STATE OF THE ART REVIEW

Glucocorticoid induced adrenal insufficiency

BMJ: first published as 10.1136/bmj.n1380 on 12 July 2021. Downloaded from http://www.bmj.com/ on 11 August 2021 by guest. Protected by copyright.
Alessandro Prete,1 Irina Bancos2
A BST RAC T
1
Institute of Metabolism and
Synthetic glucocorticoids are widely used for their anti-inflammatory and
Systems Research, University of immunosuppressive actions. A possible unwanted effect of glucocorticoid treatment
Birmingham, Birmingham, UK
2
Division of Endocrinology, is suppression of the hypothalamic-pituitary-adrenal axis, which can lead to adrenal
Metabolism and Nutrition,
Department of Internal
insufficiency. Factors affecting the risk of glucocorticoid induced adrenal insufficiency
Medicine, Mayo Clinic, (GI-AI) include the duration of glucocorticoid therapy, mode of administration,
Rochester, MN 55905, USA
Correspondence to: I Bancos glucocorticoid dose and potency, concomitant drugs that interfere with
bancos.irina@mayo.edu
(ORCID 0000-0001-9332-2524)
glucocorticoid metabolism, and individual susceptibility. Patients with exogenous
Cite this as: BMJ 2021;374:n1380 glucocorticoid use may develop features of Cushing’s syndrome and, subsequently,
http://dx.doi.org/10.1136/bmj.n1380
glucocorticoid withdrawal syndrome when the treatment is tapered down. Symptoms
Series explanation: State of the
Art Reviews are commissioned of glucocorticoid withdrawal can overlap with those of the underlying disorder, as
on the basis of their relevance
to academics and specialists
well as of GI-AI. A careful approach to the glucocorticoid taper and appropriate
in the US and internationally.
For this reason they are written
patient counseling are needed to assure a successful taper. Glucocorticoid therapy
predominantly by US authors. should not be completely stopped until recovery of adrenal function is achieved. In
this review, we discuss the factors affecting the risk of GI-AI, propose a regimen for
the glucocorticoid taper, and make suggestions for assessment of adrenal function
recovery. We also describe current gaps in the management of patients with GI-AI
and make suggestions for an approach to the glucocorticoid withdrawal syndrome,
chronic management of glucocorticoid therapy, and education on GI-AI for patients
and providers.

Introduction the main aspects of GI-AI and discontinuation of

Exogenous glucocorticoids can cause adrenal
insufficiency (glucocorticoid induced adrenal
insufficiency; GI-AI), which is among the most
common causes of cortisol deficiency.1 Its true
prevalence is difficult to ascertain because of the
heterogeneity of studies. Moreover, a mismatch
exists between the high prevalence of “biochemical”
GI-AI and the reporting of its “clinical”
consequences, suggesting potential under-diagnosis
and lack of awareness among clinicians.2 GI-AI
is one of the most dangerous adverse effects of
glucocorticoid therapy and puts patients at risk of
life threatening adrenal crises. Discontinuation of
long term glucocorticoid therapy can be difficult;
to stop treatment safely, clinicians must consider
both the recovery of normal cortisol secretion
and potential withdrawal symptoms. Despite
widespread use of glucocorticoids, the evidence
guiding the management of GI-AI originates from
very heterogeneous studies in terms of design,
patient population, sample size, types and regimens
of glucocorticoids used, and assessment of adrenal
function. Therefore, the level of evidence is low,
which results in variation in management across
different centers and clinicians. The aim of this
review is to provide an up-to-date overview of
glucocorticoids.
Epidemiology of glucocorticoid induced adrenal
insufficiency
Systemic glucocorticoids are used by 1-3% of the
general population.3-6 Focusing on the long term use
of oral glucocorticoids, the prevalence is 0.5-1.8%.5-10
Oral glucocorticoids are more commonly used by
women and older people; chronic use is reported in
1.4% of patients older than 55 years and in 3% of
women over the age of 80.3 7 8 10 A systematic review
and meta-analysis found that the absolute risk of
GI-AI induced by oral glucocorticoids was 48.7%,
with the highest risk in people with hematologic
malignancies (60%), followed by patients with a
history of renal transplant (56.2%), inflammatory
bowel disease (52.2%), and rheumatologic disorders
(39.4%).11
The use of inhaled glucocorticoids has also
increased over time in both children and adults,12 13
and the overall risk of GI-AI in these patients is
7.8%.11 Adult patients treated with topical or nasal
glucocorticoids were reported to have a lower risk
of GI-AI of 4.2-4.7%.11 Patients treated with intra-
articular glucocorticoids had biochemical evidence
of GI-AI in 52.2% of cases; however, this estimate

the bmj | BMJ 2021;374:n1380 | doi: 10.1136/bmj.n1380 1

 STATE OF THE ART REVIEW
was based on pooled evidence from only four studies
including a total of 69 patients.11
Sources and selection criteria
We searched PubMed for studies using the terms
“glucocorticoid-induced adrenal insufficiency”,
“steroid-induced adrenal insufficiency”, “tertiary
adrenal insufficiency”, “glucocorticoid withdrawal
syndrome”, and “glucocorticoid taper.” We
considered all studies published in the English
language between 1 January 2010 and 15
November 2020. Relevant publications outside this
timeline were selected on the basis of review of the
bibliography. Unless stated, we report data from
studies that assessed adrenal function by dynamic
testing (adrenocorticotropic hormone (ACTH)
stimulation tests, corticotropin releasing hormone
stimulation test, overnight metyrapone test, insulin
tolerance test). We predefined the priority of study
selection for this review according to the level of the
evidence (systematic reviews and meta-analyses of
literature and randomized controlled trials, if any),
on the basis of the population of interest (studies
reporting on GI-AI, with clear description of the type,
dose, and duration of glucocorticoid use), the sample
size (studies with larger sample size were prioritized),
and the time of publication (more recent studies were
prioritized).
Pathophysiology of hypothalamic-pituitary-adrenal axis
suppression and recovery
Glucocorticoids that directly enter the systemic
circulation and those surviving the first pass
metabolism after gastrointestinal absorption exert
negative feedback on the corticotropin releasing
hormone producing neurons and pituitary
corticotroph cells. This leads to reduced adrenal
cortisol production and, after prolonged exposure,
adrenal cortical hypoplasia and atrophy (fig 1, top
panel).14-16 After the effect of glucocorticoid therapy
on the hypothalamic-pituitary-adrenal axis (HPAA)
has worn off, production of ACTH and corticotropin
releasing hormone typically recovers first, followed
by that of cortisol, which can remain suppressed in
the long term if adrenal atrophy has ensued (fig 1,
bottom panel).17-19
Factors affecting likelihood of glucocorticoid induced
adrenal insufficiency
The risk of developing GI-AI is difficult to predict on an
individual basis. The glucocorticoid formulation used,
dose, and treatment duration can affect this risk, but
a great degree of overlap exists.11 20 21 Nevertheless,
multiple studies have assessed the various factors
that contribute to development of GI-AI (box 1), which
can help clinicians to establish the risk individualized
to each patient (table 1). This classification, together
with clinical judgment, can be useful in deciding
the management of patients exposed to exogenous
glucocorticoids (fig 2 and fig 3); in particular, we
focused on systemic and inhaled glucocorticoids, as
their effects on the HPAA have been examined more
2
extensively. However, it is important to note that high
quality evidence is limited.
BMJ: first published as 10.1136/bmj.n1380 on 12 July 2021. Downloaded from http://www.bmj.com/ on 11 August 2021 by guest. Protected by copyright.
Systemic glucocorticoid therapy
Systemic glucocorticoids, especially those with
longer half life and higher potency, are more likely
to cause GI-AI compared with other administration
routes because of the direct negative feedback on the
HPAA (box 1 and table 2).22 Treatment with bedtime
glucocorticoid administration and multiple split
doses is more likely to affect circadian ACTH release
and cause GI-AI.23-25 On the other hand, alternate day
administration, as well as pulse therapy with high
dose systemic glucocorticoids, is associated with a
lower risk of GI-AI because the HPAA has more time
to recover (box 1).23 26-30
Several studies have suggested a direct relation
between the dose and duration of systemic
glucocorticoid therapy and the likelihood of GI-AI,
although the evidence is limited.2 23 31-33 A recent
analysis of medical records from primary and
secondary care in England found that the incidence
of GI-AI and iatrogenic Cushing’s syndrome among
chronic users of oral glucocorticoids (mainly
prednisolone) increased with higher daily and
cumulative doses.2 Although these data provide
a good population based estimate of the risk of GI-
AI, establishing this risk at the individual level is
difficult.11 32-36
Short courses (<2 weeks) of high dose
glucocorticoids are usually associated with a swift
recovery of adrenal function,18 37 38 although cases
of GI-AI lasting more than seven to 14 days have
been described.31 39-44 The possible exception
to this is in patients who receive frequent short
glucocorticoid courses, as in the treatment of asthma
or chronic obstructive pulmonary disease and during
emetogenic chemotherapy. Of 37 healthy people
given prednisone at doses ranging from 2.5 mg to 60
mg over seven days on three occasions, separated by
14 day washout periods, two developed GI-AI, lasting
as long as four months in one of them.43
In a prospective study of 311 patients with
exacerbation of chronic obstructive pulmonary
disease treated with prednisolone for ≤14 days,
9%, 3%, and 2% had biochemical evidence of GI-AI
when assessed at one, three, and six months after
discontinuing glucocorticoids.45 Of note, a substantial
number of these patients were exposed to short
courses of glucocorticoid therapy for exacerbations
of chronic obstructive pulmonary disease before and
during the study.46 In a prospective study of patients
with cancer treated with at least three short courses
of high dose dexamethasone (three to four days)
every two to four weeks to counteract chemotherapy
induced nausea, 15% of patients developed GI-
AI within three to six months.47 Patients who also
received megestrol acetate had a threefold higher
risk of GI-AI, possibly because of its glucocorticoid
activity (box 1).47 48
Children also have a significant risk of GI-AI when
exposed to systemic glucocorticoids, which may be
doi: 10.1136/bmj.n1380 | BMJ 2021;374:n1380 | the bmj
 STATE OF THE ART REVIEW

A Paraventricular
Negative
nucleus of
feedback

BMJ: first published as 10.1136/bmj.n1380 on 12 July 2021. Downloaded from http://www.bmj.com/ on 11 August 2021 by guest. Protected by copyright.
hypothalamus

Gastro- Exogenous GCs

Oral intestinal First pass in systemic
GCs absorption metabolism circulation
CRH
Mouth, Long term exposure to
Inhaled Direct exogenous GCs can
pharynx
GCs absorption lead to atrophy of
from lungs Negative pituitary corticotroph cells
Anterior
feedback
IV, IM pituitary ACTH
GCs

Topical
GCs
Adrenal
glands
Possible systemic
absorption

Intra-
articular
Cortisol Long term exposure to
exogenous GCs can lead
GCs to adrenocortical atrophy
Adrenal (atrophy of zona fasciculata
androgens and zona reticularis)

Aldosterone secretion is preserved

Secretion of mineralocorticoids is
regulated by renin-angiotensin system

B
Discontinuation of ACTH
supraphysiological doses
of exogenous GCs Cortisol
Circulating levels

Normal
range

Time

Fig 1 | Pathophysiology of glucocorticoid induced hypothalamic-pituitary-adrenal axis (HPAA) suppression and recovery. Top panel: HPAA
suppression by exogenous glucocorticoids. Glucocorticoids that directly enter the systemic circulation and those surviving first pass metabolism
after gastrointestinal absorption will exert negative feedback on the HPAA by decreasing hypothalamic corticotropin releasing hormone (CRH)
synthesis and secretion and its action on release of ACTH by the anterior pituitary. The acute effect on the pituitary is suppressed synthesis of pro-
opiomelanocortin (POMC) (and consequently of adrenocorticotropic hormone (ACTH) and other POMC derived peptides); in the long term, atrophy
of corticotroph cells and Crooke’s cells can develop. Crooke’s changes can be found in both endogenous and iatrogenic Cushing’s syndrome and
include an intracytoplasmic hyaline ring (keratin filaments), paranuclear vacuoles (lysosomes), and secretory granules. In the absence of ACTH,
the adrenal cortex loses the ability to produce cortisol and androgens and, ultimately, can become atrophic. Secretion of aldosterone is preserved.
Bottom panel: schematic representation of HPAA recovery following discontinuation of glucocorticoid therapy. After short term treatment with
glucocorticoids, ACTH secretion is the first to recover, followed by CRH and eventually cortisol and androgens. After long term exposure, a swift
and marked increase of ACTH is observed, and this precedes the recovery of cortisol secretion. Abnormal cortisol secretion can last a very long
time if adrenal atrophy has developed. Adrenal androgens can also remain suppressed in the long term. GC=glucocorticoid; IM=intramuscular;
IV=intravenous

the bmj | BMJ 2021;374:n1380 | doi: 10.1136/bmj.n1380 3

STATE OF THE ART REVIEW

Box 1: Factors affecting the risk of glucocorticoid induced adrenal insufficiency (GI-AI)
Glucocorticoid mode of administration

BMJ: first published as 10.1136/bmj.n1380 on 12 July 2021. Downloaded from http://www.bmj.com/ on 11 August 2021 by guest. Protected by copyright.
Systemic administration (including oral, intravenous, intramuscular)
Factors increasing the risk of GI-AI:
• Daily administration for >2-4 weeks
• Multiple daily split doses
• Bedtime administration
Factors reducing the risk of GI-AI:
• Alternate day administration
• Pulse systemic therapy (intermittent intravenous administration of very high doses of glucocorticoids over a few days or weeks)
Inhaled glucocorticoids
Factors increasing the risk of GI-AI:
• High daily doses given for >6-12 months
• Treatment with fluticasone propionate
• Concomitant use of oral glucocorticoids (including intermittent use—eg, in chronic obstructive pulmonary disease)
• Lower body mass index (children)
• Higher compliance with treatment (children)
Intra-articular glucocorticoids
• Factors increasing the risk of GI-AI:
• Repeated injections with high doses of glucocorticoids
• Inflammatory arthropathies
Percutaneous glucocorticoids
Factors increasing the risk of GI-AI:
• Long term and frequent use of large amounts of high potency glucocorticoids
• Prolonged use on inflamed skin or with impaired barrier function
• Occlusive dressings
• Use on mucous membranes, eyelids, and scrotum
• Larger body surface area to body weight ratio (children)
Glucocorticoid half life and potency
The use of long acting glucocorticoids (ie, with a longer biological half life) and formulations with higher glucocorticoid potency (ie, stronger
binding to the glucocorticoid receptor) predispose to more pronounced adrenal suppression because of the continuous effect on the HPAA. This is
particularly relevant for systemic administration. See table 2 for a list of widely used systemic glucocorticoids.
Glucocorticoid dose
Higher doses of glucocorticoids correlate with increased inhibition of corticotropin releasing hormone secretion, especially when given daily over
a prolonged period. The evidence for the effect of the dose of systemic glucocorticoids on manifestations of GI-AI is, however, limited. A stronger
relation between the risk of GI-AI and administered doses has been described for inhaled glucocorticoids and can inform the risk of adrenal
suppression (table 1 and table 3).
Drug interactions
CYP3A4 inhibitors
CYP3A4 is the major pathway for the inactivation of most prescribed glucocorticoids. CYP3A4 inhibitors are expected to increase the systemic
exposure to synthetic glucocorticoids (ie, higher risk of GI-AI):
• Strong inhibitors include boceprevir, ceritinib, clarithromycin, cobicistat, darunavir, idelalisib, indinavir, itraconazole, ketoconazole, lopinavir,
mifepristone, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, and voriconazole
• Moderate inhibitors include amiodarone, aprepitant, cimetidine, conivaptan, crizotinib, ciclosporin, diltiazem, dronedarone, erythromycin,
fluconazole, fosamprenavir, fosaprepitant, grapefruit juice, imatinib, isavuconazole, netupitant, nilotinib, ribociclib, schisandra, and verapamil
CYP3A4 inducers
CYP3A4 inducers are expected to decrease the systemic exposure to synthetic glucocorticoids. Therefore, patients who have underlying GI-AI may
develop signs and symptoms of cortisol deficiency:
• Strong inducers include apalutamide, carbamazepine, enzalutamide, fosphenytoin, lumacaftor, lumacaftor-ivacaftor, mitotane, phenobarbital,
phenytoin, primidone, and rifampicin
• Moderate inducers include bexarotene, bosentan, cenobamate, dabrafenib, efavirenz, elagolix/estradiol/norethindrone acetate combination,
eslicarbazepine, etravirine, lorlatinib, modafinil, nafcillin, pexidartinib, rifabutin​, rifapentine, and St John’s wort (Hypericum perforatum)
Concomitant use of other drugs
• Megestrol acetate potentially increases the risk of adrenal suppression because of its glucocorticoid activity.
• High dose medroxyprogesterone acetate can inhibit release of adrenocorticotropic hormone and exerts weak glucocorticoid activity
CYP3A4=cytochrome P450 3A4; HPAA=hypothalamic-pituitary-adrenal axis

