vague. They include fatigue, anorexia, nausea
and/or vomiting, and weight loss.[32] Dizziness, orthostatic symptoms, myalgias, and arthralgias may also
be present. Abdominal pain can be mild or severe enough to lead to a misdiagnosis of acute abdomen.
Patients may report symptoms consistent with Cushing's syndrome, including central nervous system
symptoms such as depression, agitation, or sleep disorders.[34] There may be a prior history of weight
gain and increased appetite, round face, dorsocervical fat pads, and easy bruising. Other medical
7
disorders such as hypertension and diabetes may have become more difficult to control and less
responsive to medication.
Adrenal suppression in the paediatric population can present as an adrenal crisis in times of stress, but
is more likely to be subtle. The non-specific symptoms of adrenal suppression in children are similar to
those seen in adults; however, children may also exhibit growth failure and hypoglycaemia.[2]
Physical examination
Patients at risk of adrenal suppression who have suddenly ceased their glucocorticoid medication, or
not increased the dose during periods of increased stress, can present with an acute adrenal crisis with
collapse due to hypovolemic shock, hypotension, postural dizziness, and tachycardia.[32]
In less acute cases, patients may or may not appear cushingoid and hypertension may be present.
Proximal muscle weakness may also be present. The complexion may be plethoric with pigmented striae;
thin, easily bruised skin; and acne. Features associated with elevations of adrenocorticotropic hormone
(ACTH) such as mucosal or cutaneous hyperpigmentation will be absent. Also likely to be absent are
other stigmata of autoimmune disorders associated with autoimmune adrenal insufficiency, such as
vitiligo. These features help distinguish iatrogenic from endogenously induced adrenal suppression.
Tests
In cases of acute adrenal crisis, diagnostic tests should not delay treatment.[32] Investigations will include
close monitoring of blood pressure, fluid balance, and baseline bloods (full blood count, electrolytes, urea,
creatinine, thyroid function [hyperthyroidism can trigger adrenal crisis], cortisol, and ACTH level). If the
patient is haemodynamically stable, consider a short ACTH stimulation test.[32]
Although not diagnostic, incidental laboratory findings such as hypo- or hyperglycaemia, hypokalaemia,
hypomagnesaemia, and a contraction alkalosis may raise suspicion of glucocorticoid use. Electrolyte
abnormalities consistent with mineralocorticoid deficiency such as hyperkalaemia are absent because the
renin-angiotensin-aldosterone system remains intact.
DIAGNOSIS
As long as supraphysiological corticosteroids continue, evaluation of adrenal function is not helpful.

Patients with a history of glucocorticoid use who have had discontinuation or a recent reduction
in corticosteroid dose to physiological or sub-physiological levels, along with symptoms of adrenal
insufficiency, should be tested for adrenal suppression.
If corticosteroids have been discontinued, an early morning random cortisol is the simplest diagnostic
test, but results are usually inconclusive, necessitating one of the more cumbersome but more reliable
stimulation tests for confirmation. Because ACTH has been suppressed by the exogenous corticosteroid,
serum cortisol is expected to be low. Values below 110 nanomol/L (4 micrograms/dL) are consistent
with HPA axis suppression. Values between 110 and 469 nanomol/L (4 and 17 micrograms/dL) are
inconclusive.[35] Indeterminate values require confirmation with one of the stimulation tests to safely
discontinue corticosteroid therapy. Random serum cortisol levels, or ACTH levels, are not recommended
as reliable indicators of adrenal status. In lieu of completing one of the stimulation tests, many physicians
prefer to proceed with a corticosteroid tapering programme. When the morning serum cortisol value is
>497 nanomol/L (18 micrograms/dL), corticosteroids can be safely discontinued.
Midnight salivary cortisol has been recognised as an excellent diagnostic tool for identifying Cushing's
syndrome but there has been increased interest in morning salivary cortisols as a means of screening
for adrenal insufficiency. Studies have found that morning serum cortisol levels are equivalent to salivary
cortisol levels at differentiating adrenal insufficiency from normal adrenal function.[36] [37] Salivary
cortisols may be especially useful for patients with hepatic disease who have hypoalbuminaemia and
cirrhosis where salivary cortisol levels correlate better with adrenal function and plasma free cortisol
than do total plasma cortisols.[38] [39] Salivary cortisol may also be useful as a surrogate for plasma
free cortisol during the ACTH stimulation test for patients with other forms of increased or decreased
plasma binding protein levels.[40] In intensive care unit (ICU) patients, salivary and serum free cortisols
have a close correlation, provided adequate saliva samples are obtained; however, inadequate sampling
and contamination was found to be frequent problem.[41] [42] Although it is likely salivary cortisols
will become more widely used in the future it is best to use an increase in total serum cortisol of <9
micrograms/dL after ACTH 250 micrograms or a random total cortisol of <10 micrograms/dL to confirm
adrenal insufficiency in the ICU patient.[43]
ACTH stimulation tests are the preferred methods of detecting adrenal suppression. The conventional
ACTH and the low-dose ACTH stimulation tests use ACTH (synthetic ACTH such as cosyntropin
injections or infusions) to measure adrenal cortisol output and are generally reliable. The 250 microgram
dose is the most commonly used, and the test can be performed even in the office setting.[44] Using
1 or 10 micrograms of ACTH compared with 250 micrograms has been suggested as more sensitive
in identifying adrenal hypofunction, but these preparations require dilutions and intravenous infusions
rather than the simpler intramuscular and intravenous injections by which the 250 microgram dose is
administered.[45] [46] [47] [48] [49] Historically, cut-off 30-minute values for the 1-microgram test have
been acknowledged as <18 to 20 microgram/dL in non-stressed patients and <25 microgram/dL or an
increase of <9 microgram/dL from baseline in critically ill patients.[50] However, newer monoclonal assays
or liquid chromatography mass spectrometry methods to measure serum cortisol concentrations are
associated with reduced cross reactivity with other glucocorticoids, and therefore a lower 30- or 60- peak
serum cortisol cut-off of <15 microgram/dL has been proposed.[1] [51] A meta-analysis comparing the 1
mcg ACTH stimulation test versus the 250 mcg dose showed low sensitivity and high specificity of each
for diagnosing secondary adrenal insufficiency, with similar diagnostic accuracy of the two doses.[52]
The ACTH stimulation test may be unreliable in patients with recent onset of HPA axis suppression
where the adrenal glands have not had sufficient time to atrophy. If patients are taking hydrocortisone or
prednisolone, it is recommended to withhold the treatment for 24 hours before the test in order to avoid
DIAGNOSIS
false positives. Other corticosteroid preparations, such as dexamethasone, do not cross-react with the
cortisol assay used for the ACTH stimulation test.
The insulin tolerance test (ITT) and the overnight metyrapone test, although somewhat cumbersome,
evaluate the entire HPA axis and are capable of assessing partial adrenal suppression.[44] ITT can be
used if there is concomitant need to determine whether the patient also has growth hormone deficiency,
for which the ITT is also a diagnostic test. Both ITT and metyrapone tests can be used if it is pertinent
to know whether the patient has secondary adrenal insufficiency due to a recent pituitary insult (e.g.,
pituitary surgery). In this situation, the adrenal glands can still mount a normal response to the ACTH
stimulation test up to 2 to 3 weeks after the pituitary insult because of adrenal reserve. However, the ITT
may uncover that the pituitary gland is not capable of responding to stress. Because the ITT relies on
production of symptomatic hypoglycaemia to stimulate cortisol release, it evaluates the entire HPA axis
but has the associated risk of hypoglycaemic seizures and, therefore, must be performed under close
observation. It is not recommended for frail or older patients with cardiovascular disease or seizures.
The metyrapone test also evaluates the entire HPA axis but is associated with the theoretical, although
unlikely, potential to precipitate acute adrenal insufficiency.
9
In patients who have a vague recollection of being given local glucocorticoid preparations (such as
epidural or intra-articular) suspected to be causing adrenal suppression, screening of urine for synthetic
corticosteroids will confirm systemic absorption of exogenous glucocorticoids but is not diagnostic of
adrenal suppression.
DIAGNOSIS
Adrenal suppression tests table