4 doi: 10.1136/bmj.n1380 | BMJ 2021;374:n1380 | the bmj


Table 1 | Likelihood of clinically relevant adrenal suppression by exogenous glucocorticoids (GCs). Doses are reported as prednisolone equivalent
doses (PED)
Systemic GCs (including oral, intravenous, and
Risk Any administration route intramuscular administration)
Very high risk of Patients with history of exogenous GC use presenting with adrenal crisis
GI-AI Patients with history of exogenous GC use presenting with cushingoid appearance
High risk of Patients with current or recent history of Daily treatment with PED ≥5 mg for >4 weeks
GI-AI exogenous GC use presenting with signs and (adults)
symptoms suggestive of adrenal insufficiency
(excluding adrenal crisis and cushingoid
appearance) Daily treatment with PED ≥2-3 mg/m2
(=hydrocortisone 8-10 mg/m2) for >4 weeks
(children)
Concomitant use of strong CYP3A4 inhibitors Long term bedtime administration*
Moderate risk of Patients without symptoms who have Daily treatment with PED ≥5 mg for 2-4 weeks
GI-AI discontinued long term GC therapy for <1 year (adults)
(especially if further short courses of GCs are Daily treatment with PED ≥2-3 (=hydrocortisone
prescribed) 8-12 mg/m2) for 2-4 weeks (children)
Daily treatment with PED <5 mg (adults)
Daily treatment with PED <2-3 mg/m2 (children)
Multiple courses with daily administration, each
lasting <2 weeks
Long term treatment on alternate days
Low risk of GI-AI Patients without symptoms who have Single course with daily administration lasting <2
discontinued long term GC therapy for >1 year weeks (any dose)
Pulse therapy (any dose)
CYP3A4=cytochrome P450 3A4; HED=hydrocortisone equivalent dose; HPAA=hypothalamic-pituitary-adrenal axis; GI-AI=glucocorticoid induced adrenal insufficiency.
*Excluding modified release formulations (eg, modified release prednisone).
†Clinical discretion should be used to determine risk on individual basis. Patients receiving multiple or simultaneous injections have higher risk of GI-AI. Patients should be monitored for signs
and symptoms of adrenal insufficiency, especially during first 2 months after injection. Low threshold for testing advised if clinical suspicion of adrenal insufficiency exists.
higher in those aged under 5 years.49 A retrospective
study of 103 children receiving supraphysiological
doses of glucocorticoids for prolonged periods of
time (median >1 year) did not find an association
between the duration of treatment, the cumulative
glucocorticoid dose, and the risk of GI-AI.50 A
systematic review of 10 studies that included 298
children with acute lymphoblastic leukemia showed
that GI-AI occurred in nearly all cases treated with
high dose systemic glucocorticoids for less than two
months.51 Most children recovered adrenal function
within a few weeks, but GI-AI persisted in 11% of
patients retested at 12-34 weeks.51
Inhaled glucocorticoid therapy
Inhaled glucocorticoids can be absorbed directly
from the lungs or from the gastrointestinal tract. The
drug that does not reach the lungs is deposited into
the mouth and pharynx, where it can be swallowed
and absorbed. The portion of the drug that survives
the first pass metabolism in the liver exerts systemic
effects (box 1, table 3, and fig 1, top panel).52-54
A systematic review and meta-analysis found
that patients with asthma or chronic obstructive
pulmonary disease who used only inhaled
glucocorticoids had a 6.8% risk of GI-AI.11 This
risk had a positive correlation with both the
glucocorticoid dose (up to 18.5% risk in those using
high doses) and the treatment duration (risk up
to 20.3% if used for longer than one year).11 This
dose-response relation was also observed in other
large cohorts.55 56 Several studies have also shown
that patients treated with inhaled glucocorticoids
who also use oral glucocorticoids are much more
likely to develop GI-AI (up to 43.7%).11 56 Moreover,
the bmj | BMJ 2021;374:n1380 | doi: 10.1136/bmj.n1380
STATE OF THE ART REVIEW
BMJ: first published as 10.1136/bmj.n1380 on 12 July 2021. Downloaded from http://www.bmj.com/ on 11 August 2021 by guest. Protected by copyright.
Inhaled GCs Intra-articular GCs
Use of high doses (regardless of Robust evidence
treatment duration). Fluticasone is lacking. HPAA
propionate carries particularly suppression is
high risk common up to
Continuous treatment for >12 2 months after
months (regardless of dose used) injections†
Concomitant use of other GCs
Use of low/intermediate doses for
6-12 months
Use of low/intermediate doses for
less than 6 months
the cumulative dose of inhaled glucocorticoids, the
concomitant use of nasal glucocorticoids, higher
adherence to treatment, and low body mass index in
children increase the likelihood of GI-AI.57-60
Most cases of GI-AI in patients using inhaled
glucocorticoids have been linked to fluticasone
propionate.61-64 This drug has a long half life
(14.4 hours) and a strong binding affinity for
the glucocorticoid receptor (18 times that of
dexamethasone), which may lead to pronounced
negative feedback on the HPAA.22 Fluticasone furoate
has the same steroidal backbone as fluticasone
propionate but a different ester substituent and has
a longer retention time in respiratory tissues.65 This
may explain the lower levels of systemic absorption
and the low impact on the HPAA observed in both
children and adults (box 1),66-69 although East Asian
people may have a higher risk of systemic exposure
to the drug.69 Ciclesonide and its active metabolite
desisobutyryl-ciclesonide have high concentrations
of plasma protein binding (that is, reduced biological
activity) and high clearance rate (that is, reduced
systemic exposure)52 70; this might explain the low
degree of HPAA suppression observed with this
compound.71-73 Therefore, inhaled ciclesonide may
be a safer alternative than fluticasone propionate,52 74
although cases of GI-AI have been associated with its
use.55 75 76
In children and adults with asthma, most studies
did not find GI-AI when inhaled glucocorticoids were
used at fluticasone equivalent doses below 400 µg/
day and 500 µg/day, respectively.52 77-80 However,
long term users of inhaled glucocorticoids (>6-12
months) can develop GI-AI even at intermediate and
low doses.68 7 581 A study in 70 children with asthma
5
STATE OF THE ART REVIEW

9(5<+,*+5,6. +,*+5,6. 02'(5$7(5,6. /2:5,6.

BMJ: first published as 10.1136/bmj.n1380 on 12 July 2021. Downloaded from http://www.bmj.com/ on 11 August 2021 by guest. Protected by copyright.
(GXFDWHSDWLHQWVDERXWWKHULVNRI*,$,DQGRQZD\VWRUHGXFHWKLVULVN

(GXFDWHSDWLHQWVWRDOZD\VLQIRUPKHDOWKSURIHVVLRQDOVLIWKH\DUHWDNLQJ*&VLIWKH\KDYHUHFHQWO\WDNHQ*&VRULI*&V
KDYHEHHQGLVFRQWLQXHGLQWKHSUHYLRXV\HDU

+HDOWKSURIHVVLRQDOVVKRXOGSD\SDUWLFXODUDWWHQWLRQWRRYHUWKHFRXQWHUGUXJVFRQWDLQLQJ*&VHJQDVDODQGWRSLFDO*&V
DQGUHFHQWLQWUDDUWLFXODURUHSLGXUDO*&LQMHFWLRQV

(GXFDWHSDWLHQWVUHODWLYHVDQGFDUHJLYHUVDERXWV\PSWRPDZDUHQHVVDQGSRVVLEOH
SUHFLSLWDWLQJIDFWRUVRIDGUHQDOFULVLV

3DWLHQWVVKRXOGUHFHLYHZULWWHQLQIRUPDWLRQDERXWWKHULVNRIDGUHQDOFULVLV
HJVWHURLGHPHUJHQF\FDUG

(GXFDWHSDWLHQWVQRWWRGLVFRQWLQXH*&VDEUXSWO\LIWKH\KDYHEHHQRQORQJWHUP
FRQWLQXRXVWUHDWPHQW

(GXFDWHSDWLHQWVUHODWLYHVDQGFDUHJLYHUV
DERXWWKHVLFNGD\UXOHVŦ

3URYLGHSDWLHQWVZLWKD &OLQLFDOGLVFUHWLRQ
VWHURLGHPHUJHQF\ VKRXOGEHXVHGJLYH
LQMHFWLRQNLW VWHURLGHPHUJHQF\
LQMHFWLRQNLWVWRSDWLHQWV
2ƷHUWUDLQLQJRQKRZWR DWKLJKULVNDVFOLQLFDOO\
VHOIDGPLQLVWHUDQG DSSURSULDWH
LQMHFWK\GURFRUWLVRQH

Fig 2 | Suggested patient education according to the likelihood of hypothalamic-pituitary-adrenal axis (HPAA)
suppression. Education of patients and increased awareness of glucocorticoid induced adrenal insufficiency
(GI-AI) among patients and health professionals are key to improving clinical outcomes. *For example, using
the lowest effective dose of glucocorticoids for the shortest period of time, especially if self-medicating with
over-the-counter drugs, or using spacers and mouth rinsing if taking inhaled glucocorticoids. †For patients not
taking oral glucocorticoids, provide immediate release hydrocortisone tablets (to be used in case of sick days).
GC=glucocorticoid

treated with inhaled glucocorticoids for at least six
months found GI-AI in 24% of cases, with most
being treated for more than 24 months at fluticasone
equivalent doses above 400 µg/day.82
Patients with cystic fibrosis often need inhaled
glucocorticoids if they develop symptoms of asthma
or in the setting of allergic bronchopulmonary
aspergillosis. Limited evidence suggests that they may
be at particularly high risk of GI-AI.11 83 Patients who
need prolonged courses of systemic glucocorticoids
and antifungal drugs (strong inhibitors of CYP3A4)
for acute allergic bronchopulmonary aspergillosis
are more susceptible to HPAA suppression.83
Intra-articular and epidural glucocorticoid therapy
Intra-articular glucocorticoid injections are
commonly used for symptom relief in patients with
osteoarthritis and inflammatory arthropathies.
They are favored over oral glucocorticoids because
of the much lower systemic absorption and risk of
adverse effects. However, a proportion of injected
glucocorticoid reaches the systemic circulation
and can affect the HPAA (box 1). Exogenous
glucocorticoids can be detected in the urine for
months after the injection, pointing to possible
prolonged systemic absorption.84 85 Repeated
injections and higher doses of glucocorticoids
increase the risk of GI-AI.86-90 Moreover, patients
with inflammatory arthropathies have a higher
risk of systemic glucocorticoid absorption because
of its injection into a highly vascularized area
(box 1).89 This is particularly relevant in the
pediatric population, as inflammatory (rather than
degenerative) arthropathies are more common.86

6 doi: 10.1136/bmj.n1380 | BMJ 2021;374:n1380 | the bmj

 STATE OF THE ART REVIEW

3DWLHQWVZLWK

BMJ: first published as 10.1136/bmj.n1380 on 12 July 2021. Downloaded from http://www.bmj.com/ on 11 August 2021 by guest. Protected by copyright.
9(5<+,*+5,6. 7KHVHSDWLHQWVKDYH*,$,DQGPXVWUHFHLYHDSSURSULDWHPDQDJHPHQWVHHƟJ
&RQƟUPDWRU\WHVWLQJIRU*&$,LVQRWQHHGHG

,IV\VWHPLF*&VDUHQR
ORQJHUQHHGHG
JUDGXDOO\WDSHUGRVH $IWHUZHHNV
0HDVXUHHDUO\PRUQLQJVHUXP
GRZQWRPJ FRUWLVROKDIWHUODVWGRVHRI*&Vŧ
+,*+5,6. SUHGQLVRORQHHTXLYDOHQW
GRVHVHHƟJ

,IWDNLQJLQKDOHG*&V QPRO/ QPRO/ QPRO/ !QPRO/

UHJXODUPRQLWRULQJRI wJG/*,$, wJG/ wJG/ wJG/
HDUO\PRUQLQJVHUXP SRVVLEOH*,$, *,$,LVSRVVLEOHEXW *,$,LVXQOLNHO\
FRUWLVRODQGVLJQVRI*,$,Ŧ XQOLNHO\WREHUHOHYDQW
LQEDVDOFRQGLWLRQV

02'(5$7(5,6. /RZWKUHVKROGWRWHVW+3$$ &RQWLQXH*&V&RQVLGHUVZLWFKLQJ 'DLO\*&VFDQEH 6WRS*&Vx

IXQFWLRQ Ŧ)RUH[DPSOH WRK\GURFRUWLVRQH VWRSSHG+RZHYHU*&
HJPJDPPJHDUO\SPi IRUVWUHVVGRVHFRYHU
,ISDWLHQWLVXQGHUPDMRU QHHGVWRFRQWLQXH
$IWHUDIHZ $IWHUD VLFNGD\UXOHV
VWUHVVHJVHSVLVWUDXPD
PRQWKV IHZZHHNV
HPHUJHQF\VXUJHU\FKHFN
UDQGRPVHUXPFRUWLVROLI
!QPRO/wJG/ 5HWHVWHDUO\PRUQLQJFRUWLVRO
ZRXOGH[FOXGHDGUHQDO &RQVLGHUWHVWLQJHDUO\PRUQLQJ$&7+
LQVXƸFLHQF\:KHQ
ODERUDWRU\WHVWVFDQQRWEH
FDUULHGRXWSDWLHQWVVKRXOG
UHFHLYHVWUHVVGRVH*&VLI
FOLQLFDOFRQFHUQRIDGUHQDO &RQVLGHUG\QDPLFWHVWLQJZKHQ 1RUPDO
LQVXƸFLHQF\H[LVWV UHVXOWVDUHLQGHWHUPLQDWHŦŦ UHVSRQVH

,ISDWLHQWKDVSODQQHG
VXUJHU\DGUHQDO
LQVXƸFLHQF\VKRXOGEH
H[FOXGHGHDUO\PRUQLQJ $EQRUPDO %RUGHUOLQHUHVSRQVH*,$,XQOLNHO\WREHUHOHYDQWLQEDVDO
FRUWLVROG\QDPLF UHVSRQVH FRQGLWLRQV6LQJOHPRUQLQJGRVHRIK\GURFRUWLVRQHRURQO\VWUHVV
WHVWLQJ FRQWLQXH*&V GRVHK\GURFRUWLVRQHFDQEHFRQVLGHUHG3DWLHQWVKRXOGEH
UHWHVWHGSHULRGLFDOO\WRDVVHVV+3$$UHFRYHU\

/2:5,6. *&WDSHULQJDQGWHVWLQJIRU*,$,DUHQRWURXWLQHO\UHFRPPHQGHGXQOHVVVXVSLFLRQRIDGUHQDOLQVXƸFLHQF\H[LVWV

RI+3$$
VXSSUHVVLRQ

&RUWLVROFXWRƷVUHSRUWHGLQWKLVƠRZFKDUWDUHRQO\DVXJJHVWLRQ&XWRƷVYDU\DFFRUGLQJWRWKHDVVD\XVHGDQGGRQRWDSSO\WRSDWLHQWVWUHDWHGZLWKRUDOHVWURJHQV