History and exam

Key diagnostic factors
presence of risk factors (common)
• A history of exposure to glucocorticoid therapy is key to the diagnosis of adrenal suppression. High
potency, supraphysiological doses of glucocorticosteroid, and prolonged duration of glucocorticoid
treatment increase the risk. Patients may need prompting: for example, asking specifically about eye
drops, nasal sprays, inhalers for breathing problems, or injections for pain.
sudden cessation or rapid tapering of glucocorticoids (common)

• Patients who have received high corticosteroid doses for prolonged periods and whose treatment is
suddenly stopped or rapidly weaned might present with symptoms of adrenal insufficiency.
acute circulatory collapse with hypotension and tachycardia (uncommon)
• Patients at risk of adrenal suppression can present with an acute adrenal crisis if glucocorticoid
treatment is suddenly ceased or if it is not increased during periods of increased stress (e.g., febrile
illness, trauma, or surgery). Patients with adrenal crisis present with collapse due to hypovolemic
shock, hypotension, postural dizziness, and tachycardia and should be treated urgently.[32] Tests may
be taken as baseline, but diagnostic tests should not delay treatment.[32]
Other diagnostic factors

lassitude and generalised constitutional symptoms (common)
• These are non-specific symptoms associated with adrenal insufficiency. They include fatigue,
anorexia, weight loss, nausea and vomiting, dizzinesss or orthostatic symptoms, myalgia or arthralgia.
Abdominal pain may be present and can be mild or severe enough to lead to a misdiagnosis of acute
abdomen.[7] [32]
history of weight gain and increased appetite (common)

• These are non-specific symptoms associated with Cushing's syndrome.[34] Not all patients appear
cushingoid, so a high index of suspicion for adrenal suppression is necessary.
history of depression, agitation, or sleep disorders (common)

• These are non-specific symptoms associated with Cushing's syndrome.[34] Not all patients appear
cushingoid, so a high index of suspicion for adrenal suppression is necessary.
cushingoid examination features (common)

• Patients receiving supraphysiological doses of oral glucocorticoids for corticosteroid-responsive
illnesses may develop a cushingoid appearance (moon facies, facial plethora, dorsocervical fat
pad, bruising, violaceous abdominal striae, thin skin, proximal muscle weakness, and centripetal
obesity).[34] This should prompt recognition of possible hypothalamic-pituitary-adrenal (HPA) axis
suppression. HPA axis suppression has been described after only 4 to 5 days of corticosteroid therapy.
• Not all patients appear cushingoid, so a high index of suspicion for adrenal suppression is necessary.
DIAGNOSIS
history of difficult-to-control diabetes or hypertension (common)
• Medical disorders such as hypertension and diabetes may have become less responsive to medication
in people with Cushing's syndrome.[7] [34]
absence of hyperpigmentation or autoimmune stigmata (common)

• Helps distinguish from adrenal insufficiency due to Addison's disease (primary adrenal insufficiency).
• For example, vitiligo is typically absent.
medrox yprogesterone use (uncommon)

• Although the most frequent inciting event for adrenal suppression is the use of exogenous
glucocorticoids, medroxyprogesterone has also been linked with adrenal suppression.[17]
history of treatment for endogenous Cushing's syndrome (uncommon)

• A unilateral adrenal adenoma or carcinoma causing Cushing's syndrome can suppress the
hypothalamic-pituitary-adrenal axis. Adrenal suppression can be manifest for a period after surgical
removal.[19] [20]
• In addition, after removal of a pituitary tumour in Cushing's disease (Cushing's syndrome secondary
to an adrenocorticotropic hormone (ACTH)-secreting pituitary tumour), the remaining ACTH-
11
secreting cells in the pituitary gland may be sluggish in their recovery, resulting in a period of adrenal
suppression and necessitating glucocorticoid supplementation.
Risk factors
Strong
systemic glucocorticoid administration
• Systemic (oral and intravenous) glucocorticoids in supraphysiological doses are well known to cause
adrenal suppression.[1] [7]
• Doses of glucocorticoids equivalent to prednisolone 5 to 7.5 mg/day (5 mg once daily in the morning,
or 5 mg in the morning and 2.5 mg in the evening) or less, are generally considered physiological
replacement doses. Physiological doses are used, for example, to treat adrenal insufficiency stemming
from Addison's disease or from pituitary surgery.
high potency or dose of exogenous glucocorticoids

• Potent glucocorticoids (such as dexamethasone or betamethasone) are more likely than less potent
formulations (such as prednisolone) to cause adrenal suppression.[22] High doses of glucocorticoids
can cause adrenal suppression even after brief exposure.
• The dose of supraphysiological exogenous corticosteroids that might result in adrenal suppression is
variable and may depend on a variety of factors such as duration of exposure and patient health.[1] In
studies on the effects of inhaled corticosteroids, the risk of adrenal suppression increased with higher
doses.[11] [12]
prolonged glucocorticoid treatment (e.g., >3 weeks)

• In one study of patients receiving systemic glucocorticoids for chronic obstructive pulmonary disease
exacerbation, more patients had a blunted peak cortisol response to adrenocorticotropic hormone
stimulation at day 14 compared with day 1.[23] Some reports have suggested that adrenal suppression
can occur as early as 4 to 5 days after starting glucocorticoids, but that recovery is also rapid when
DIAGNOSIS
the duration of corticosteroid treatment is <1 week.[24] [25] However, even a single intra-articular
injection has been reported to cause adrenal suppression.[26] [27] Moreover, repeated intra-articular
glucocorticoid administration may result in adrenal suppression for several months.[9]
local glucocorticoid administration

• Local routes of administration were developed with the hope of targeting the specific underlying organ
or condition for which the corticosteroid is needed. However, local administration may result in adrenal
suppression.
• Of the local administration routes, inhaled corticosteroids seem to be cited most often, but this may
stem from physician and patient awareness.[11] [12] Intra-articular and epidural administration routes
are less recognised, perhaps because of infrequency of use or lack of awareness by patients that they
have received glucocorticoids.[9] [10] [28]
• Intranasal and topical administration routes are also reported causes of adrenal suppression.[14]
Those at higher risk of systemic absorption of topical corticosteroids include children, those with
an impaired cutaneous barrier, and those with corticosteroids applied over large areas or under
occlusion.[15]
megestrol use
• Megestrol, often given as an appetite stimulant, has been reported to cause decreased cortisol
responses after adrenocorticotropic hormone stimulation testing.[16] Patients may present with either
Cushing's syndrome or adrenal insufficiency.
Weak
non-physiological scheduling of glucocorticoid dose
• Mimicking the normal diurnal rhythm by giving short-acting glucocorticoids in the morning decreases
the chance of developing adrenal suppression.[7] Alternate-day scheduling also confers less risk
of suppression.[1] Giving corticosteroids late in the day or at night may inhibit the diurnal surge of
adrenocorticotropic hormone release, increasing the risk of adrenal suppression.
medrox yprogesterone use

• Medroxyprogesterone has been reported to decrease plasma cortisol or adrenocorticotropic hormone
(ACTH) levels, and some reports show a reduced response to ACTH stimulation tests.[17] Reports
have been mostly in patients receiving medroxyprogesterone as part of cancer therapy, especially
women.
DIAGNOSIS
13
Investigations
1st test to order
Test Result
serum comprehensive chemistry panel possible hypo- or
hyperglycaemia,
• Although not diagnostic, incidental laboratory findings such as
hypokalaemia,
hypo- or hyperglycaemia, hypokalaemia, hypomagnesaemia, and a
hypomagnesaemia,
contraction alkalosis may raise suspicion of glucocorticoid use.
• Electrolyte abnormalities consistent with mineralocorticoid deficiency contraction alkalosis
such as hyperkalaemia are absent because the renin-angiotensin-
aldosterone system remains intact.
serum a.m. cortisol <110 nanomol/L (4
micrograms/dL): likely
• The morning serum cortisol has been used as a screening
adrenal insufficiency
test, but it is not reliable in predicting adrenal reserve. Because
adrenocorticotropic hormone (ACTH) has been suppressed by the
exogenous corticosteroid, serum cortisol is expected to be low.
• Results: ≥497 nanomol/L (18 micrograms/dL): predicts normal serum
cortisol response to insulin-induced hypoglycaemia or short ACTH
test; 110 to 469 nanomol/L (4-17 micrograms/dL): unclear, best to
proceed to a stimulation test; <110 nanomol/L (4 micrograms/dL):
likely adrenal insufficiency.[35]
• Usually, values fall in the range where adrenal status is unclear.
Further confirmation with a stimulation test is suggested if there
is any doubt that an exogenous corticosteroid regimen can be
discontinued.
salivary a.m. cortisol <414 nanomol/L (<0.15
micrograms/dL): likely
• Like the morning serum cortisol, the morning salivary cortisol
can be used as a screening test but it is not reliable in predicting
adrenal reserve.[36] [37] Salivary cortisol is expected to be low as
a consequence of adrenocorticotropic hormone suppression by
exogenous corticosteroid.
DIAGNOSIS
• Results: ≥1849 nanomol/L (≥0.67 micrograms/dL): predicts normal