Fig 3 | Approach to patients with different risks of glucocorticoid (GC) induced adrenal insufficiency. Schematic approach to the management of GC
therapy according to the likelihood of hypothalamic-pituitary-adrenal axis (HPAA) suppression. This is a guide only—management must be tailored
on an individual basis. ACTH=adrenocorticotropic hormone; GI-AI=glucocorticoid induced adrenal insufficiency; PED=prednisolone equivalent
dose. *If the patient is taking long acting GCs (eg, dexamethasone), switch to a replacement dose of hydrocortisone (eg, 15 mg am + 5 mg early pm)
before testing serum cortisol. This would otherwise be affected by the long half life of the GCs. †Patients should also be tested to see if they can
stop the inhaled GCs, reduce the dose, or switch to a different formulation. ‡Patients should be tested 24 h after the last dose of exogenous GCs.
Predniso(lo)ne can interfere with immunoassays and cause falsely elevated cortisol values. §Hydrocortisone has a short half life and should be
favored in case of delayed recovery of the HPAA. ¶If taking hydrocortisone: stop immediately. If taking prednisolone: taper down and stop. **If ACTH
is low or suppressed, the HPAA is very unlikely to have recovered. ††Dynamic testing options include: (1) 250 μg ACTH stimulation test—cortisol is
measured after injection of synthetic ACTH (cosyntropin). Examples of normal responses: 30 minute cortisol >350-550 nmol/L (12.7-20 µg/dL); 60
minute cortisol >380-500 nmol/L (13.8-18.1 µg/dL). Cut-offs vary according to the cortisol assay used and local practices. The cut-offs proposed here
should be seen as a guide only. (2) Overnight metyrapone stimulation test: a normal response consists of early morning serum 11-deoxycortisol
concentration of 200-635 nmol/L. (3) Insulin tolerance test: a normal response is achieved if serum cortisol increases to >350-550 nmol/L (12.7-19.9
µg/dL, depending on the cortisol assay used) and if the serum glucose falls to <2.8 mmol/L (50 mg/dL)

the bmj | BMJ 2021;374:n1380 | doi: 10.1136/bmj.n1380 7

STATE OF THE ART REVIEW

Table 2 | Commonly prescribed systemic glucocorticoids also observed after injections of methylprednisolone
Prednisolone equivalent doses acetate,96 97 with patients receiving higher doses (80
(using 5 mg prednisolone as mg) being at higher risk of GI-AI.97

BMJ: first published as 10.1136/bmj.n1380 on 12 July 2021. Downloaded from http://www.bmj.com/ on 11 August 2021 by guest. Protected by copyright.
Drug type Drug reference)*
Short acting glucocorticoids with lower Hydrocortisone 20 mg
Topical and rectal glucocorticoid therapy
potency (biological half life <12 h) Cortisone acetate 25 mg
The evidence of an effect of topical glucocorticoids
Deflazacort 6 mg
Intermediate acting glucocorticoids with Prednisone 5 mg on the HPAA is mostly anecdotal. Cases of GI-
intermediate potency (biological half life Prednisolone 5 mg AI have been reported after exposure to nasal,
12-36 h) Methylprednisolone 4 mg intradermal, and cutaneous glucocorticoids.62 98-102
Triamcinolone 4 mg The pharmacokinetic and pharmacodynamic
Long acting glucocorticoids with higher Dexamethasone 0.50 mg characteristics of the glucocorticoid used can
potency (biological half life 36-54 h) Betamethasone 0.50 mg influence its effect on adrenal function; however,
*Glucocorticoid potency equivalences apply to oral and/or intravenous administration and take no account of
mineralocorticoid effects. Potency and conversion reported are estimates and should be seen as guide only.
short term administration at the recommended
dosages is safe.103 104 Skin inflammation, impaired
barrier function due to damage, use of occlusive
In patients treated for osteoarthritis of the knee, dressings, and the site of application affect the rate of
biochemical evidence of GI-AI was observed two systemic absorption in case of topical glucocorticoid
to four weeks after the injection of intra-articular use.101 105 For example, percutaneous absorption is
methylprednisolone acetate and betamethasone higher through mucous membranes, eyelids, and
acetate/betamethasone sodium phosphate in 25% scrotum.101 The risk of GI-AI may be higher in infants
and 5% of people, respectively.91 92 Asymptomatic because of a larger body surface area to body weight
GI-AI was observed in 60% of patients receiving ratio (box 1).22
simultaneous bilateral knee injections of Rectal glucocorticoids are often used to limit
methylprednisolone acetate and persisted for eight systemic exposure in patients with inflammatory
weeks in 10% of cases.93 Interestingly, a minority bowel diseases affecting the lower part of the colon
of these patients had intermittent abnormalities and rectum. Although short term use is safe, systemic
in cortisol secretion over time, suggesting possible glucocorticoid absorption is possible.106 GI-AI has
variation in systemic absorption of the glucocorticoid been described in users of prednisolone enemas.107
from the knee joint.93 Rectal budesonide and beclometasone dipropionate
The effects of epidural glucocorticoids on the may be safer than other glucocorticoids108-111;
HPAA have been assessed in a few small studies. however, most of the evidence is based on single
Eight people receiving a single epidural injection of serum cortisol measurements.
triamcinolone had a significant reduction in 24 hour
urinary cortisol after 12 weeks, as well as a blunted Oral budesonide
response of ACTH and cortisol to corticotropin Oral budesonide, frequently used to treat
releasing hormone stimulation.94 Another study inflammatory bowel disease, undergoes extensive
showed that 35% of patients receiving multiple inactivation during first pass metabolism. However,
epidural injections of triamcinolone acetate had GI- the drug can be absorbed systemically and cases of
AI, which resolved within three months.95 This was adrenal crisis and Cushing’s syndrome have been

Table 3 | Commonly prescribed inhaled glucocorticoids

Dose* Adults ≥17 years Children 5-11 years
Low doses Fluticasone propionate <300 µg/day Fluticasone propionate <150 µg/day
Beclometasone dipropionate (standard particle inhalers) <600 µg/day Beclometasone dipropionate (standard particle inhalers) <300 µg/day
Beclometasone dipropionate (extra fine particle inhalers) <300 µg/day Beclometasone dipropionate (extra fine particle inhalers) <150 µg/day
Budesonide <600 µg/day Budesonide <300 µg/day
Ciclesonide <240 µg/day Ciclesonide <160 µg/day
Mometasone furoate <400 µg/day
Intermediate doses Fluticasone propionate 300-500 µg/day Fluticasone propionate 150-20 0µg/day
Beclometasone dipropionate (standard particle inhalers) 600-1000 µg/day Beclometasone dipropionate (standard particle inhalers) 300-400 µg/day
Beclometasone dipropionate (extra fine particle inhalers) 300-400 µg/day Beclometasone dipropionate (extra fine particle inhalers) 150-200 µg/day
Budesonide 600-800 µg/day Budesonide 300-400 µg/day
Ciclesonide 240-320 µg/day Ciclesonide 160 µg/day
Fluticasone furoate 100 µg/day
Mometasone furoate 400 µg/day
High doses Fluticasone propionate >500 µg/day Fluticasone propionate >200 µg/day
Beclometasone dipropionate (standard particle inhalers) >1000 µg/day Beclometasone dipropionate (standard particle inhalers) >400 µg/day
Beclometasone dipropionate (extra fine particle inhalers) >400 µg/day Beclometasone dipropionate (extra fine particle inhalers) >200 µg/day
Budesonide >800 µg/day Budesonide >400 µg/day
Ciclesonide >320 µg/day Ciclesonide >160 µg/day
Fluticasone furoate >100 µg/day
Mometasone furoate >400 µg/day
*Doses should be seen as a guide only. Doses are based on information from manufactures’ summaries of product characteristics, Global Initiative for Asthma (2018), British National Formulary,
and British National Formulary for Children. London Respiratory Network has proposed different cut-offs to define low, intermediate, or high doses for some inhaled glucocorticoids in adults.

8 doi: 10.1136/bmj.n1380 | BMJ 2021;374:n1380 | the bmj


reported following prolonged use.112 113 Patients
who are taking higher doses of oral budesonide (eg,
>6 mg) for more than eight weeks and those on long
term treatment (regardless of the dose used) should
be considered at higher risk of GI-AI.11-117 This is
particularly relevant in patients with recent exposure
to oral glucocorticoids.
Drug interactions
Dexamethasone and, to a lesser extent, predniso(lo)
ne are metabolized by the hepatic cytochrome
P450 3A4 (CYP3A4). Therefore, CYP3A4 inhibitors
are expected to increase systemic exposure
to glucocorticoid (box 1).51 118 For example,
coadministration of ritonavir and prednisone
increased the circulating concentrations of the active
metabolite prednisolone by up to 37%.118 The newer
protease inhibitor dolutegravir does not inhibit
CYP3A4 and could be an alternative in patients
treated with glucocorticoids.119
Concomitant treatment with strong CYP3A4
inhibitors and inhaled, intranasal, and injectable
fluticasone, budesonide, and triamcinolone is
not recommended because of the preferential
metabolism of these drugs by CYP3A4.90 118 120-123
Beclometasone and flunisolide may be
safer alternatives because of their different
metabolism.124  125 Ritonavir has been linked to
many cases of iatrogenic Cushing’s syndrome and
symptomatic GI-AI when used in combination
with inhaled and intranasal glucocorticoids
(mostly fluticasone propionate).52  103  122 126 This is
particularly relevant because asthma and chronic
obstructive pulmonary disease are more prevalent in
HIV infected populations.127
Other factors affecting risk of glucocorticoid
induced adrenal insufficiency
Inter-individual variability in the sensitivity of
the HPAA to exogenous glucocorticoids has been
observed.44  128  129 For example, higher cortisol after
administration of dexamethasone was associated
with an inadequate response to the low dose ACTH
stimulation test after a 14 day course of prednisolone
in healthy volunteers.44 This variation is possibly
linked—among other factors—to polymorphisms
of the genes encoding the glucocorticoid
and mineralocorticoid receptors.14  129-132
Glucocorticoid receptor polymorphisms were
reported to be associated with increased sensitivity
to glucocorticoids, leading to a higher prevalence of
features associated with hypercortisolism and efficacy of
glucocorticoids or, by contrast, a relative glucocorticoid
resistance with lower rates of development of features
suggestive of iatrogenic Cushing’s syndrome.133-142
Time of glucocorticoid administration during the day is
another important factor that likely contributes to the
risk of GI-AI. Clock related genes in circulating blood
cells from patients taking exogenous glucocorticoid
multiple times a day were found to be abnormal, and
they partially normalized after a switch to once a day
administration.143 Administration of glucocorticoid
the bmj | BMJ 2021;374:n1380 | doi: 10.1136/bmj.n1380
STATE OF THE ART REVIEW
in the evening is more likely to lead to GI-AI and
glucocorticoid induced side effects as glucocorticoid
sensitivity is higher at that time, parallel to the
BMJ: first published as 10.1136/bmj.n1380 on 12 July 2021. Downloaded from http://www.bmj.com/ on 11 August 2021 by guest. Protected by copyright.
clock gene down-regulation.144 The metabolism of
exogenous glucocorticoids (and hence exposure of
the HPAA to negative feedback) can also be affected
by sex, age, body mass index, liver and kidney failure,
proinflammatory cytokines, and polymorphisms of CYP
enzymes and the cytochrome P450 oxidoreductase.145
Clinical relevance of glucocorticoid induced adrenal
insufficiency
We showed in the previous sections that a biochemical
diagnosis of GI-AI is common in patients treated with
glucocorticoids. However, a fundamental question
needs to be answered—is this just a biochemical
abnormality, or is it clinically relevant? A crucial
point to consider is whether GI-AI without apparent
signs and symptoms of cortisol deficiency is clinically
relevant. A review of the literature found that very few
studies assessing the risk of GI-AI in patients treated
with glucocorticoids also focused on symptoms
of adrenal insufficiency.11 In the pooled analysis,
only 2% of patients reported symptoms consistent
with adrenal insufficiency but, on dynamic testing,
19% of patients failed to achieve a normal cortisol
response.11 Notably, although symptom assessment
in this study was not standardized, these data
suggest that patients with symptoms are only the
tip of the iceberg. Moreover, patients with GI-AI can
often present with non-specific signs and symptoms
that can be attributed to other causes. Importantly,
events such as infections and surgery in a patient
with undiagnosed and untreated GI-AI can trigger a
life threatening adrenal crisis because of the inability
to mount an adequate stress response.146
Adrenal crisis and symptomatic glucocorticoid
induced adrenal insufficiency
Several cases of adrenal crisis and hospital admission
for GI-AI have been described, including a few
deaths.14 35 147-150 Of note, many patients presenting
with adrenal crisis were treated with inhaled
glucocorticoids only (mostly high dose fluticasone
propionate), emphasizing the potential risks
associated with their systemic absorption.14 55 150-153
Symptomatic GI-AI and adrenal crises have also been
described in patients exposed to oral glucocorticoids
for less than two months, as well as in patients
receiving topical, intra-articular, epidural, and rectal
glucocorticoids.14 85 87 150 154-158 Two studies found
that patients with GI-AI had a higher incidence of
adrenal crisis than did patients with other causes
of adrenal insufficiency.159 160 The most common
triggering factor was infections; of note, several
patients developed an adrenal crisis after reducing or
discontinuing the dose of exogenous glucocorticoids,
which is a preventable cause of morbidity.160
The tapering down and discontinuation of
glucocorticoids is a crucial time, as an underlying
GI-AI can become clinically apparent. A Danish
population based study showed that discontinuation
9
STATE OF THE ART REVIEW
of long term oral glucocorticoids increased the risk of
developing hypotension, gastrointestinal symptoms,
hypoglycemia, and hyponatremia.161 These signs,
which are suggestive of untreated GI-AI, peaked
up to three months after the glucocorticoids were
stopped and persisted for several months; older
patients taking higher daily doses of glucocorticoids
for longer periods of time, as well as those exposed
to infections, had the highest risk of developing
symptoms.161 Intriguingly, mortality after cessation
of chronic oral glucocorticoid therapy markedly
increased in the first months after discontinuation,
raising the suspicion of possible undiagnosed
adrenal crises in this population.2 Another
retrospective cohort study showed that 36 adrenal
crises (7.1% of all cases) occurred within 30 days
of discontinuation of glucocorticoids.152 Adrenal
crises have also been reported in patients tapering
down inhaled glucocorticoids or switching between
different glucocorticoid preparations.153
Risks associated with inhaled glucocorticoid therapy
Cases of symptomatic GI-AI and iatrogenic
Cushing’s syndrome have been linked to inhaled
glucocorticoids.52 62 162 Most cases involved patients
treated with fluticasone propionate ≥500 μg/day. A
retrospective cohort study from Canada identified 392
hospital admissions due to GI-AI over a 15 year period
among adults treated with inhaled glucocorticoids.59
Patients using higher daily doses (≥1000 µg/day) and
cumulative doses (>157 000 µg/year) of glucocorticoids
had an almost twofold higher risk of hospital admission
than those with lower exposure.59 A study focusing
on the medical records of general practices in the UK
identified only 31 cases of established GI-AI linked
to inhaled glucocorticoids in a cohort of 2.4 million
people.56 Considering the widespread use of inhaled
glucocorticoids, the low rates of GI-AI observed in
these studies would suggest that this problem is largely
unrecognized or under-reported.62
Clinical presentation of patients with hypothalamic-
pituitary-adrenal axis suppression
A high degree of clinical suspicion is paramount when
a history of glucocorticoid exposure exists. Patients
with GI-AI may have no symptoms, present with
varying degrees of symptoms of cortisol deficiency,
or present with life threatening adrenal crisis (fig 4).
Clinical diagnosis of GI-AI seems to be difficult, with
most patients reporting multiple symptoms at the
time of diagnosis and 66% of patients needing to see
more than one physician to make the diagnosis of GI-
AI.159 GI-AI generally has a less dramatic presentation
than primary adrenal insufficiency; acute circulatory
collapse and electrolyte abnormalities are infrequent
because the secretion of mineralocorticoids is
preserved (fig 1, top panel).114 Symptoms such
as fatigue and abdominal pain are non-specific,
and their onset may be insidious and mistakenly
attributed to other causes or to the disease for
which glucocorticoids were prescribed.14  162-164
In children, stunted growth, reduced final height,
10
and unexplained hypoglycemia can be signs of GI-
AI and should prompt an assessment of adrenal
function.76 153 165 Patients with untreated GI-AI may
BMJ: first published as 10.1136/bmj.n1380 on 12 July 2021. Downloaded from http://www.bmj.com/ on 11 August 2021 by guest. Protected by copyright.
be more susceptible to infections and recover more
slowly than those with normal adrenal function;
this could be another warning sign in patients with
chronic obstructive pulmonary disease and asthma
treated with glucocorticoids.153
Patients presenting with signs and symptoms of
cortisol excess due to glucocorticoid use (iatrogenic
Cushing’s syndrome) have had marked systemic
exposure and must be assumed to have a fully
suppressed HPAA (fig 4). Iatrogenic Cushing’s
syndrome can occur with any formulation of
glucocorticoids and can take several months to resolve
after the dose of glucocorticoid is decreased.87 158 166
Approaches to glucocorticoid taper
The goal of glucocorticoid therapy is the shortest
treatment with the lowest effective dose (box 2).
Glucocorticoid taper and eventual discontinuation
in patients treated with exogenous glucocorticoids
require consideration of several aspects of the care
of patients. The first one relates to the original
reason for the exogenous glucocorticoid therapy.
If prescribed for a chronic condition (for example,
rheumatoid arthritis, asthma, inflammatory bowel
disease), this may relapse after discontinuation
of glucocorticoids. A close collaboration with the
medical team is needed to ensure that the patient
is able to discontinue glucocorticoids and the
underlying disorder is in remission or well controlled
with an alternative, non-glucocorticoid therapy.
Secondly, symptoms related to the glucocorticoid
withdrawal should be anticipated and necessitate a
careful approach. Thirdly, GI-AI should be expected
and glucocorticoids should not be discontinued until
recovery of the HPAA is documented.
Considerations for glucocorticoid taper
The best choice of glucocorticoid to use during
glucocorticoid taper has not been explored. However,
differences in the pharmacokinetics and potency
of various glucocorticoids likely influence both
glucocorticoid withdrawal syndrome (GWS) and
the rapidity of HPAA recovery.167 Glucocorticoid
dose and taper are not standardized, leading to
significant differences in practice. Reported tapering
regimens are based on very low quality evidence.168
In several studies investigating the effect of different
types and dosage of glucocorticoid therapy on the
duration of HPAA recovery and/or GWS, evidence
was inconclusive.169-171
Approaches to the glucocorticoid taper
should include consideration of the duration of
supraphysiological glucocorticoid use, the average
dose used over this period, clinical manifestations
of iatrogenic Cushing’s syndrome, overall functional
status, and the risk of relapse of the underlying
disorder that was treated with glucocorticoids
(box 3). Rapid taper protocols were found to be
less effective than a standard taper in maintaining
doi: 10.1136/bmj.n1380 | BMJ 2021;374:n1380 | the bmj
 STATE OF THE ART REVIEW