serum cortisol response to insulin-induced hypoglycaemia; 414 to
1849 nanomol/L (0.15-0.67 micrograms/dL): unclear, best to proceed
to a stimulation test; <414 nanomol/L (<0.15 micrograms/dL): likely
adrenal insufficiency.
• Values usually fall within the equivocal range. Further confirmation
with a stimulation test is suggested if there is any doubt.
adrenocorticotropic hormone (ACTH) stimulation test rise of cortisol to
an absolute level
• Relatively easy to do and reliable.
>497 nanomol/L (18
• A synthetic derivative of ACTH is injected intravenously or
micrograms/dL) excludes
intramuscularly in a dose of 250 micrograms.[44] This dose is the
most commonly used in practice and can be prepared even in the
office setting.[44] Cortisol levels are drawn at 0, 30, and 60 minutes
after the administration of cosyntropin. Normal is a rise to >497
nanomol/L (18 micrograms/dL) at any time during the test.
• Using 1 or 10 micrograms of ACTH, compared with 250 micrograms,
has been suggested as more sensitive in identifying adrenal
hypofunction. However, these preparations require dilutions
and intravenous infusions rather than the simpler intramuscular
and intravenous injections by which the 250 microgram dose is
administered.[45] [46] [47] [48] [49] A meta-analysis comparing the
Test Result
1 mcg ACTH stimulation test versus the 250 mcg dose showed low
sensitivity and high specificity of each for diagnosing secondary
adrenal insufficiency, with similar diagnostic accuracy of the two
doses.[52]
• The ACTH stimulation test may be unreliable in patients with recent
onset of hypothalamic-pituitary-adrenal axis suppression, where the
adrenal glands have not had sufficient time to atrophy. If patients
are taking hydrocortisone or prednisolone, it is recommended
to withhold the treatment for 24 hours before the test in order to
avoid false positives. Other corticosteroid preparations, such as
dexamethasone, do not cross-react with the cortisol assay used for
the ACTH stimulation test.
FBC possible elevated WBC
• In cases of acute adrenal crisis, diagnostic tests should not delay
treatment.[32]
• FBC is suggested at baseline in people with suspected adrenal
crises, and may be abnormal if underlying infection is present.[32]
thyroid function tests possible elevated free
thyroxine
• In cases of acute adrenal crisis, diagnostic tests should not delay
treatment.[32]
• Thyroid function tests are suggested at baseline in people with
suspected adrenal crises, as hyperthyroidism can trigger adrenal
crisis.[32]
DIAGNOSIS
15
Other tests to consider
Test Result
insulin tolerance test (ITT) serum cortisol
<497 nanomol/L
• Although somewhat cumbersome, the ITT evaluates the entire
(18 micrograms/dL)
hypothalamic-pituitary-adrenal axis and is capable of assessing
with symptomatic
partial adrenal suppression.[44]
hypoglycaemia and
• ITT can be used if there is concomitant need to determine whether
glucose <2.2 mmol/L (40
the patient also has growth hormone deficiency, for which the ITT is
mg/dL)
also a diagnostic test. It can also be used to evaluate whether the
patient has secondary adrenal insufficiency due to a recent pituitary
insult (e.g., pituitary surgery). In this situation, the adrenal glands can
still mount a normal response to the adrenocorticotropic hormone
stimulation test up to 2 to 3 weeks after the pituitary insult because
of adrenal reserve; however, the ITT may uncover that the pituitary
gland is not capable of responding to stress.
• Short-acting insulin at a dose of 0.1 to 0.15 units/kg is given
intravenously. Plasma cortisol and glucose levels are taken at
0, 30, and 60 minutes. The test is stopped when the patient has
symptomatic hypoglycaemia with a glucose level <2.2 mmol/L (40
mg/dL).[44]
• Normal is a rise of serum cortisol to greater than or equal to 497
nanomol/L (18 micrograms/dL). Abnormal is cortisol <497 nanomol/L
(18 micrograms/dL).
• Requires vigilance because hypoglycaemia is an endpoint.
Contraindicated in older adults and in people with cardiovascular
disease or seizure disorder.
overnight metyrapone test abnormal when 11-
deox ycortisol <200
• Although somewhat cumbersome, it evaluates the entire
nanomol/L (7 micrograms/
hypothalamic-pituitary-adrenal axis and is capable of assessing
dL) regardless of cortisol
partial adrenal suppression.[44]
• It can be used to evaluate whether the patient has secondary adrenal level
insufficiency due to a recent pituitary insult (e.g., pituitary surgery).
• Metyrapone is given at a dose of 30 mg/kg, with a maximum of 3 g
DIAGNOSIS
given orally at midnight. Serum cortisol and 11-deoxycortisol levels

are taken at 8 a.m. the following day.
• Normal if 11-deoxycortisol >200 nanomol/L (7 micrograms/dL)
regardless of cortisol level. Abnormal when 11-deoxycortisol <200
nanomol/L (7 micrograms/dL) regardless of cortisol level.
• This test assesses the entire hypothalamic-pituitary-adrenal axis.
There is a risk of precipitating adrenal insufficiency because
metyrapone blocks a step in cortisol synthesis. Phenytoin and
phenobarbital may lead to false negative results.
urine synthetic glucocorticoids may be positive
• Performed if there is doubt that the patient received exogenous
glucocorticoids that could have caused adrenal suppression. An
example would be a patient who had intra-articular injections for
pain a few months ago, presents with fatigue, and has an abnormal
adrenocorticotropic hormone stimulation test.[28]
• Not well studied but may be useful as a marker of absorption. A
negative test is not helpful.
Differentials
Condition Differentiating signs / Differentiating tests

symptoms
Primary adrenal • Features associated • Hyperkalaemia may be
insufficiency with elevations of present.
adrenocorticotropic • Serum ACTH is high.
hormone (ACTH), such • Urine screen for exogenous
as mucosal or cutaneous corticosteroids is negative.
hyperpigmentation, may be • Computed tomography
present. of adrenals may show
• Stigmata of autoimmune infiltrative or haemorrhagic
disorders (e.g., vitiligo) disease.
associated with autoimmune
adrenal insufficiency may be
present.
• Cushingoid features such as
moon facies, dorsocervical
fat pad, centripetal obesity,
or striae are absent.
• No history of exogenous
corticosteroid use.
• May be a history of
tuberculosis or anticoagulant
use.
Pituitary compression, • Headaches and visual loss • Computed tomography or

tumour, head trauma, and may occur. magnetic resonance imaging
surgery (non-Cushing's) • Cushingoid features such as may show compression.
moon facies, dorsocervical • Urine screen for exogenous
fat pad, centripetal obesity, corticosteroids is negative.
or striae will be absent.
• Patient may have a history
of head trauma or surgery
DIAGNOSIS
affecting the pituitary.
Corticosteroid withdrawal • Poorly understood. • Adrenocorticotropic hormone

syndrome Characterised by a variety or other stimulation tests
of vague symptoms such show normal adrenal
as fatigue, abdominal pain, reserve.
and myalgias, which are very • If testing shows no evidence
similar to those of adrenal of adrenal insufficiency,
insufficiency. symptoms are likely due to
• However, when adrenal corticosteroid withdrawal
function is evaluated, syndrome.
these patients demonstrate
normal adrenal function and
reserve. They are therefore
not in danger of adrenal
crisis if corticosteroids are
discontinued, but many
are reluctant to taper
treatment. Appropriate action
requires a great deal of
discussion between patient
and physician. There are
17
Condition Differentiating signs / Differentiating tests

symptoms
no well-controlled studies
of corticosteroid withdrawal
syndrome.
Screening
There are no national screening guidelines for adrenal suppression. However, screening is recommended
in all patients with symptoms consistent with adrenal suppression, and in those who have received systemic
corticosteroids for >2 consecutive weeks or >3 cumulative weeks in the last 6 months, or in those who have
been receiving high-dose inhaled corticosteroid therapy for 3 to 6 months.[7] [53] A suggested screening
approach is to measure early morning cortisol. If morning cortisol is normal, but the patient has symptoms
of adrenal suppression, a low-dose adrenocorticotropic hormone stimulation test should be performed to
confirm diagnosis.[7]
DIAGNOSIS
Adrenal suppression Management
Approach
Issues encountered in patients with corticosteroid-induced adrenal suppression include tapering of therapy,
prophylaxis for stress situations, and treatment of overt clinical adrenal insufficiency.
Management of adrenal crisis

Patients with a history compatible with adrenal suppression and presenting with features of adrenal
crisis (i.e., hypotension, circulatory failure) should be treated urgently.[32] If a diagnosis has not yet been
established, it can be deferred until the patient is stabilised.
• Hydrocortisone should be given intravenously or intramuscularly immediately, and then continued

as an infusion or as intermittent doses. If improvement has occurred within 24 hours, which is
common, the hydrocortisone dose can be decreased. This can be changed to an oral formulation
whenever the patient is stable. The dose can be decreased by one third to one half the dose daily
until a maintenance dose is attained.
• Intravenous fluids, in the form of 5% dextrose in normal saline, should be given to address the
volume depletion that is often present.
• A search for the condition that precipitated the crisis, such as infection, should be undertaken.
Treatment of the underlying cause should be instituted.
• Patients will not need mineralocorticoid replacement, because the renin-angiotensin-aldosterone
axis is intact.
Management of intercurrent stress in patients taking

corticosteroids for underlying disease
Additional glucocorticoid administration is given to patients with adrenal insufficiency at times of stress
due to the possible failure of cortisol secretion to cope with increased cortisol requirements, which may
result in haemodynamic instability and the risk of adrenal crisis.[32] However, evidence for the timing and
dosage of perioperative stress-dose corticosteroids is limited, even in patients with confirmed adrenal
suppression, and will benefit from studies comparing different strategies.[54] [55] [56]
Minor stress
• Patients experiencing minor intercurrent stress (e.g., febrile illness; minor procedure/surgery not
requiring fasting such as tooth extraction or procedures that require local anaesthesia) should be
instructed to double their chronic maintenance dose of corticosteroid on the day of the procedure or
for the duration of illness.[1]
Severe stress
• Patients who undergo severe stress situations (e.g., unable to take oral glucocorticoid, such as
acute gastroenteritis or prolonged fasting for colonoscopy; surgery under general or regional
anaesthesia; critical illness requiring ventilation; major trauma; active phase of labour and delivery)
require parenteral corticosteroid (usually hydrocortisone).[1] [57]
MANAGEMENT
• If patients are out of the critical phase of illness in less than 1 week but remain ill, then the dose of
the corticosteroid can be tapered, using an oral formulation, back to previous pre-illness doses. The
taper can be stopped sooner (i.e., at a higher dose) if the pre-illness dose is already achieved.
19
Stable patients taking corticosteroids for underlying disease:
suitable for discontinuation or taper
As long as supraphysiological corticosteroids continue, evaluation of adrenal function is not helpful.
Corticosteroid doses can be rapidly reduced to physiological replacement equivalents without fear of
adrenal insufficiency. This corresponds to a dose of 20 to 30 mg/day of hydrocortisone or 5 to 7.5 mg/day
of prednisolone. However, disease reactivation or the development of glucocorticoid withdrawal symptoms
might dictate a slower tapering schedule.
Dose equivalency for glucocorticoids

Once physiological replacement levels are reached, tapering should continue at a slower rate. At this
point, many physicians prefer to switch to a product with a short half-life, such as hydrocortisone, because
the fluctuating serum levels allow for greater hypothalamic-pituitary-adrenal axis stimulation and recovery.
Reports on dose and duration of therapy resulting in adrenal suppression vary, and there are no good
predictors of susceptibility.[58] Therefore, several tapering protocols have been offered.[58] [59] Although
not formally tested, the following tapering regimen provides a framework for clinical practice. This is a
reasonable approach based on the literature regarding dose and duration of corticosteroids that have
caused suppression and the time to recovery after cessation of the corticosteroid:[58] [59]
• Duration <1 week: can stop, regardless of dose

• Duration 1 to 3 weeks: controversial with regard to need to taper. This depends on dose and the
patient's general health/constitution. Consider tapering if the dose is greater than the equivalent of
prednisolone 7.5 mg/day or hydrocortisone 30 mg/day
• Duration >3 weeks: taper hydrocortisone by 10 mg (equivalent to prednisone 2.5 mg) every 3
to 4 days down to physiological dose, then a more gradual reduction of hydrocortisone 2.5 mg
MANAGEMENT
every 2 to 4 weeks should be considered. It has been suggested that a morning cortisol level or
a stimulation test should be checked once the dose is at an equivalent of hydrocortisone 10 mg/
day, with discontinuation of corticosteroids if the cortisol level is normal.[58] [59] The corticosteroid
can also be discontinued if a stimulation test performed at any point during the physiologically
dosed portion of the taper reveals normal cortisol levels. If patients develop signs and symptoms of
adrenal insufficiency at any time, the dose decrement can be reduced.
Treatment algorithm overview

Please note that formulations/routes and doses may differ between drug names and brands, drug
formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer
Initial ( summary )
features of adrenal crisis
1st parenteral hydrocortisone
plus supportive measures
plus treatment of any precipitating event
plus oral corticosteroid taper when stable
Acute ( summary )
minor intercurrent stress
1st temporary double dose of existing

corticosteroid
severe intercurrent stress
1st intravenous hydrocortisone (stress dose)
Ongoing ( summary )
stable patients taking
corticosteroids for underlying
disease: suitable for discontinuation
or taper
duration of 1st corticosteroid discontinuation

corticosteroids <1 week
duration of 1st corticosteroid discontinuation or taper

corticosteroids 1 to 3
weeks
duration of 1st corticosteroid taper

corticosteroids >3 weeks
MANAGEMENT
21
Treatment algorithm
Please note that formulations/routes and doses may differ between drug names and brands, drug
formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer
MANAGEMENT
Initial
features of adrenal crisis
1st parenteral hydrocortisone