&OLQLFDOSUHVHQWDWLRQRI 3DWLHQWVFDQSUHVHQWZLWKLDWURJHQLFDGUHQDOLQVXƸFLHQF\DQGLDWURJHQLF&XVKLQJšVV\QGURPH,PSRUWDQWO\VLJQVDQG
JOXFRFRUWLFRLGLQGXFHG V\PSWRPVFDQFRH[LVWGHSHQGLQJRQZKHQWKHVXSUDSK\VLRORJLFDOGRVHRIH[RJHQRXVJOXFRFRUWLFRLGVLVGLVFRQWLQXHG

BMJ: first published as 10.1136/bmj.n1380 on 12 July 2021. Downloaded from http://www.bmj.com/ on 11 August 2021 by guest. Protected by copyright.
DGUHQDOLQVXƸFLHQF\ 3DWLHQWVZLWKLDWURJHQLF&XVKLQJšVV\QGURPHDUHDVVXPHGWRKDYHDVXSSUHVVHGK\SRWKDODPLFSLWXLWDU\DGUHQDOD[LV
7KHUHIRUHWKH\FDQGHYHORSV\PSWRPVRIDGUHQDOLQVXƸFLHQF\LQFOXGLQJDGUHQDOFULVLVLIWKHH[RJHQRXV
JOXFRFRUWLFRLGLVGLVFRQWLQXHGDEUXSWO\RUWKHGRVHUHGXFHGEHORZUHSODFHPHQWGRVHV

,$752*(1,&$'5(1$/,168)),&,(1&< ,$752*(1,&&86+,1*š66<1'520(

  *HQHUDOPDODLVH   3UR[LPDOPXVFOHZHDNQHVV
  )DWLJXH   :HLJKWJDLQDQGFHQWUDOREHVLW\
  :HDNQHVV   'LVSURSRUWLRQDWHVXSUDFODYLFXODUDQGGRUVRFHUYLFDO
  'L]]LQHVVLQFOXGLQJSRVWXUDOGL]]LQHVV IDWSDGV
  *DVWURLQWHVWLQDOV\PSWRPVQDXVHDYRPLWLQJ   )DFLDODQGXSSHUQHFNSOHWKRUD
GLDUUKHDFUDPSVORVVRIDSSHWLWH   )DFLDOURXQGLQJ
  :HLJKWORVV   6NLQDWURSK\HDV\EUXLVLQJUHGVWUHWFKPDUNV
  +\SRWHQVLRQLQFOXGLQJSRVWXUDOK\SRWHQVLRQ   $FQH
  +HDGDFKHVXVXDOO\LQWKHPRUQLQJ   3RRUZRXQGKHDOLQJ
  $UWKUDOJLDVHVSHFLDOO\LQKDQGMRLQWV   ,QVRPQLD
  0\DOJLDV   ,QFUHDVHGDSSHWLWH
  5HFXUUHQWUHVSLUDWRU\LQIHFWLRQVZLWKVORZUHFRYHU\   ,UULWDELOLW\LPSDLUHGPHPRU\GHSUHVVLRQ
  $ODEDVWHUOLNHSDOHVNLQ   +\SHUWHQVLRQ
  3RRUOLQHDUJURZWKFKLOGUHQ   $EQRUPDOJOXFRVHPHWDEROLVP
  3RRUZHLJKWJDLQFKLOGUHQ   0HQVWUXDOLUUHJXODULWLHVZRPHQ
  +\SRJO\FHPLDPRUHIUHTXHQWLQFKLOGUHQ   3RRUOLQHDUJURZWKFKLOGUHQ
  +\SRQDWUHPLD
  /\PSKRF\WRVLVDQGHRVLQRSKLOLD

$'5(1$/&5,6,6

$GUHQDOFULVLVLVDOLIHWKUHDWHQLQJHPHUJHQF\%RWKSDWLHQWVZLWKLDWURJHQLFDGUHQDOLQVXƸFLHQF\DQGWKRVHZLWK
&XVKLQJšVV\QGURPHFDQGHYHORSDGUHQDOFULVLV3DWLHQWVSUHVHQWZLWKDWOHDVWWZRRIWKHIROORZLQJ
  +\SRWHQVLRQRUK\SRYROHPLFVKRFN
  1DXVHDRUYRPLWLQJ
  6HYHUHIDWLJXH
  )HYHU
  ,PSDLUHGFRQVFLRXVQHVVLQFOXGLQJOHWKDUJ\FRQIXVLRQVRPQROHQFHFROODSVHGHOLULXPFRPDVHL]XUHV
3DWLHQWVFDQDOVRSUHVHQWZLWKODERUDWRU\DEQRUPDOLWLHVK\SRJO\FHPLDK\SRQDWUHPLDO\PSKRF\WRVLVHRVLQRSKLOLD

)DFWRUVWKDWFDQ   ,QIHFWLRQVLQFOXGLQJJDVWURLQWHVWLQDOLQIHFWLRQVUHVSLUDWRU\LQIHFWLRQVVHSVLV

SUHFLSLWDWHDQDGUHQDO   6XUJHU\
FULVLVRUWULJJHU   $FXWHLOOQHVV
V\PSWRPVRIDGUHQDO   )HYHU
LQVXƸFLHQF\   6HYHUHVWUHVVDQGSDLQLQFOXGLQJVHYHUHDQ[LHW\EHUHDYHPHQW
  3K\VLFDOWUDXPD
  6WUHQXRXVH[HUFLVH
  'HQWDOSURFHGXUHV
  /DERUDQGGHOLYHU\
  $EUXSWJOXFRFRUWLFRLGZLWKGUDZDO
  *OXFRFRUWLFRLGWDSHULQJEHORZUHSODFHPHQWGRVHV
  6ZLWFKEHWZHHQGLƷHUHQWW\SHVDQGGRVHVRILQKDOHGJOXFRFRUWLFRLGV
  ,QLWLDWLRQRIDF\WRFKURPH3$LQGXFHU

Fig 4 | Glucocorticoid induced adrenal insufficiency and adrenal crisis

remission.172 The patient’s previous experience glucocorticoid taper, an individualized approach is

with glucocorticoid taper and GWS can also guide needed for each patient. As most patients are treated
the aggressiveness of taper. In the absence of with either predniso(lo)ne or dexamethasone, we
well designed studies evaluating approaches to suggest conversion to predniso(lo)ne therapy taken

the bmj | BMJ 2021;374:n1380 | doi: 10.1136/bmj.n1380 11

STATE OF THE ART REVIEW

Box 2: Recommendations to reduce the risk of glucocorticoid induced adrenal insufficiency

Systemic glucocorticoid administration (including oral)

BMJ: first published as 10.1136/bmj.n1380 on 12 July 2021. Downloaded from http://www.bmj.com/ on 11 August 2021 by guest. Protected by copyright.
• Whenever possible, use the lowest effective dose of glucocorticoids for the shortest period of time
• Whenever possible, favor once daily dosing when using intermediate and long acting glucocorticoids (eg, prednisone, prednisolone,
dexamethasone)
• Whenever possible, avoid bedtime administration of glucocorticoids*
• Do not taper down glucocorticoids if the treatment course is <2 weeks. The risk of HPAA axis suppression in such cases is low, and glucocorticoids
can be discontinued abruptly. If treatment is prolonged beyond 2 weeks, the risk of HPAA suppression increases
Inhaled glucocorticoids
• Whenever possible, use the lowest effective dose of glucocorticoids for the shortest period of time
• Use spacers and mouth rinsing to reduce systemic absorption through the gastrointestinal tract
Intra-articular glucocorticoids
• Whenever possible, reduce the number of injections and space out the administration of intra-articular glucocorticoids†
• Whenever possible, avoid simultaneous injections of multiple joints
• Use the lowest effective dose of glucocorticoids
• Favor triamcinolone hexacetonide over triamcinolone acetonide because of its higher residence time in the joint (lower risk of systemic absorption)
HPAA=hypothalamic-pituitary-adrenal axis.
*Excluding modified release formulations (eg, modified release prednisone).
†Based on very low quality evidence and personal experience, the risk of sustained glucocorticoid induced adrenal insufficiency is higher in patients receiving multiple glucocorticoid injections,
especially if over a short period of time. Patients should be considered to be at moderate to high risk of sustained glucocorticoid induced adrenal insufficiency if they receive >3 injections over
the course of a year. Nevertheless, transient adrenal suppression is observed in >50% of patients for up to 2 months after intra-articular glucocorticoid injection. Health professionals should
educate patients to report signs and symptoms of adrenal insufficiency, especially during the first 2 months after the injection.

once a day in the morning as soon as possible.
Initial rapid glucocorticoid taper of 5-10 mg weekly
increments down to 20 mg daily is usually possible
for patients taking predniso(lo)ne at >20-40 mg per
day. A much slower taper is subsequently needed
for most patients, which includes a weekly-monthly
predniso(lo)ne decrease of 1-2.5 mg to avoid severe
GWS (box 3). All patients should be extensively
counseled on the symptoms of GWS and provided
with a plan on management of severe GWS. The
management plan includes supportive measures
and a recommendation to incrementally increase
glucocorticoid to the most recent dose associated
with symptoms that were tolerable.
Glucocorticoid withdrawal syndrome
GWS is a withdrawal reaction that may occur
during the glucocorticoid taper owing to developed
dependence on supraphysiological glucocorticoid
concentrations.173 The pathophysiology of
GWS is multifactorial and is likely mediated by
suppressed corticotropin releasing hormone,
central noradrenergic and dopaminergic system,
decrease in pro-opiomelanocortin related peptides
due to chronic suppression of HPAA, and the
increase in cytokines (interleukin 6, tumor necrosis
factor α) and prostaglandins.173-175 Patients who
taper glucocorticoids often feel unwell even when
still taking doses that are supraphysiological
but lower than their usual glucocorticoid doses.
Symptoms may include anorexia, nausea, emesis,
lethargy, somnolence, arthralgia, myalgia, low
grade fever, postural hypotension, and psychiatric
symptoms (mainly depression, anxiety, and panic
attacks).173  176 GWS may last months, and patients
report poor quality of life and wellbeing.170 176 GWS
is under-recognized as a separate entity, partly
because of overlap of GWS symptoms with those of
adrenal insufficiency and possibly the underlying
disorder glucocorticoids were initially prescribed
to treat. When physicians and patients do not
recognize GWS as a separate entity, the recovery
process can be difficult and prolonged, especially if
glucocorticoid doses are increased unnecessarily. In
the published evidence so far, very little emphasis
has been placed on assessment of the severity of
GWS during glucocorticoid taper. In a retrospective
study of patients undergoing curative surgery for
endogenous hypercortisolism, GWS was reported in
67% of patients and was associated with the severity
of cortisol excess before surgery.170
Assessment of hypothalamic-pituitary-adrenal axis
The recovery of the HPAA should be assessed only
in patients taking a prednisolone equivalent dose of
no higher than 5 mg a day. HPAA recovery is likely
to occur more rapidly if the patient is switched to
hydrocortisone (short acting glucocorticoid) as
opposed to predniso(lo)ne (box 1); however, head
to head studies have not been performed. HPAA
recovery is unlikely in patients treated with long
acting glucocorticoids, such as dexamethasone. In a
patient who is undergoing glucocorticoid taper, our
approach is to assess HPAA recovery once the patient
is treated with prednisolone equivalent doses of 5 mg
for at least one to four weeks and reassess every three
months until recovery occurs. In patients with GI-AI
lasting for more than one to two years, reassessment
can be spanned out to every six to 12 months. Several
approaches to HPAA assessment can be used, all
done after 24 hours without any glucocorticoid
therapy other than dexamethasone. These most
commonly include measurement of morning cortisol
concentrations, synthetic ACTH stimulation tests,
and, less commonly, the overnight metyrapone test
and the insulin tolerance test (fig 3).

12 doi: 10.1136/bmj.n1380 | BMJ 2021;374:n1380 | the bmj

 STATE OF THE ART REVIEW

Box 3: Approach to glucocorticoid taper and management of glucocorticoid induced adrenal insufficiency
Patient education (see fig 2)