Primary options
» hydrocortisone sodium succinate: 100 mg

intravenously/intramuscularly as a single
dose, followed by 200 mg per 24 hours as a
continuous infusion (or 50 mg intravenously/
intramuscularly every 6 hours), taper dose
according to response as patient becomes
stable
» Patients with a history compatible with adrenal

suppression and presenting with features
of adrenal crisis (hypotension, circulatory
failure) should be treated urgently with
hydrocortisone.[32]
» If improvement has occurred within 24 hours,

which is common, the hydrocortisone dose can
be decreased.
» Patients can be switched to an oral dosing

regimen once they are stable. Consult your local
guidelines for a suitable corticosteroid taper
regimen.
plus supportive measures
Treatment recommended for ALL patients in
selected patient group
» Patients with a history compatible with adrenal
suppression and presenting with features of
adrenal crisis (i.e., hypotension, circulatory
failure) should be treated urgently.[32]
» Intravenous fluids in the form of 5% dextrose

in normal saline should be given to address the
volume depletion that is often present.
plus treatment of any precipitating event
» A search for the condition that precipitated the
crisis, such as infection, should be undertaken.
Treatment of the underlying cause should be
instituted.
MANAGEMENT

Primary options
» hydrocortisone: consult specialist for

guidance on dose
23
Initial
» Consult your local protocols for a suitable taper
regimen. An example would be to decrease
the dose by one third to one half the dose
daily until a maintenance dose of 20 mg in the
morning and 10 mg in the afternoon or at night is
attained. Some patients may need only a dose of
20 mg/day total (i.e., 20 mg every morning, or 15
mg in the morning and 5 mg in the afternoon or
at night).
MANAGEMENT
Acute
minor intercurrent stress
1st temporary double dose of existing

corticosteroid
» Patients experiencing minor intercurrent stress

(e.g., febrile illness; minor procedure/surgery
not requiring fasting such as tooth extraction
or procedures that require local anaesthesia)
should be instructed to double their chronic
maintenance dose of corticosteroid on the day
of the procedure or for the duration of illness.[1]
They then return to the usual dose when the
stress resolves.
severe intercurrent stress
1st intravenous hydrocortisone (stress dose)

Primary options
» hydrocortisone sodium succinate: 100 mg

intravenously/intramuscularly as a single
dose, followed by 200 mg per 24 hours as a
continuous infusion (or 50 mg intravenously/
intramuscularly every 6 hours), taper dose
according to response as patient becomes
stable
» Patients who undergo severe stress situations

(e.g., unable to take oral glucocorticoid, such
as acute gastroenteritis or prolonged fasting
for colonoscopy; surgery under general or
regional anaesthesia; critical illness requiring
ventilation; major trauma; active phase of labour
and delivery) require parenteral corticosteroid
(usually hydrocortisone).[1] [57]
Primary options
» hydrocortisone: consult specialist for

guidance on dose
OR
» prednisolone: consult specialist for

guidance on dose
MANAGEMENT
» If patients are out of the critical phase of illness

in less than 1 week but remain ill, then the dose
of the corticosteroid can be tapered, using an
oral formulation, back to previous pre-illness
doses.
25
Acute
» Consult your local protocols for a suitable
taper regimen. An example of a taper until the
previous pre-illness dose is reached would be
decreasing from hydrocortisone 100 mg orally
three times daily (equivalent to prednisone 25
mg three times daily), down to 75 mg twice daily
for 1 to 2 days, then 50 mg twice daily for 1 to 2
days, then 25 mg twice daily for 1 to 2 days, then
20 mg in the morning and 10 mg in the afternoon
for 1 month (a dose that most consider being
physiological). The taper can be stopped sooner
(i.e., at a higher dose) if the pre-illness dose is
already achieved.
MANAGEMENT
Ongoing
stable patients taking
corticosteroids for underlying
disease: suitable for discontinuation
or taper
duration of 1st corticosteroid discontinuation

corticosteroids <1 week
» Can stop regardless of dose.
» In discontinuing corticosteroid therapy,

the underlying disease state may become
reactivated, limiting reductions in corticosteroid
dose.
duration of 1st corticosteroid discontinuation or taper
corticosteroids 1 to 3
weeks » Controversial with regard to need to taper.
This depends on dose and the patient's general
health/constitution.
» Consider tapering if the dose is greater than

the equivalent of prednisolone 7.5 mg/day or
hydrocortisone 30 mg/day.
» In tapering and discontinuation of

corticosteroid therapy, the underlying disease
state may become reactivated, limiting
reductions in corticosteroid dose.
duration of 1st corticosteroid taper
corticosteroids >3 weeks
» Taper hydrocortisone by 10 mg (equivalent
to prednisone 2.5 mg) every 3 to 4 days down
to physiological dose, then a more gradual
reduction of hydrocortisone 2.5 mg every 2
to 4 weeks should be considered. It has been
suggested that a morning cortisol level or a
stimulation test should be checked once the
dose is at an equivalent of hydrocortisone 10
mg/day, with discontinuation of corticosteroids
if the cortisol level is normal.[58] [59] The
corticosteroid can also be discontinued if a
stimulation test performed at any point during the
physiologically dosed portion of the taper reveals
normal cortisol levels. If patients develop signs
and symptoms of adrenal insufficiency at any
time, the dose decrement can be reduced.
» So long as supraphysiological corticosteroids

continue, evaluation of adrenal function is not
helpful.
MANAGEMENT
» Corticosteroid doses can be rapidly reduced

to physiological replacement equivalents
without fear of adrenal insufficiency. This
corresponds to a prednisone dose of 5 to
7.5 mg/day or its equivalent. However, in
tapering and discontinuation of corticosteroid
27
Ongoing
therapy, the underlying disease state may
become reactivated, or patients may experience
glucocorticoid withdrawal syndrome, limiting
reductions in corticosteroid dose.
» Once physiological replacement levels are