BMJ: first published as 10.1136/bmj.n1380 on 12 July 2021. Downloaded from http://www.bmj.com/ on 11 August 2021 by guest. Protected by copyright.
• Education on symptoms and management of GWS
• Education on the symptoms and management of GI-AI
Provider education (see fig 2)
• Written recommendations in patient’s medical record and letter on the management of glucocorticoid and adrenal insufficiency
Considerations for glucocorticoid taper
• Duration of glucocorticoid use and average glucocorticoid dose (see box 1 and table 1)
• Previous experience with glucocorticoid taper
• Functional status
• Risk of relapse of the underlying disorder that required glucocorticoid therapy
• Avoidance of glucocorticoid administration in the afternoon/evening
Initial rapid glucocorticoid taper
• For patients on an average daily glucocorticoid dose of:
○○PED >40 mg daily—decrease daily glucocorticoid dose by 5-10 mg weekly increments until PED 20 mg daily
○○PED 20-40 mg daily—decrease daily glucocorticoid dose by 5 mg weekly increments until PED 20 mg daily
○○PED 10-20 mg daily—proceed to the slow glucocorticoid taper recommendations
• For patients taking twice a day predniso(lo)ne, or evening doses, switch predniso(lo)ne to once a day, in the morning
• For patients taking dexamethasone, switch to predniso(lo)ne equivalent dose
Subsequent slow glucocorticoid taper
(Note that the decrement and the frequency of glucocorticoid decrease can be adapted according to the severity of the GWS.)
• For patients transitioning after the initial rapid glucocorticoid taper or patients taking PED ≤20 mg daily:
○○PED 10-20 mg daily—decrease daily glucocorticoid dose by 1-2.5 mg weekly decrements until 10 mg daily. If severe GWS, consider bi-monthly decrements
○○PED 5-10 mg daily—decrease by 1 mg weekly decrements until 5 mg daily. If severe GWS, consider bi-monthly or even monthly decrements
○○PED 5 mg daily*—do not stop or decrease glucocorticoid until HPAA recovery has been documented. Consider switching to hydrocortisone 20 mg (15 on waking,
5 mg at noon) if HPAA recovery is delayed
Assessment of HPAA recovery (see fig 3)
Timing of reassessment—should be done only after reaching PED 5 mg or a replacement dose of hydrocortisone (eg, 15 mg in the morning, 5 mg in the afternoon) for
1-4 weeks.
Frequency of reassessment—every 2-3 months. If HPAA has not recovered for 1-2 years, consider reassessment every 3-6 months.
Testing—assessment should be done in the morning, 24 hours off glucocorticoid therapy with the following tests:
• Morning serum cortisol
• Additional tests to consider (only if indeterminate morning cortisol results)
○○Synthetic ACTH stimulation test
○○Overnight metyrapone test (where available)
○○Insulin tolerance test (very rarely)
Management of patients with established GC-AI (see fig 2)
Physician
• Periodic clinical assessment for symptoms and signs of glucocorticoid over-replacement and under-replacement
• Periodic biochemical assessment of HPAA recovery
• Assure patient has optimal supplies (oral glucocorticoid, injectables)
• Patient counseling on glucocorticoid therapy, special situations (shift work, pregnancy, concomitant diabetes mellitus, excessive physical activity), sick day rules
Patient
• Chronic glucocorticoid replacement therapy:
○○Hydrocortisone (eg, 15 mg on waking, 5 mg 6-8 hours later), or
○○Predniso(lo)ne 4-5 mg on waking
○○See “Emergent treatments” section for novel preparations
• Sick day rules:
○○Sick day rule 1—double or triple daily oral glucocorticoid dose during illness that requires bed rest and/or antibiotics or is associated with high fever (>38°C)
until recovery. Double or triple the dose on the day of any minor procedure/surgery that does not require fasting (eg, procedures requiring local anesthesia and
tooth extraction)
○○Sick day rule 2†—self-inject glucocorticoid when unable to take oral glucocorticoid (eg, acute gastroenteritis), during severe illness, after major trauma, and if
the patient is confused, drowsy, or unconscious. Also, self-inject glucocorticoid in preparation for surgery and procedures requiring general anesthesia, during
prolonged fasting (eg, preparation for colonoscopy), and at the onset of adrenal crisis. Examples of recommended injectable doses in adults: hydrocortisone
50 mg every 6 hours, dexamethasone 4 mg/24 hours, methylprednisolone 40 mg/12 hours. If the patient is admitted to hospital, continuous hydrocortisone
infusion should be favored over intermittent bolus administration
• Wear medical alert bracelet/necklace
• Carry steroid card/letter outlining GC-AI management
• Become comfortable with GC-AI management
• Practice glucocorticoid injections
• Communicate with other members of the medical team with regard to GC-AI
ACTH=adrenocorticotropic hormone; HPAA=hypothalamic-pituitary-adrenal axis; GC-AI=glucocorticoid induced adrenal insufficiency; GWS=glucocorticoid withdrawal syndrome;
PED=prednisolone equivalent dose.
Further decrease of glucocorticoid dose <5 mg PED can be considered in a subset of patients to accelerate the recovery of adrenal function (ie, 4 mg, or even 3 mg, PED). By contrast, a subset of
patients may achieve recovery of adrenal function at higher PED (ie, 6-7.5 mg PED).
†All patients with GI-AI and their family members/partners should receive appropriate education and a demonstration of glucocorticoid injection.

the bmj | BMJ 2021;374:n1380 | doi: 10.1136/bmj.n1380 13

STATE OF THE ART REVIEW
In a recent study of patients recovering from
endogenous hypercortisolism, a morning cortisol
≥270 nmol/L (10 µg/dL) was associated with no
reported symptoms of GWS or instances of adrenal
crisis and thus could serve as a simple approach to
HPAA assessment.170 Another large study of patients
who had synthetic ACTH stimulation testing to
assess for GI-AI also suggested that morning cortisol
measurements can replace the dynamic testing, with
cortisol cut-offs of 221 and 347 nmol/L showing
86% and 95% sensitivity, respectively.55
Notably, accurate interpretation of cortisol
concentrations can be challenging. Morning cortisol
concentrations vary according to the individual
circadian rhythm and assays used for measurements.
In addition, total cortisol concentrations can be
elevated during pregnancy and in patients using
oral estrogens, owing to higher concentrations
of cortisol binding globulin.177 By contrast, total
cortisol concentrations can be decreased in patients
with low albumin and cortisol binding globulin, as in
cirrhosis or critical illness.178 179 In addition, cortisol
concentrations vary depending on the assays used.
For example, in a large study of patients undergoing
synthetic ACTH stimulation testing, basal cortisol that
excluded adrenal insufficiency varied between 336
and 506 nmol/L when measured by three different
immunoassays.180 These special circumstances
and assay variability need to be considered when
interpreting cortisol cut-offs (fig 3).
The insulin tolerance test is traditionally
considered the reference standard dynamic test for
secondary adrenal insufficiency but is rarely needed
for the diagnosis of GI-AI.181-183 Both high dose and
low dose ACTH stimulation testing can be used in
making the diagnosis of adrenal insufficiency.184
However, the performance of both tests is suboptimal
in secondary adrenal insufficiency, with a high rate
of false negative results (sensitivity of 64-83%).185
The overnight metyrapone stimulation test can also
be used to assess the HPAA. Metyrapone inhibits
the conversion of 11-deoxycortisol to cortisol, with
subsequent stimulation of ACTH and accumulation
of 11-deoxycortisol. The overnight metyrapone
stimulation test was reported to have a similar
performance to the insulin tolerance test and a
superior performance to the ACTH stimulation
tests.186-188 Use of the overnight metyrapone is
limited by the availability of metyrapone and
11-deoxycortisol assays.
Management of glucocorticoid induced adrenal
insufficiency
HPAA recovery in patients with GI-AI can take months
to years.20 Patients taking higher glucocorticoid
doses for a longer duration, those with a lower body
mass index, and those with features of iatrogenic
Cushing’s syndrome are likely to take longer to
recover.170 A proportion of patients may develop
chronic or permanent GI-AI. As reported in a
systematic review of GI-AI, 15% of patients may have
persistent GI-AI when reassessed three years after
14
discontinuation of supraphysiological glucocorticoid
therapy, and 2-7% of patients may never recover
adrenal function.20 189 190
BMJ: first published as 10.1136/bmj.n1380 on 12 July 2021. Downloaded from http://www.bmj.com/ on 11 August 2021 by guest. Protected by copyright.
In a recent survey study that included 179
patients with GI-AI, patients reported a median age
at diagnosis of 54 years and a median duration of
GI-AI of three years.159 One in five patients with
GI-AI reported not being aware of the diagnosis.
Notably, compared with other causes of adrenal
insufficiency, patients with GI-AI were more likely to
report difficulty with management and less likely to
have available injectable glucocorticoid at home or
to wear medical alert gear. Despite taking a higher
daily glucocorticoid dose, more patients with GI-
AI reported symptoms due to under-replacement
(fatigue, nausea). A higher number of patients with
GI-AI needed stress dose steroids. When seeking care
in the emergency setting, patients with GI-AI were
around two times less likely to receive proper care
than those with other causes of adrenal insufficiency.
Overall, 59% of patients with GI-AI reported poor
general health.159 These data reflect the fact that
patients with GI-AI are less likely to receive adequate
education on adrenal insufficiency than other
patients, possibly owing to lack of awareness and the
belief that the problem is temporary.
All patients at risk of or with established GI-AI
should receive adequate education (fig 2). Special
attention should be paid to increasing patient
awareness (including over-the-counter drugs
containing glucocorticoids and intra-articular
glucocorticoid injections), measures targeted
toward prevention of adrenal crisis, and the sick
day rules (box 3). This includes counseling on
glucocorticoid therapy, special situations that may
require adaptation of glucocorticoid therapy (box
3), use of injectable glucocorticoid therapy, and
signs and symptoms of over-replacement and under-
replacement, including those of adrenal crisis (table
2). Patients with GI-AI should receive adequate
education regardless of the projected duration of
adrenal insufficiency.
Chronic glucocorticoid therapy most commonly
consists of either twice daily hydrocortisone or
predniso(lo)ne once in the morning. In the absence
of a reliable biomarker, periodic clinical assessment
will ensure that the dose is individualized to the
patient’s needs. Guidelines suggest twice or thrice
daily hydrocortisone as a valid replacement scheme
in patients with adrenal insufficiency to mimic the
physiological cortisol rhythm.191 This is also an
appropriate option for GI-AI and should especially be
considered when patients complain of glucocorticoid
withdrawal symptoms; however, we postulate that
avoiding late afternoon exposure to hydrocortisone
by twice daily administration might accelerate the
recovery of ACTH secretion by negative feedback.
In adult patients with adrenal crisis in a hospital
setting, hydrocortisone 100 mg bolus injection
followed by the intravenous infusion of 100 mg
hydrocortisone per 24 hours is the preferable
mode of treatment.192 Children with adrenal crisis
doi: 10.1136/bmj.n1380 | BMJ 2021;374:n1380 | the bmj

should be treated with a lower hydrocortisone dose
depending on their weight, usually 25-50 mg bolus
injection followed by infusion of hydrocortisone 50-
100 mg per 24 hours. When clinical improvement
is seen, hydrocortisone should be converted to oral
administration at an increased dose (usually double
the usual daily dose) and gradually tapered to the
usual regimen.191 193-195
Emerging treatments
The HPAA and the peripheral sensitivity to
glucocorticoids follow a circadian rhythm, which
can affect the negative feedback response.196 197
Novel modified release glucocorticoids have been
designed as either immunosuppressive therapy to
mirror the morning cortisol rise and improve clinical
outcomes (for example, modified release prednisone
in patients with rheumatoid arthritis) or replacement
therapy to reproduce the circadian cortisol rhythm in
patients with established adrenal insufficiency (for
example, modified release hydrocortisone).197 198
Potentially these modified release formulations could
reduce the risk of adrenal insufficiency and promote
recovery of adrenal function in patients exposed to
glucocorticoids, but further research in this area is
needed. No interventional trials in patients with GI-
AI are ongoing.
Guidelines
Clear guidance exists about the prevention and
emergency management of patients with confirmed
or suspected adrenal insufficiency, including patient
education, sick day rules, and management of adrenal
crisis.21 194 To the best of our knowledge, however,
guidelines specifically focusing on GI-AI are lacking.
Considering the widespread use of glucocorticoids in
different doses and formulations for a vast number of
conditions across multiple specialties, the fact that
the recommendations of several medical societies do
not fully cover or differ in terms of who is at risk of GI-
AI, when glucocorticoid therapy can be discontinued,
and how to do so comes as no surprise.191 194
Although the decision to stop glucocorticoids is
clearly linked to the underlying disease, the lack of
a multidisciplinary consensus on the stratification
of patients according to their risk of developing GI-
AI and the management of glucocorticoid taper and
GI-AI is likely associated with suboptimal outcomes.
Conclusion
Patients exposed to exogenous glucocorticoids
are at risk of developing GI-AI, which needs to be
promptly recognized, anticipated, and optimally
managed. Patients treated with high doses of
glucocorticoids for a longer duration may develop
severe GWS when the treatment is tapered down.
Individualized glucocorticoid taper can help with
symptoms of glucocorticoid withdrawal and a
quicker eventual recovery of adrenal function. Every
patient with GI-AI should receive optimal education
on management of adrenal insufficiency, including
management of glucocorticoid therapy during an
the bmj | BMJ 2021;374:n1380 | doi: 10.1136/bmj.n1380
STATE OF THE ART REVIEW
illness. Guidelines need to be developed to cover
gaps in the management of patients treated with
chronic glucocorticoids to raise awareness of GI-AI
BMJ: first published as 10.1136/bmj.n1380 on 12 July 2021. Downloaded from http://www.bmj.com/ on 11 August 2021 by guest. Protected by copyright.
and GWS and provide clear recommendations that
can be applied in the interdisciplinary setting.
RESEARCH QUESTIONS
• What are the best predictors of glucocorticoid
induced adrenal insufficiency and its duration?
• What is the best approach to glucocorticoid taper to
alleviate glucocorticoid withdrawal syndrome while
achieving the quickest recovery of adrenal function?
• What is the best approach to assessing the
hypothalamic-pituitary-adrenal axis?
• What strategies can be developed to increase
awareness of glucocorticoid induced adrenal
insufficiency among patients and health
professionals?
We thank Wiebke Arlt and William Young for their critical review and
useful suggestions on tables and figures.
Contributors: IB and AP conceptualized and performed the literature
review for this manuscript. AP and IB drafted the manuscript. IB and
AP contributed to the critical revision of the article. AP and IB gave
final approval of the version to be published. IB is the guarantor.
Funding: AP is a Diabetes UK Sir George Alberti research training
fellow (grant reference number 18/0005782). This research was
supported by the Catalyst Award for Advancing in Academics from the
Mayo Clinic (to IB) and the National Institute of Diabetes and Digestive
and Kidney Diseases of the NIH under award K23DK121888 (to IB).
The views expressed are those of the authors and not necessarily
those of the NIH. The funders of the study had no role in the
conceptualization, writing, and decision to publish the manuscript. All
researchers were independent from funders.
Competing interests: We have read and understood the BMJ policy
on declaration of interests and declare the following interests: IB is a
consultant to CinCor, Corcept, Sparrow Pharmaceutics, Strongbridge,
and HRA Pharma, outside this work. IB has received research support
from HRA Pharma for an investigator initiated study outside this work.
Patient and public involvement: Patients or the public were not
involved in the design, conduct, reporting, or dissemination plans for
this work.
Provenance and peer review: Commissioned; externally peer
reviewed.
1  Charmandari E, Nicolaides NC, Chrousos GP. Adrenal
insufficiency. Lancet 2014;383:2152-67. doi:10.1016/S0140-
6736(13)61684-0 
2  Mebrahtu TF, Morgan AW, Keeley A, Baxter PD, Stewart PM, Pujades-
Rodriguez M. Dose dependency of iatrogenic glucocorticoid excess
and adrenal insufficiency and mortality: a cohort study in England. J
Clin Endocrinol Metab 2019;104:3757-67. doi:10.1210/jc.2019-
00153 
3  van Staa TP, Leufkens HG, Abenhaim L, Begaud B, Zhang B,
Cooper C. Use of oral corticosteroids in the United Kingdom.
QJM 2000;93:105-11. doi:10.1093/qjmed/93.2.105 
4  Laugesen K, Jørgensen JOL, Sørensen HT, Petersen I. Systemic
glucocorticoid use in Denmark: a population-based prevalence study.
BMJ Open 2017;7:e015237. doi:10.1136/bmjopen-2016-015237 
5  Overman RA, Yeh JY, Deal CL. Prevalence of oral glucocorticoid usage
in the United States: a general population perspective. Arthritis Care
Res (Hoboken) 2013;65:294-8. doi:10.1002/acr.21796 
6  Laugesen K, Jørgensen JOL, Petersen I, Sørensen HT. Fifteen-year
nationwide trends in systemic glucocorticoid drug use in Denmark.
Eur J Endocrinol 2019;181:267-73. doi:10.1530/EJE-19-0305 
7  Fardet L, Petersen I, Nazareth I. Prevalence of long-term oral
glucocorticoid prescriptions in the UK over the past 20 years.
Rheumatology (Oxford) 2011;50:1982-90. doi:10.1093/
rheumatology/ker017 
8  Walsh LJ, Wong CA, Pringle M, Tattersfield AE. Use of oral
corticosteroids in the community and the prevention of secondary
osteoporosis: a cross sectional study. BMJ 1996;313:344-6.
doi:10.1136/bmj.313.7053.344 
15
STATE OF THE ART REVIEW

9  Gudbjornsson B, Juliusson UI, Gudjonsson FV. Prevalence of long 32  Schlaghecke R, Kornely E, Santen RT, Ridderskamp P. The
term steroid treatment and the frequency of decision making to effect of long-term glucocorticoid therapy on pituitary-adrenal
prevent steroid induced osteoporosis in daily clinical practice. Ann responses to exogenous corticotropin-releasing hormone. N Engl J