reached, tapering should continue at a slower
rate. At this point, many physicians prefer to
switch to a product with a short half-life, such as
hydrocortisone, because the fluctuating serum
levels allow for greater hypothalamic-pituitary-
adrenal axis stimulation and recovery.
Primary prevention
It is important to use the lowest dose of glucocorticoid for the shortest time needed to treat an underlying
disease and to re-evaluate the dose and need regularly.[29] Administration of corticosteroids in the morning
rather than at night, especially when using short-acting corticosteroids, will help mimic the normal diurnal
cortisol rhythm and allow for corticotropin-releasing hormone and adrenocorticotropic hormone secretion. An
alternate-day corticosteroid regimen can also help prevent adrenal suppression.[30] The use of superpotent
topical corticosteroids should be limited to 50 grams per week for a maximum of 2 to 4 weeks to reduce
the risk of Cushing's syndrome and pathological adrenal suppression.[31] Whenever possible, alternative
non-systemic routes of administration should be considered, and every effort should be made to minimise
systemic absorption.
Secondary prevention
In diseases for which glucocorticoids have traditionally been part of the treatment armamentarium but for
which there are non-corticosteroid management options, consideration should be given to these alternatives
after weighing up possible risks and benefits. An example is the use of disease-modifying antirheumatic
drugs for rheumatoid arthritis.[60]
Patient discussions
Patients should be advised to be aware of recurrent symptoms of their original disease. As the dose of
corticosteroids is reduced to physiological levels and below, patients should also be instructed to take
note of symptoms of adrenal insufficiency. It is important that patients maintain medication compliance
because an abrupt decrease or discontinuation of corticosteroid therapy may produce adrenal crisis. A
subset of patients may exhibit basal adrenal function with limited adrenal reserves. Therefore, patients
should be instructed to advise physicians immediately of their prior corticosteroid use so that the need
for stress doses of corticosteroids can be assessed either clinically or by testing. Patients should carry
some type of medical alert notification for emergencies. Morning cortisol or stimulation tests can be
repeated every few months until the morning cortisol level is >497 nanomol/L (18 micrograms/dL) or the
appropriate stimulation test confirms hypothalamic-pituitary-adrenal axis integrity.
MANAGEMENT
Adrenal suppression Follow up
Monitoring
Monitoring
FOLLOW UP
As corticosteroid doses are reduced from supraphysiological to physiological levels, patients should
be observed for symptoms related to their original disease state. Once physiological replacement
doses are initiated, patients should also be observed for symptoms of adrenal insufficiency such as
fatigue, abdominal pain, and weakness. An appropriate stimulation test can be used to assess the
hypothalamic-pituitary-adrenal axis at this time. Some physicians prefer obtaining a morning cortisol
level and performing a stimulation test only for those patients whose morning cortisol falls within the
indeterminate range (110-469 nanomol/L [4-17 micrograms/dL]).
Complications
Complications Timeframe Likelihood

corticosteroid dependence variable low
Clinicians should be aware that dependence is an unusual, although serious, complication of

corticosteroid use. Due to the underlying disease itself or a significantly depressed hypothalamic-pituitary-
adrenal axis, some patients should undergo an extremely slow corticosteroid taper.
permanent sequelae of adrenal crisis variable low
Untreated adrenal crisis may result in permanent serious sequelae, such as end-organ damage or death.
Prognosis
Adrenal insufficiency secondary to corticosteroid treatment has a generally good prognosis. Time to recovery
depends on dose and/or potency of glucocorticoid used and treatment length. Signs and symptoms of
Cushing's syndrome will disappear with time as the inciting medication is stopped.
Adrenal insufficiency
With care and persistence, most patients are able to recover adrenal function and permanently discontinue
corticosteroid therapy. In addition, patients who have had adrenal suppression may have enough partial
recovery or adrenal reserve to sustain their daily basal needs. However, they may not have enough
adrenal reserve to surmount any encountered severe stress, such as systemic infections, injury, or surgery.
Therefore, patients must be reminded to inform medical personnel of prolonged corticosteroid intake in the
past few months because they may need stress-dose corticosteroids during these events, followed by a rapid
taper to physiological doses and discontinuation within 1 week if possible.
29
Adrenal suppression Guidelines
Diagnostic guidelines
United Kingdom
Emergency management of acute adrenal insufficiency (adrenal crisis) in

adult patients (ht tps://www.endocrinology.org/clinical-practice/clinical-
guidance/society-for-endocrinology-guidance)
Published by: Society for Endocrinology Last published: 2016;
reviewed 2019
Adrenal suppression secondary to exogenous glucocorticoid: guidance

for children on long term steroid therapy (ht tps://www.sprun.scot.nhs.uk/
professionals/guidelines)
Published by: Scottish Paediatric Renal Urology Network Last published: 2017
GUIDELINES
North America
Adrenal suppression from exogenous glucocorticoids: recognizing risk

factors and preventing morbidity (ht tps://www.cps.ca/en/documents/position/
adrenal-suppression)
Published by: Canadian Paediatric Society Last published: 2021
Adrenal suppression Guidelines
Treatment guidelines
United Kingdom
Adrenal insufficiency and adrenal crisis-who is at risk and how should they
be managed safely (ht tps://www.endocrinology.org/clinical-practice/clinical-
Published by: Society for Endocrinology; British Association of Last published: 2021
Dermatologists
Guidelines for the management of glucocorticoids during the peri-

operative period for patients with adrenal insufficiency (ht tps://
www.endocrinology.org/clinical-practice/clinical-guidance/society-for-
endocrinology-guidance)
Published by: Association of Anaesthetists; Royal College of Last published: 2020
Physicians; Society for Endocrinology
GUIDELINES
Emergency management of acute adrenal insufficiency (adrenal crisis) in
adult patients (ht tps://www.endocrinology.org/clinical-practice/clinical-
Published by: Society for Endocrinology Last published: 2016;
reviewed 2019
Adrenal suppression secondary to exogenous glucocorticoid: guidance

for children on long term steroid therapy (ht tps://www.sprun.scot.nhs.uk/
professionals/guidelines)
Published by: Scottish Paediatric Renal Urology Network Last published: 2017
Secondary care management of suspected adrenal crisis in children and

young people (ht tps://www.speg.scot.nhs.uk/professional-pages/speg-
guidelines)
Published by: Scottish Paediatric Endocrine Group Last published: 2017
Europe
Management and prevention of acute adrenal insufficiency (ht tps://

pubmed.ncbi.nlm.nih.gov/31003863)
Published by: Spanish Society of Endocrinology and Nutrition Last published: 2020
Oceania
Adrenal insufficiency - emergency management#practice guideline (ht tps://