BMJ: first published as 10.1136/bmj.n1380 on 12 July 2021. Downloaded from http://www.bmj.com/ on 11 August 2021 by guest. Protected by copyright.
Rheum Dis 2002;61:32-6. doi:10.1136/ard.61.1.32  Med 1992;326:226-30. doi:10.1056/NEJM199201233260403 
10  Bénard-Laribière A, Pariente A, Pambrun E, Bégaud B, Fardet L, Noize 33  LaRochelle GEJr, LaRochelle AG, Ratner RE, Borenstein DG. Recovery
P. Prevalence and prescription patterns of oral glucocorticoids in of the hypothalamic-pituitary-adrenal (HPA) axis in patients
adults: a retrospective cross-sectional and cohort analysis in France. with rheumatic diseases receiving low-dose prednisone. Am J
BMJ Open 2017;7:e015905. doi:10.1136/bmjopen-2017-015905  Med 1993;95:258-64. doi:10.1016/0002-9343(93)90277-V 
11  Broersen LH, Pereira AM, Jørgensen JO, Dekkers OM. Adrenal 34  Karangizi AHK, Al-Shaghana M, Logan S, et al. Glucocorticoid induced
Insufficiency in Corticosteroids Use: Systematic Review and Meta- adrenal insufficiency is common in steroid treated glomerular
Analysis. J Clin Endocrinol Metab 2015;100:2171-80. doi:10.1210/ diseases - proposed strategy for screening and management. BMC
jc.2015-1218  Nephrol 2019;20:154. doi:10.1186/s12882-019-1354-6 
12  Bloom CI, Saglani S, Feary J, Jarvis D, Quint JK. Changing 35  Borresen SW, Thorgrimsen TB, Jensen B, et al. Adrenal insufficiency
prevalence of current asthma and inhaled corticosteroid treatment in prednisolone-treated patients with polymyalgia rheumatica or
in the UK: population-based cohort 2006-2016. Eur Respir giant cell arteritis-prevalence and clinical approach. Rheumatology
J 2019;53:1802130. doi:10.1183/13993003.02130-2018  (Oxford) 2020;59:2764-73. doi:10.1093/rheumatology/keaa011 
13  van Staa TP, Cooper C, Leufkens HG, Lammers JW, Suissa S. The use of 36  Borresen SW, Klose M, Baslund B, et al. Adrenal insufficiency is
inhaled corticosteroids in the United Kingdom and the Netherlands. seen in more than one-third of patients during ongoing low-
Respir Med 2003;97:578-85. doi:10.1053/rmed.2002.1453  dose prednisolone treatment for rheumatoid arthritis. Eur J
14  Dinsen S, Baslund B, Klose M, et al. Why glucocorticoid withdrawal Endocrinol 2017;177:287-95. doi:10.1530/EJE-17-0251 
may sometimes be as dangerous as the treatment itself. Eur J Intern 37  Lević Z, Micić D, Nikolić J, et al. Short-term high dose steroid therapy
Med 2013;24:714-20. doi:10.1016/j.ejim.2013.05.014  does not affect the hypothalamic-pituitary-adrenal axis in relapsing
15  Kannisto S, Korppi M, Remes K, Voutilainen R. Serum multiple sclerosis patients. Clinical assessment by the insulin
dehydroepiandrosterone sulfate concentration as an indicator of tolerance test. J Endocrinol Invest 1996;19:30-4. doi:10.1007/
adrenocortical suppression in asthmatic children treated with inhaled BF03347855 
steroids. J Clin Endocrinol Metab 2001;86:4908-12. doi:10.1210/ 38  Aljebab F, Choonara I, Conroy S. Systematic review of the
jcem.86.10.7975  toxicity of short-course oral corticosteroids in children. Arch Dis
16  Uei Y, Kanzaki M, Ohta T. Immunohistochemical study of crooke’s Child 2016;101:365-70. doi:10.1136/archdischild-2015-309522 
hyaline change. Endocr Pathol 1991;2:12-5. doi:10.1007/ 39  Spiegel RJ, Vigersky RA, Oliff AI, Echelberger CK, Bruton J, Poplack
BF02915321  DG. Adrenal suppression after short-term corticosteroid therapy.
17  Raff H, Sharma ST, Nieman LK. Physiological basis for the etiology, Lancet 1979;1:630-3. doi:10.1016/S0140-6736(79)91077-8 
diagnosis, and treatment of adrenal disorders: Cushing’s syndrome, 40  Carella MJ, Srivastava LS, Gossain VV, Rovner DR. Hypothalamic-
adrenal insufficiency, and congenital adrenal hyperplasia. Compr pituitary-adrenal function one week after a short burst of steroid
Physiol 2014;4:739-69. doi:10.1002/cphy.c130035  therapy. J Clin Endocrinol Metab 1993;76:1188-91.
18  Brigell DF, Fang VS, Rosenfield RL. Recovery of responses to ovine 41  Schuetz P, Christ-Crain M, Schild U, et al. Effect of a 14-day course of
corticotropin-releasing hormone after withdrawal of a short course of systemic corticosteroids on the hypothalamic-pituitary-adrenal-axis
glucocorticoid. J Clin Endocrinol Metab 1992;74:1036-9. in patients with acute exacerbation of chronic obstructive pulmonary
19  Graber AL, Ney RL, Nicholson WE, Island DP, Liddle GW. disease. BMC Pulm Med 2008;8:1. doi:10.1186/1471-2466-8-1 
Natural History of Pituitary-Adrenal Recovery Following Long- 42  Streck WF, Lockwood DH. Pituitary adrenal recovery following short-
Term Suppression with Corticosteroids. J Clin Endocrinol term suppression with corticosteroids. Am J Med 1979;66:910-4.
Metab 1965;25:11-6. doi:10.1210/jcem-25-1-11  doi:10.1016/0002-9343(79)90444-3 
20  Joseph RM, Hunter AL, Ray DW, Dixon WG. Systemic glucocorticoid 43  Fleishaker DL, Mukherjee A, Whaley FS, Daniel S, Zeiher BG.
therapy and adrenal insufficiency in adults: A systematic review. Safety and pharmacodynamic dose response of short-term
Semin Arthritis Rheum 2016;46:133-41. doi:10.1016/j. prednisone in healthy adult subjects: a dose ranging, randomized,
semarthrit.2016.03.001  placebo-controlled, crossover study. BMC Musculoskelet
21  Simpson H, Tomlinson J, Wass J, Dean J, Arlt W. Guidance for the Disord 2016;17:293. doi:10.1186/s12891-016-1135-3 
prevention and emergency management of adult patients with 44  Neidert S, Schuetz P, Mueller B, Christ-Crain M. Dexamethasone
adrenal insufficiency. Clin Med (Lond) 2020;20:371-8. doi:10.7861/ suppression test predicts later development of an impaired adrenal
clinmed.2019-0324  function after a 14-day course of prednisone in healthy volunteers.
22  Paragliola RM, Papi G, Pontecorvi A, Corsello SM. Treatment with Eur J Endocrinol 2010;162:943-9. doi:10.1530/EJE-09-0930 
Synthetic Glucocorticoids and the Hypothalamus-Pituitary-Adrenal 45  Schuetz P, Leuppi JD, Bingisser R, et al. Prospective analysis of
Axis. Int J Mol Sci 2017;18:2201. doi:10.3390/ijms18102201  adrenal function in patients with acute exacerbations of COPD:
23  Jasani MK, Boyle JA, Greig WR, et al. Corticosteroid-induced the Reduction in the Use of Corticosteroids in Exacerbated COPD
suppression of the hypothalamo-pituitary-adrenal axis: observations (REDUCE) trial. Eur J Endocrinol 2015;173:19-27. doi:10.1530/EJE-
on patients given oral corticosteroids for rheumatoid arthritis. Q J 15-0182 
Med 1967;36:261-76. 46  Leuppi JD, Schuetz P, Bingisser R, et al. Short-term vs conventional
24  Nichols T, Nugent CA, Tyler FH. Diurnal Variation in Suppression glucocorticoid therapy in acute exacerbations of chronic obstructive
of Adrenal Function by Glucocorticoids. J Clin Endocrinol pulmonary disease: the REDUCE randomized clinical trial.
Metab 1965;25:343-9. doi:10.1210/jcem-25-3-343  JAMA 2013;309:2223-31. doi:10.1001/jama.2013.5023 
25  Grant SD, Forsham PH, DiRaimondo VC. Suppression of 47  Han HS, Park JC, Park SY, et al. A Prospective Multicenter
17-hydroxycorticosteroids in plasma and urine by single and Study Evaluating Secondary Adrenal Suppression After
divided doses of triamcinolone. N Engl J Med 1965;273:1115-8. Antiemetic Dexamethasone Therapy in Cancer Patients
doi:10.1056/NEJM196511182732101  Receiving Chemotherapy: A Korean South West Oncology
26  Ackerman GL, Nolsn CM. Adrenocortical responsiveness after Group Study. Oncologist 2015;20:1432-9. doi:10.1634/
alternate-day corticosteroid therapy. N Engl J Med 1968;278:405-9. theoncologist.2015-0211 
doi:10.1056/NEJM196802222780801  48  Han HS, Shim YK, Kim JE, et al. A pilot study of adrenal suppression
27  Sturge RA, Beardwell C, Hartog M, Wright D, Ansell BM. Cortisol and after dexamethasone therapy as an antiemetic in cancer patients.
growth hormone secretion in relation to linear growth: patients Support Care Cancer 2012;20:1565-72. doi:10.1007/s00520-011-
with Still’s disease on different therapeutic regimens. Br Med 1248-z 
J 1970;3:547-51. doi:10.1136/bmj.3.5722.547  49  Abu Bakar K, Khalil K, Lim YN, et al. Adrenal Insufficiency in Children
28  Carter ME, James VH. Effect of alternate-day, single-dose, With Nephrotic Syndrome on Corticosteroid Treatment. Front
corticosteroid therapy on pituitary-adrenal function. Ann Rheum Pediatr 2020;8:164. doi:10.3389/fped.2020.00164 
Dis 1972;31:379-83. doi:10.1136/ard.31.5.379  50  Wildi-Runge S, Deladoëy J, Bélanger C, et al. A search for
29  Jespersen S, Nygaard B, Kristensen LO. Methylprednisolone Pulse variables predicting cortisol response to low-dose corticotropin
Treatment of Graves’ Ophthalmopathy Is Not Associated with stimulation following supraphysiological doses of glucocorticoids. J
Secondary Adrenocortical Insufficiency. Eur Thyroid J 2015;4:222-5. Pediatr 2013;163:484-8. doi:10.1016/j.jpeds.2013.01.011 
doi:10.1159/000440834  51  Rensen N, Gemke RJ, van Dalen EC, Rotteveel J, Kaspers
30  Giotaki Z, Fountas A, Tsirouki T, Bargiota A, Tigas S, Tsatsoulis A. GJ. Hypothalamic-pituitary-adrenal (HPA) axis suppression
Adrenal reserve following treatment of Graves’ orbitopathy with after treatment with glucocorticoid therapy for childhood
intravenous glucocorticoids. Thyroid 2015;25:462-3. doi:10.1089/ acute lymphoblastic leukaemia. Cochrane Database Syst
thy.2014.0533  Rev 2017;11:CD008727. doi:10.1002/14651858.CD008727.pub4 
31  Henzen C, Suter A, Lerch E, Urbinelli R, Schorno XH, Briner VA. 52  Ahmet A, Kim H, Spier S. Adrenal suppression: A practical guide
Suppression and recovery of adrenal response after short-term, to the screening and management of this under-recognized
high-dose glucocorticoid treatment. Lancet 2000;355:542-5. complication of inhaled corticosteroid therapy. Allergy Asthma Clin
doi:10.1016/S0140-6736(99)06290-X  Immunol 2011;7:13. doi:10.1186/1710-1492-7-13 

16 doi: 10.1136/bmj.n1380 | BMJ 2021;374:n1380 | the bmj

 STATE OF THE ART REVIEW

53  National Institute for Health and Care Excellence. Inhaled 75  Cavkaytar O, Vuralli D, Arik Yilmaz E, et al. Evidence of hypothalamic-
corticosteroid doses for NICE’s asthma guideline. 2018 https://www. pituitary-adrenal axis suppression during moderate-to-high-dose
nice.org.uk/guidance/ng80/resources/inhaled-corticosteroid-doses- inhaled corticosteroid use. Eur J Pediatr 2015;174:1421-31.

BMJ: first published as 10.1136/bmj.n1380 on 12 July 2021. Downloaded from http://www.bmj.com/ on 11 August 2021 by guest. Protected by copyright.
pdf-4731528781. doi:10.1007/s00431-015-2610-9 
54  London Respiratory Network. Guidance for healthcare professionals 76  Leung JS, Johnson DW, Sperou AJ. A systematic review of adverse
on inhaled corticosteroids in adults. https://www.networks.nhs.uk/ drug events associated with administration of common asthma
nhs-networks/london-lungs/documents/inhaled-corticosteroids-in- medications in children. PLoS One 2017;12:e0182738.
adults. doi:10.1371/journal.pone.0182738 
55  Woods CP, Argese N, Chapman M, et al. Adrenal suppression 77  Lipworth BJ, et al. Systemic adverse effects of inhaled corticosteroid
in patients taking inhaled glucocorticoids is highly prevalent therapy: A systematic review and meta-analysis. Arch Intern
and management can be guided by morning cortisol. Eur J Med 1999;159:941-55. doi:10.1001/archinte.159.9.941 
Endocrinol 2015;173:633-42. doi:10.1530/EJE-15-0608  78  Sorkness CA, LaForce C, Storms W, Lincourt WR, Edwards L, Rogenes
56  Mortimer KJ, Tata LJ, Smith CJ, et al. Oral and inhaled corticosteroids PR. Effects of the inhaled corticosteroids fluticasone propionate,
and adrenal insufficiency: a case-control study. Thorax 2006;61:405- triamcinolone acetonide, and flunisolide and oral prednisone on the
8. doi:10.1136/thx.2005.052456  hypothalamic-pituitary-adrenal axis in adult patients with asthma.
57  Kapadia CR, Nebesio TD, Myers SE, et al, Drugs and Therapeutics Clin Ther 1999;21:353-67. doi:10.1016/S0149-2918(00)88292-2 
Committee of the Pediatric Endocrine Society. Endocrine Effects of 79  Wasserman SI, Gross GN, Schoenwetter WF, et al. A 12-
Inhaled Corticosteroids in Children. JAMA Pediatr 2016;170:163-70. week dose-ranging study of fluticasone propionate powder
doi:10.1001/jamapediatrics.2015.3526  in the treatment of asthma. J Asthma 1996;33:265-74.
58  Zöllner EW, Lombard C, Galal U, Hough S, Irusen E, Weinberg E. doi:10.3109/02770909609055367 
Hypothalamic-pituitary-adrenal axis suppression in asthmatic 80  Masoli M, Weatherall M, Holt S, Shirtcliffe P, Beasley R. Inhaled
children on inhaled and nasal corticosteroids--more common fluticasone propionate and adrenal effects in adult asthma:
than expected?J Pediatr Endocrinol Metab 2011;24:529-34. systematic review and meta-analysis. Eur Respir J 2006;28:960-7. do
doi:10.1515/jpem.2011.198  i:10.1183/09031936.06.00119305 
59  Lapi F, Kezouh A, Suissa S, Ernst P. The use of inhaled corticosteroids 81  Choi IS, Sim DW, Kim SH, Wui JW. Adrenal insufficiency associated
and the risk of adrenal insufficiency. Eur Respir J 2013;42:79-86. with long-term use of inhaled steroid in asthma. Ann Allergy Asthma
doi:10.1183/09031936.00080912  Immunol 2017;118:66-72.e1. doi:10.1016/j.anai.2016.10.002 
60  Zöllner EW, Lombard CJ, Galal U, Hough FS, Irusen EM, Weinberg E. 82  Kwda A, Gldc P, Baui B, et al. Effect of long term inhaled corticosteroid
Hypothalamic-pituitary-adrenal axis suppression in asthmatic school therapy on adrenal suppression, growth and bone health in children
children. Pediatrics 2012;130:e1512-9. doi:10.1542/peds.2012- with asthma. BMC Pediatr 2019;19:411. doi:10.1186/s12887-019-
1147  1760-8 
61  Paton J, Jardine E, McNeill E, et al. Adrenal responses to low dose 83  Préville-Ratelle S, Coriati A, Ménard A, Bourdeau I, Tremblay
synthetic ACTH (Synacthen) in children receiving high dose inhaled F, Berthiaume Y. Adrenal Insufficiency in Cystic Fibrosis: A
fluticasone. Arch Dis Child 2006;91:808-13. doi:10.1136/ Rare Phenomenon?Can Respir J 2018;2018:3629031.
adc.2005.087247  doi:10.1155/2018/3629031 
62  Molimard M, Girodet PO, Pollet C, et al. Inhaled corticosteroids and 84  Guaraldi F, Gori D, Calderoni P, et al. Comparative assessment of
adrenal insufficiency: prevalence and clinical presentation. Drug hypothalamic-pituitary-adrenal axis suppression secondary to
Saf 2008;31:769-74. doi:10.2165/00002018-200831090-00005  intrabursal injection of different glucocorticoids: a pilot study. J
63  Boorsma M, Andersson N, Larsson P, Ullman A. Assessment of the Endocrinol Invest 2019;42:1117-24. doi:10.1007/s40618-019-
relative systemic potency of inhaled fluticasone and budesonide. Eur 01033-6 
Respir J 1996;9:1427-32. doi:10.1183/09031936.96.09071427  85  Lansang MC, Farmer T, Kennedy L. Diagnosing the unrecognized
64  Clark DJ, Lipworth BJ. Adrenal suppression with chronic dosing of systemic absorption of intra-articular and epidural steroid injections.
fluticasone propionate compared with budesonide in adult asthmatic Endocr Pract 2009;15:225-8. doi:10.4158/EP.15.3.225 
patients. Thorax 1997;52:55-8. doi:10.1136/thx.52.1.55  86  Johnston PC, Lansang MC, Chatterjee S, Kennedy L. Intra-articular
65  Allen A, Bareille PJ, Rousell VM. Fluticasone furoate, a novel glucocorticoid injections and their effect on hypothalamic-
inhaled corticosteroid, demonstrates prolonged lung absorption pituitary-adrenal (HPA)-axis function. Endocrine 2015;48:410-6.
kinetics in man compared with inhaled fluticasone propionate. Clin doi:10.1007/s12020-014-0409-5 
Pharmacokinet 2013;52:37-42. doi:10.1007/s40262-012-0021-x  87  Gondwe JS, Davidson JE, Deeley S, Sills J, Cleary AG. Secondary
66  Salter M, Biggadike K, Matthews JL, et al. Pharmacological properties Cushing’s syndrome in children with juvenile idiopathic arthritis
of the enhanced-affinity glucocorticoid fluticasone furoate in vitro following intra-articular triamcinolone acetonide administration.
and in an in vivo model of respiratory inflammatory disease. Am Rheumatology (Oxford) 2005;44:1457-8. doi:10.1093/
J Physiol Lung Cell Mol Physiol 2007;293:L660-7. doi:10.1152/ rheumatology/kei154 
ajplung.00108.2007  88  Reid DM, Eastmond C, Rennie JA. Hypothalamic-pituitary-adrenal
67  Allen A, Schenkenberger I, Trivedi R, et al. Inhaled fluticasone furoate/ axis suppression after repeated intra-articular steroid injections. Ann
vilanterol does not affect hypothalamic-pituitary-adrenal axis function Rheum Dis 1986;45:87. doi:10.1136/ard.45.1.87 
in adolescent and adult asthma: randomised, double-blind, placebo- 89  Mader R, Lavi I, Luboshitzky R. Evaluation of the pituitary-
controlled study. Clin Respir J 2013;7:397-406. doi:10.1111/ adrenal axis function following single intraarticular injection of
crj.12026  methylprednisolone. Arthritis Rheum 2005;52:924-8. doi:10.1002/
68  Bareille P, Tomkins S, Imber V, et al. A randomized, double-blind, art.20884 
placebo-controlled, parallel-group study of once-daily inhaled 90  Hyle EP, Wood BR, Backman ES, et al. High frequency of
fluticasone furoate on the hypothalamic-pituitary-adrenocortical axis hypothalamic-pituitary-adrenal axis dysfunction after local
of children with asthma. Allergy Asthma Clin Immunol 2020;16:11. corticosteroid injection in HIV-infected patients on protease inhibitor
doi:10.1186/s13223-020-0406-6  therapy. J Acquir Immune Defic Syndr 2013;63:602-8. doi:10.1097/
69  Allen A, Bal J, Cheesbrough A, Hamilton M, Kempsford R. QAI.0b013e31829b662b 
Pharmacokinetics and pharmacodynamics of intravenous and 91  Habib G, Jabbour A, Artul S, Hakim G. Intra-articular
inhaled fluticasone furoate in healthy Caucasian and East Asian methylprednisolone acetate injection at the knee joint and the
subjects. Br J Clin Pharmacol 2014;77:808-20. doi:10.1111/ hypothalamic-pituitary-adrenal axis: a randomized controlled study.
bcp.12263  Clin Rheumatol 2014;33:99-103. doi:10.1007/s10067-013-
70  Christie P. Ciclesonide: a novel inhaled corticosteroid for 2374-4 
asthma. Drugs Today (Barc) 2004;40:569-76. doi:10.1358/ 92  Habib G, Artul S, Chernin M, Hakim G, Jabbour A. The effect of intra-
dot.2004.40.7.850475  articular injection of betamethasone acetate/betamethasone sodium
71  Rohatagi S, Arya V, Zech K, et al. Population pharmacokinetics and phosphate at the knee joint on the hypothalamic-pituitary-adrenal
pharmacodynamics of ciclesonide. J Clin Pharmacol 2003;43:365- axis: a case-controlled study. J Investig Med 2013;61:1104-7.
78. doi:10.1177/0091270002250998  doi:10.2310/JIM.0b013e3182a67871 
72  Xu J, Nave R, Lahu G, Derom E, Derendorf H. Population 93  Habib G, Khazin F, Jabbour A, et al. Simultaneous bilateral knee
pharmacokinetics and pharmacodynamics of inhaled ciclesonide injection of methylprednisolone acetate and the hypothalamic-
and fluticasone propionate in patients with persistent asthma. J Clin pituitary adrenal axis: a single-blind case-control study. J Investig
Pharmacol 2010;50:1118-27. doi:10.1177/0091270009354994  Med 2014;62:621-6. doi:10.2310/JIM.0000000000000048 
73  El Baou C, Di Santostefano RL, Alfonso-Cristancho R, et al. Effect of 94  Iranmanesh A, Gullapalli D, Singh R, Veldhuis JD. Hypothalamo-
inhaled corticosteroid particle size on asthma efficacy and safety pituitary-adrenal axis after a single epidural triamcinolone injection.
outcomes: a systematic literature review and meta-analysis. BMC Endocrine 2017;57:308-13. doi:10.1007/s12020-017-1357-7 
Pulm Med 2017;17:31. doi:10.1186/s12890-016-0348-4  95  Kay J, Findling JW, Raff H. Epidural triamcinolone suppresses
74  Heller MK, Laks J, Kovesi TA, Ahmet A. Reversal of adrenal the pituitary-adrenal axis in human subjects. Anesth
suppression with ciclesonide. J Asthma 2010;47:337-9. Analg 1994;79:501-5. doi:10.1213/00000539-199409000-
doi:10.3109/02770900903509081  00017 

the bmj | BMJ 2021;374:n1380 | doi: 10.1136/bmj.n1380 17

STATE OF THE ART REVIEW

96  Jacobs S, Pullan PT, Potter JM, Shenfield GM. Adrenal suppression 119  Cottrell ML, Hadzic T, Kashuba AD. Clinical pharmacokinetic,
following extradural steroids. Anaesthesia 1983;38:953-6. pharmacodynamic and drug-interaction profile of the integrase
doi:10.1111/j.1365-2044.1983.tb12025.x  inhibitor dolutegravir. Clin Pharmacokinet 2013;52:981-94.

BMJ: first published as 10.1136/bmj.n1380 on 12 July 2021. Downloaded from http://www.bmj.com/ on 11 August 2021 by guest. Protected by copyright.
97  Habib G, Jabbour A, Salman J, Hakim G, Haddad H. The effect of doi:10.1007/s40262-013-0093-2 
epidural methylprednisolone acetate injection on the hypothalamic- 120  Dort K, Padia S, Wispelwey B, Moore CC. Adrenal suppression due to
pituitary-adrenal axis. J Clin Anesth 2013;25:629-33. doi:10.1016/j. an interaction between ritonavir and injected triamcinolone: a case
jclinane.2013.07.002  report. AIDS Res Ther 2009;6:10. doi:10.1186/1742-6405-6-10 
98  Perry RJ, Findlay CA, Donaldson MD. Cushing’s syndrome, growth 121  Yombi JC, Maiter D, Belkhir L, Nzeusseu A, Vandercam B. Iatrogenic
impairment, and occult adrenal suppression associated with intranasal Cushing’s syndrome and secondary adrenal insufficiency after a
steroids. Arch Dis Child 2002;87:45-8. doi:10.1136/adc.87.1.45  single intra-articular administration of triamcinolone acetonide
99  Finken MJ, Mul D. Cushing’s syndrome and adrenal insufficiency in HIV-infected patients treated with ritonavir. Clin Rheumatol
after intradermal triamcinolone acetonide for keloid scars. Eur J 2008;27(Suppl 2):S79-82. doi:10.1007/s10067-008-1022-x 
Pediatr 2010;169:1147-9. doi:10.1007/s00431-010-1165-z  122  Foisy MM, Yakiwchuk EM, Chiu I, Singh AE. Adrenal suppression and
100  Sukhumthammarat W, Putthapiban P, Sriphrapradang C. Local Cushing’s syndrome secondary to an interaction between ritonavir
Injection of Triamcinolone Acetonide: A Forgotten Aetiology and fluticasone: a review of the literature. HIV Med 2008;9:389-96.
of Cushing’s Syndrome. J Clin Diagn Res 2017;11:OR01-02. doi:10.1111/j.1468-1293.2008.00579.x 
doi:10.7860/JCDR/2017/27238.10091  123  De Wachter E, Vanbesien J, De Schutter I, Malfroot A, De Schepper J.
101  Hengge UR, Ruzicka T, Schwartz RA, Cork MJ. Adverse effects of Rapidly developing Cushing syndrome in a 4-year-old patient during
topical glucocorticosteroids. J Am Acad Dermatol 2006;54:1-15, quiz combined treatment with itraconazole and inhaled budesonide. Eur J
16-8. doi:10.1016/j.jaad.2005.01.010  Pediatr 2003;162:488-9. doi:10.1007/s00431-003-1233-8 
102  Borresen SW, Klose M, Rasmussen AK, Feldt-Rasmussen U. Adrenal 124  Saberi P, Phengrasamy T, Nguyen DP. Inhaled corticosteroid use
Insufficiency Caused by Locally Applied Glucocorticoids-Myth or in HIV-positive individuals taking protease inhibitors: a review of
Fact?Curr Med Chem 2015;22:2801-9. doi:10.2174/0929867322 pharmacokinetics, case reports and clinical management. HIV
666150716113003  Med 2013;14:519-29. doi:10.1111/hiv.12039 
103  Raveendran AV. Inhalational Steroids and Iatrogenic Cushing’s 125  Boyd SD, Hadigan C, McManus M, et al. Influence of low-dose
Syndrome. Open Respir Med J 2014;8:74-84. doi:10.2174/187430 ritonavir with and without darunavir on the pharmacokinetics and
6401408010074  pharmacodynamics of inhaled beclomethasone. J Acquir Immune Defic
104  Bachert C, Lukat KF, Lange B. Effect of intranasal fluticasone Syndr 2013;63:355-61. doi:10.1097/QAI.0b013e31829260d6 
propionate and triamcinolone acetonide on basal and dynamic 126  van den Berg SAA, van ’t Veer NE, Emmen JMA, van Beek RHT.
measures of hypothalamic-pituitary-adrenal-axis activity in healthy Fluticasone furoate induced iatrogenic Cushing syndrome in a
volunteers. Clin Exp Allergy 2004;34:85-90. doi:10.1111/j.1365- pediatric patient receiving anti-retroviral therapy. Endocrinol Diabetes
2222.2004.01843.x  Metab Case Rep 2017;2017:16-0158. doi:10.1530/EDM-16-0158 
105  Carruthers JA, August PJ, Staughton RC. Observations on the 127  Drummond MB, Kirk GD. HIV-associated obstructive lung
systemic effect of topical clobetasol propionate (Dermovate). Br Med diseases: insights and implications for the clinician. Lancet Respir
J 1975;4:203-4. doi:10.1136/bmj.4.5990.203  Med 2014;2:583-92. doi:10.1016/S2213-2600(14)70017-7 
106  Lee DA, Taylor GM, James VH, Walker G. Plasma prednisolone 128  Vulto A, Minović I, de Vries LV, et al. Endogenous urinary
levels and adrenocortical responsiveness after administration glucocorticoid metabolites and mortality in prednisolone-treated
of prednisolone-21-phosphate as a retention enema. renal transplant recipients. Clin Transplant 2020;34:e13824.
Gut 1979;20:349-55. doi:10.1136/gut.20.5.349  doi:10.1111/ctr.13824 
107  Luman W, Gray RS, Pendek R, Palmer KR. Prednisolone 129  de Ruiter RD, Gordijn MS, Gemke RJ, et al. Adrenal insufficiency
metasulphobenzoate foam retention enemas suppress the during treatment for childhood acute lymphoblastic leukemia is
hypothalamo-pituitary-adrenal axis. Aliment Pharmacol associated with glucocorticoid receptor polymorphisms ER22/23EK
Ther 1994;8:255-8. doi:10.1111/j.1365-2036.1994.tb00284.x  and BclI. Haematologica 2014;99:e136-7. doi:10.3324/
108  Marshall JK, Irvine EJ. Rectal corticosteroids versus alternative haematol.2014.105056 
treatments in ulcerative colitis: a meta-analysis. Gut 1997;40:775- 130  Manenschijn L, van den Akker EL, Lamberts SW, van Rossum
81. doi:10.1136/gut.40.6.775  EF. Clinical features associated with glucocorticoid receptor
109  Mulder CJ, Endert E, van der Heide H, et al. Comparison of polymorphisms. An overview. Ann N Y Acad Sci 2009;1179:179-98.
beclomethasone dipropionate (2 and 3 mg) and prednisolone doi:10.1111/j.1749-6632.2009.05013.x 
sodium phosphate enemas (30 mg) in the treatment of ulcerative 131  Derijk RH. Single nucleotide polymorphisms related to HPA
proctitis. An adrenocortical approach. Neth J Med 1989;35:18-24. axis reactivity. Neuroimmunomodulation 2009;16:340-52.
110  Kumana CR, Seaton T, Meghji M, Castelli M, Benson R, Sivakumaran doi:10.1159/000216192 
T. Beclomethasone dipropionate enemas for treating inflammatory 132  van Leeuwen N, Kumsta R, Entringer S, et al. Functional
bowel disease without producing Cushing’s syndrome or mineralocorticoid receptor (MR) gene variation influences
hypothalamic pituitary adrenal suppression. Lancet 1982;1:579-83. the cortisol awakening response after dexamethasone.
doi:10.1016/S0140-6736(82)91747-0  Psychoneuroendocrinology 2010;35:339-49. doi:10.1016/j.
111  Gionchetti P, D’Arienzo A, Rizzello F, et al, Italian BDP Study psyneuen.2009.07.006 
Group. Topical treatment of distal active ulcerative colitis with 133  Müller LM, Kienitz T, Deutschbein T, et al. Glucocorticoid Receptor
beclomethasone dipropionate or mesalamine: a single-blind Polymorphisms Influence Muscle Strength in Cushing’s Syndrome.
randomized controlled trial. J Clin Gastroenterol 2005;39:291-7. J Clin Endocrinol Metab 2020;105:dgz052. doi:10.1210/clinem/
doi:10.1097/01.mcg.0000155124.74548.61  dgz052 
112  Arntzenius A, van Galen L. Budesonide-related adrenal insufficiency. 134  Akurugu WA, Van Heerden CJ, Mulder N, Zöllner EW. Hypothalamic-
BMJ Case Rep 2015;2015:bcr2015212216. doi:10.1136/bcr- pituitary-adrenal axis suppression in asthma: A glucocorticoid
2015-212216  receptor polymorphism may protect. Pediatr Allergy
113  Tripathi K, Dunzendorfer T. Budesonide-Related Iatrogenic Cushing’s Immunol 2021;32:273-9. doi:10.1111/pai.13379 
Syndrome in Microscopic Colitis. ACG Case Rep J 2017;4:e5. 135  Bazsó A, Kövesdi A, Rásonyi R, et al. Glucocorticoid receptor
doi:10.14309/crj.2017.5  polymorphisms in rheumatoid arthritis: results from a single centre.
114  Kirwan JR, Hickey SH, Hällgren R, et al. The effect of therapeutic Clin Exp Rheumatol 2020;38:858-63.
glucocorticoids on the adrenal response in a randomized 136  Huang J, Hu X, Zheng X, et al. Effects of STIP1 and GLCCI1
controlled trial in patients with rheumatoid arthritis. Arthritis polymorphisms on the risk of childhood asthma and inhaled
Rheum 2006;54:1415-21. doi:10.1002/art.21747  corticosteroid response in Chinese asthmatic children. BMC Pulm
115  Campieri M, Ferguson A, Doe W, Persson T, Nilsson LG, The Global Med 2020;20:303. doi:10.1186/s12890-020-01332-2 
Budesonide Study Group. Oral budesonide is as effective as oral 137  Lou QY, Li Z, Teng Y, et al. Associations of FKBP4 and FKBP5 gene
prednisolone in active Crohn’s disease. Gut 1997;41:209-14. polymorphisms with disease susceptibility, glucocorticoid efficacy,
doi:10.1136/gut.41.2.209  anxiety, depression, and health-related quality of life in systemic
116  Ferguson A, Campieri M, Doe W, Persson T, Nygård G, Global lupus erythematosus patients. Clin Rheumatol 2021;40:167-79.
Budesonide Study Group. Oral budesonide as maintenance therapy doi:10.1007/s10067-020-05195-0 
in Crohn’s disease--results of a 12-month study. Aliment Pharmacol 138  Lin RC, Wang XL, Dalziel B, Caterson ID, Morris BJ. Association of
Ther 1998;12:175-83. doi:10.1046/j.1365-2036.1998.00285.x  obesity, but not diabetes or hypertension, with glucocorticoid
117  Löfberg R, Rutgeerts P, Malchow H, et al. Budesonide prolongs receptor N363S variant. Obes Res 2003;11:802-8. doi:10.1038/
time to relapse in ileal and ileocaecal Crohn’s disease. A placebo oby.2003.111 
controlled one year study. Gut 1996;39:82-6. doi:10.1136/ 139  Giordano R, Marzotti S, Berardelli R, et al. BClI polymorphism of
gut.39.1.82  the glucocorticoid receptor gene is associated with increased
118  European Medicines Agency. Norvir (ritonavir): Summary of Product obesity, impaired glucose metabolism and dyslipidaemia in patients
Characteristics. 2021. https://www.ema.europa.eu/en/documents/ with Addison’s disease. Clin Endocrinol (Oxf) 2012;77:863-70.
product-information/norvir-epar-product-information_en.pdf. doi:10.1111/j.1365-2265.2012.04439.x 