www.schn.health.nsw.gov.au/our-policies/index/clinical)
Published by: Sydney Children’s Hospital Network Last published: 2020
31
Adrenal suppression References
Key articles
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tool=bestpractice.bmj.com)
• Broersen LH, Pereira AM, Jørgensen JO, et al. Adrenal insufficiency in corticosteroids use: systematic
review and meta-analysis. J Clin Endocrinol Metab. 2015 Jun;100(6):2171-80. Full text (https://
academic.oup.com/jcem/article/100/6/2171/2829580) Abstract (http://www.ncbi.nlm.nih.gov/
pubmed/25844620?tool=bestpractice.bmj.com)
• Liu D, Ahmet A, Ward L, et al. A practical guide to the monitoring and management of the
complications of systemic corticosteroid therapy. Allergy Asthma Clin Immunol. 2013 Aug
15;9(1):30. Full text (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3765115) Abstract (http://
www.ncbi.nlm.nih.gov/pubmed/23947590?tool=bestpractice.bmj.com)
• Ahmet A, Kim H, Spier S. Adrenal suppression: a practical guide to the screening and management
of this under-recognized complication of inhaled corticosteroid therapy. Allergy Asthma Clin Immunol.
2011 Aug 25;7(1):13. Full text (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3177893) Abstract
(http://www.ncbi.nlm.nih.gov/pubmed/21867553?tool=bestpractice.bmj.com)
• Arlt W, Society for Endocrinology Clinical Committee. Society for Endocrinology endocrine emergency
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Endocr Connect. 2016 Sep;5(5):G1-3. Full text (https://www.ncbi.nlm.nih.gov/pmc/articles/
PMC5314805) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/27935813?tool=bestpractice.bmj.com)
• Ahmet A, Kim H, Spier S. Adrenal suppression: a practical guide to the screening and management
2011 Aug 25;7(1):13 Full text (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3177893) Abstract
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1. Prete A, Bancos I. Glucocorticoid induced adrenal insufficiency. BMJ. 2021 Jul 12;374:n1380. Full text
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15;9(1):30. Full text (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3765115) Abstract (http://
8. Bowden SA, Connolly AM, Kinnett K, et al. Management of adrenal insufficiency risk after long-term
systemic glucocorticoid therapy in duchenne muscular dystrophy: clinical practice recommendations.
J Neuromuscul Dis. 2019;6(1):31-41. Full text (https://content.iospress.com/articles/journal-of-
neuromuscular-diseases/jnd180346) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/30614808?
9. Johnston PC, Lansang MC, Chatterjee S, et al. Intra-articular glucocorticoid injections and their effect
on hypothalamic-pituitary-adrenal (HPA)-axis function. Endocrine. 2015 Mar;48(2):410-6. Abstract
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triamcinolone injection. Endocrine. 2017 Aug;57(2):308-13. Abstract (http://www.ncbi.nlm.nih.gov/
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2011 Aug 25;7(1):13. Full text (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3177893) Abstract
12. Wlodarczyk JH, Gibson PG, Caeser M. Impact of inhaled corticosteroids on cortisol suppression
in adults with asthma: a quantitative review. Ann Allergy Asthma Immunol. 2008 Jan;100(1):23-30.
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Adrenal suppression Images
Images
IMAGES
Figure 1: Dose equivalency for glucocorticoids
39
IMAGES Adrenal suppression Images
Figure 2: Adrenal suppression tests table

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// Authors:
Suzanne L. Quinn Martinez, MD

Staff Endocrinologist
Orlando Veterans Administration Hospital, Associate Professor Internal Medicine, University of Central
Florida, Orlando, FL
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// Acknowledgements:
Dr Suzanne L. Quinn Martinez would like to gratefully acknowledge Dr M. Cecilia Lansang, a previous
contributor to this topic.
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references cited in this topic.
// Peer Reviewers:
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Assistant Professor of Medicine
Indiana University, Indianapolis, MI
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investigator for Corcept and Chiasma.
Antoine Tabarin, MD
Head
Department of Endocrinology, University Hospital of Bordeaux, Pessac, France
DISCLOSURES: AT declares that he has no competing interests.
Maralyn Druce, MA, MBBS, MRCP, PhD

Clinical Lecturer
Honorary Consultant, Department of Endocrinology, Barts and The London School of Medicine and
Dentistry, St Bartholomew's Hospital, London, UK
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Adrenal suppression

Straight to the point of care

Last updated: Apr 12, 2022

Susceptibility to corticosteroid-induced adrenal suppression may be linked to a specific genetic variation in

History and symptoms

• Inhaled corticosteroids for asthma or chronic obstructive pulmonary disease[11] [12]

Dose equivalency for glucocorticoids

Non-prescribed sources of corticosteroids such as over-the-counter eczema treatments, skin-lightening

As long as supraphysiological corticosteroids continue, evaluation of adrenal function is not helpful.

Adrenal suppression tests table

History and exam

sudden cessation or rapid tapering of glucocorticoids (common)

acute circulatory collapse with hypotension and tachycardia (uncommon)

Other diagnostic factors

history of weight gain and increased appetite (common)

history of depression, agitation, or sleep disorders (common)

cushingoid examination features (common)

absence of hyperpigmentation or autoimmune stigmata (common)

medrox yprogesterone use (uncommon)

history of treatment for endogenous Cushing's syndrome (uncommon)

high potency or dose of exogenous glucocorticoids

prolonged glucocorticoid treatment (e.g., >3 weeks)

local glucocorticoid administration

medrox yprogesterone use

• Results: ≥1849 nanomol/L (≥0.67 micrograms/dL): predicts normal

Other tests to consider

given orally at midnight. Serum cortisol and 11-deoxycortisol levels

Condition Differentiating signs / Differentiating tests

Pituitary compression, • Headaches and visual loss • Computed tomography or

Corticosteroid withdrawal • Poorly understood. • Adrenocorticotropic hormone

Condition Differentiating signs / Differentiating tests

Management of adrenal crisis

• Hydrocortisone should be given intravenously or intramuscularly immediately, and then continued

Management of intercurrent stress in patients taking

Dose equivalency for glucocorticoids

• Duration <1 week: can stop, regardless of dose

Treatment algorithm overview

1st parenteral hydrocortisone

plus supportive measures

plus treatment of any precipitating event

plus oral corticosteroid taper when stable

1st temporary double dose of existing

severe intercurrent stress

1st intravenous hydrocortisone (stress dose)

plus oral corticosteroid taper when stable

duration of 1st corticosteroid discontinuation

duration of 1st corticosteroid discontinuation or taper

duration of 1st corticosteroid taper

1st parenteral hydrocortisone

» hydrocortisone sodium succinate: 100 mg

» Patients with a history compatible with adrenal

» If improvement has occurred within 24 hours,

» Patients can be switched to an oral dosing

» Intravenous fluids in the form of 5% dextrose

selected patient group

» hydrocortisone: consult specialist for

1st temporary double dose of existing

» Patients experiencing minor intercurrent stress

1st intravenous hydrocortisone (stress dose)

» hydrocortisone sodium succinate: 100 mg

» Patients who undergo severe stress situations

» hydrocortisone: consult specialist for

» prednisolone: consult specialist for

» If patients are out of the critical phase of illness