18 doi: 10.1136/bmj.n1380 | BMJ 2021;374:n1380 | the bmj

 STATE OF THE ART REVIEW

140  van Rossum EF, Voorhoeve PG, te Velde SJ, et al. The ER22/23EK the United Kingdom. Arch Dis Child 2002;87:457-61. doi:10.1136/
polymorphism in the glucocorticoid receptor gene is associated with adc.87.6.457 
a beneficial body composition and muscle strength in young adults. 163  Spera K, Rubin D, Gupta T, Fantaneanu T, Henderson GV. Clinical

BMJ: first published as 10.1136/bmj.n1380 on 12 July 2021. Downloaded from http://www.bmj.com/ on 11 August 2021 by guest. Protected by copyright.
J Clin Endocrinol Metab 2004;89:4004-9. doi:10.1210/jc.2003- Reasoning: An 87-year-old man with chronic obstructive pulmonary
031422  disease and acute encephalopathy. Neurology 2016;87:e135-9.
141  van Rossum EF, Koper JW, Huizenga NA, et al. A polymorphism doi:10.1212/WNL.0000000000003149 
in the glucocorticoid receptor gene, which decreases sensitivity 164  Da Silva AN, Schiff D. Adrenal insufficiency secondary to
to glucocorticoids in vivo, is associated with low insulin and glucocorticoid withdrawal in patients with brain tumor. Surg
cholesterol levels. Diabetes 2002;51:3128-34. doi:10.2337/ Neurol 2007;67:508-10. doi:10.1016/j.surneu.2006.07.018 
diabetes.51.10.3128  165  Christensson C, Thorén A, Lindberg B. Safety of inhaled budesonide:
142  Trementino L, Appolloni G, Concettoni C, Cardinaletti M, Boscaro clinical manifestations of systemic corticosteroid-related adverse
M, Arnaldi G. Association of glucocorticoid receptor polymorphism effects. Drug Saf 2008;31:965-88. doi:10.2165/00002018-
A3669G with decreased risk of developing diabetes in patients 200831110-00002 
with Cushing’s syndrome. Eur J Endocrinol 2012;166:35-42. 166  Iglesias P, González J, Díez JJ. Acute and persistent iatrogenic
doi:10.1530/EJE-11-0722  Cushing’s syndrome after a single dose of triamcinolone acetonide. J
143  Venneri MA, Hasenmajer V, Fiore D, et al. Circadian Rhythm Endocrinol Invest 2005;28:1019-23. doi:10.1007/BF03345342 
of Glucocorticoid Administration Entrains Clock Genes in 167  Meikle AW, Tyler FH. Potency and duration of action of
Immune Cells: A DREAM Trial Ancillary Study. J Clin Endocrinol glucocorticoids. Effects of hydrocortisone, prednisone and
Metab 2018;103:2998-3009. doi:10.1210/jc.2018-00346  dexamethasone on human pituitary-adrenal function. Am J
144  Kino T. Circadian rhythms of glucocorticoid hormone actions in Med 1977;63:200-7. doi:10.1016/0002-9343(77)90233-9 
target tissues: potential clinical implications. Sci Signal 2012;5:pt4. 168  Prete A, Paragliola RM, Bottiglieri F, et al. Factors predicting the
doi:10.1126/scisignal.2003333  duration of adrenal insufficiency in patients successfully treated
145  Zanger UM, Schwab M. Cytochrome P450 enzymes in drug for Cushing disease and nonmalignant primary adrenal Cushing
metabolism: regulation of gene expression, enzyme activities, and syndrome. Endocrine 2017;55:969-80. doi:10.1007/s12020-016-
impact of genetic variation. Pharmacol Ther 2013;138:103-41. 1007-5 
doi:10.1016/j.pharmthera.2012.12.007  169  Berr CM, Di Dalmazi G, Osswald A, et al. Time to recovery of adrenal
146  Wass JA, Arlt W. How to avoid precipitating an acute adrenal crisis. function after curative surgery for Cushing’s syndrome depends on
BMJ 2012;345:e6333. doi:10.1136/bmj.e6333  etiology. J Clin Endocrinol Metab 2015;100:1300-8. doi:10.1210/
147  Allen G, Mitchell A, Ramirez M, Holsten S, Shah N. A Case of a jc.2014-3632 
Post-Operative Addisonian Crisis from HPA Axis Suppression 170  Hurtado MD, Cortes T, Natt N, Young WFJr, Bancos I. Extensive clinical
from Inhaled Corticosteroids. Am Surg 2019;85:e483-4. experience: Hypothalamic-pituitary-adrenal axis recovery after
doi:10.1177/000313481908500920  adrenalectomy for corticotropin-independent cortisol excess. Clin
148  Moritani K, Tauchi H, Ochi F, et al. Prolonged adrenal insufficiency Endocrinol (Oxf) 2018;89:721-33. doi:10.1111/cen.13803 
after high-dose glucocorticoid in infants with leukemia. Pediatr 171  Richter B, Neises G, Clar C. Glucocorticoid withdrawal schemes
Hematol Oncol 2018;35:355-61. doi:10.1080/08880018.2018.15 in chronic medical disorders. A systematic review. Endocrinol
39148  Metab Clin North Am 2002;31:751-78. doi:10.1016/S0889-
149  Rushworth RL, Chrisp GL, Torpy DJ. Glucocorticoid-Induced Adrenal 8529(02)00008-7 
Insufficiency: A Study of the Incidence in Hospital Patients and a 172  Hellmich B, Agueda A, Monti S, et al. 2018 Update of the
Review of Peri-Operative Management. Endocr Pract 2018;24:437- EULAR recommendations for the management of large vessel
45. doi:10.4158/EP-2017-0117  vasculitis. Ann Rheum Dis 2020;79:19-30. doi:10.1136/
150  Goldbloom EB, Mokashi A, Cummings EA, et al. Symptomatic annrheumdis-2019-215672 
adrenal suppression among children in Canada. Arch Dis 173  Hochberg Z, Pacak K, Chrousos GP. Endocrine withdrawal syndromes.
Child 2017;102:338-9. doi:10.1136/archdischild-2016-311223  Endocr Rev 2003;24:523-38. doi:10.1210/er.2001-0014 
151  Todd GR, Acerini CL, Buck JJ, et al. Acute adrenal crisis in asthmatics 174  Erkut ZA, Pool C, Swaab DF. Glucocorticoids suppress corticotropin-
treated with high-dose fluticasone propionate. Eur Respir releasing hormone and vasopressin expression in human
J 2002;19:1207-9. doi:10.1183/09031936.02.00274402  hypothalamic neurons. J Clin Endocrinol Metab 1998;83:2066-73.
152  Iwasaku M, Shinzawa M, Tanaka S, Kimachi K, Kawakami K. Clinical doi:10.1210/jc.83.6.2066 
characteristics of adrenal crisis in adult population with and without 175  Papanicolaou DA, Tsigos C, Oldfield EH, Chrousos GP. Acute
predisposing chronic adrenal insufficiency: a retrospective cohort glucocorticoid deficiency is associated with plasma elevations of
study. BMC Endocr Disord 2017;17:58. doi:10.1186/s12902-017- interleukin-6: does the latter participate in the symptomatology
0208-0  of the steroid withdrawal syndrome and adrenal insufficiency?J
153  Sannarangappa V, Jalleh R. Inhaled corticosteroids and secondary Clin Endocrinol Metab 1996;81:2303-6. doi:10.1210/
adrenal insufficiency. Open Respir Med J 2014;8:93-100. doi:10.217 jcem.81.6.8964868 
4/1874306401408010093  176  Dorn LD, Burgess ES, Friedman TC, Dubbert B, Gold PW, Chrousos
154  Nathan AW, Rose GL. Fatal iatrogenic Cushing’s syndrome. GP. The longitudinal course of psychopathology in Cushing’s
Lancet 1979;1:207. doi:10.1016/S0140-6736(79)90597-X  syndrome after correction of hypercortisolism. J Clin Endocrinol
155  Barlow AD, Clarke GA, Kelly MJ. Acute adrenal crisis in a patient Metab 1997;82:912-9.
treated with rectal steroids. Colorectal Dis 2004;6:62-4. 177  Bancos I, Erickson D, Bryant S, et al. Performance of Free Versus Total
doi:10.1111/j.1463-1318.2004.00540.x  Cortisol Following Cosyntropin Stimulation Testing in an Outpatient
156  Jansen TL, Van Roon EN. Four cases of a secondary Cushingoid state Setting. Endocr Pract 2015;21:1353-63. doi:10.4158/EP15820.OR 
following local triamcinolone acetonide (Kenacort) injection. Neth J 178  Rauschecker M, Abraham SB, Abel BS, et al. Cosyntropin-Stimulated
Med 2002;60:151-3. Serum Free Cortisol in Healthy, Adrenally Insufficient, and Mildly
157  Kumar S, Singh RJ, Reed AM, Lteif AN. Cushing’s syndrome after Cirrhotic Populations. J Clin Endocrinol Metab 2016;101:1075-81.
intra-articular and intradermal administration of triamcinolone doi:10.1210/jc.2015-2285 
acetonide in three pediatric patients. Pediatrics 2004;113:1820-4. 179  Hamrahian AH, Oseni TS, Arafah BM. Measurements of serum free
doi:10.1542/peds.113.6.1820  cortisol in critically ill patients. N Engl J Med 2004;350:1629-38.
158  Leary J, Swislocki A. Hypothalamic-Pituitary-Adrenal Suppression doi:10.1056/NEJMoa020266 
and Iatrogenic Cushing’s Syndrome as a Complication of Epidural 180  Sbardella E, Isidori AM, Woods CP, et al. Baseline morning cortisol
Steroid Injections. Case Rep Endocrinol 2013;2013:617042. level as a predictor of pituitary-adrenal reserve: a comparison across
doi:10.1155/2013/617042  three assays. Clin Endocrinol (Oxf) 2017;86:177-84. doi:10.1111/
159  Li D, Genere N, Behnken E, et al. Determinants of Self-reported cen.13232 
Health Outcomes in Adrenal Insufficiency: A Multisite Survey Study. J 181  Kane KF, Emery P, Sheppard MC, Stewart PM. Assessing the
Clin Endocrinol Metab 2021;106:e1408-19. doi:10.1210/clinem/ hypothalamo-pituitary-adrenal axis in patients on long-term
dgaa668  glucocorticoid therapy: the short synacthen versus the insulin
160  Smans LC, Van der Valk ES, Hermus AR, Zelissen PM. Incidence of tolerance test. QJM 1995;88:263-7.
adrenal crisis in patients with adrenal insufficiency. Clin Endocrinol 182  Hurel SJ, Thompson CJ, Watson MJ, Harris MM, Baylis PH,
(Oxf) 2016;84:17-22. doi:10.1111/cen.12865  Kendall-Taylor P. The short Synacthen and insulin stress tests
161  Laugesen K, Petersen I, Sørensen HT, Jørgensen JOL. Clinical in the assessment of the hypothalamic-pituitary-adrenal axis.
indicators of adrenal insufficiency following discontinuation of oral Clin Endocrinol (Oxf) 1996;44:141-6. doi:10.1046/j.1365-
glucocorticoid therapy: A Danish population-based self-controlled 2265.1996.555381.x 
case series analysis. PLoS One 2019;14:e0212259. doi:10.1371/ 183  Hartzband PI, Van Herle AJ, Sorger L, Cope D. Assessment of
journal.pone.0212259  hypothalamic-pituitary-adrenal (HPA) axis dysfunction: comparison
162  Todd GR, Acerini CL, Ross-Russell R, Zahra S, Warner JT, McCance D. of ACTH stimulation, insulin-hypoglycemia and metyrapone. J
Survey of adrenal crisis associated with inhaled corticosteroids in Endocrinol Invest 1988;11:769-76. doi:10.1007/BF03350221 

the bmj | BMJ 2021;374:n1380 | doi: 10.1136/bmj.n1380 19

STATE OF THE ART REVIEW

184  Agha A, Tomlinson JW, Clark PM, Holder G, Stewart PM. The long-term Guideline. J Clin Endocrinol Metab 2016;101:364-89. doi:10.1210/
predictive accuracy of the short synacthen (corticotropin) stimulation jc.2015-1710 
test for assessment of the hypothalamic-pituitary-adrenal axis. J Clin 192  Prete A, Taylor AE, Bancos I, et al. Prevention of Adrenal Crisis:

BMJ: first published as 10.1136/bmj.n1380 on 12 July 2021. Downloaded from http://www.bmj.com/ on 11 August 2021 by guest. Protected by copyright.
Endocrinol Metab 2006;91:43-7. doi:10.1210/jc.2005-1131  Cortisol Responses to Major Stress Compared to Stress Dose
185  Ospina NS, Al Nofal A, Bancos I, et al. ACTH Stimulation Tests for the Hydrocortisone Delivery. J Clin Endocrinol Metab 2020;105:2262-
Diagnosis of Adrenal Insufficiency: Systematic Review and Meta-Analysis. 74. doi:10.1210/clinem/dgaa133 
J Clin Endocrinol Metab 2016;101:427-34. doi:10.1210/jc.2015-1700  193  Arlt W, Baldeweg SE, Pearce SHS, Simpson HL. ENDOCRINOLOGY IN
186  Fiad TM, Kirby JM, Cunningham SK, McKenna TJ. The overnight THE TIME OF COVID-19: Management of adrenal insufficiency. Eur J
single-dose metyrapone test is a simple and reliable index Endocrinol 2020;183:G25-32. doi:10.1530/EJE-20-0361 
of the hypothalamic-pituitary-adrenal axis. Clin Endocrinol 194  Woodcock T, Barker P, Daniel S, et al. Guidelines for the management
(Oxf) 1994;40:603-9. doi:10.1111/j.1365-2265.1994.tb03011.x  of glucocorticoids during the peri-operative period for patients
187  Rose SR, Lustig RH, Burstein S, Pitukcheewanont P, Broome DC, with adrenal insufficiency: Guidelines from the Association of
Burghen GA. Diagnosis of ACTH deficiency. Comparison of overnight Anaesthetists, the Royal College of Physicians and the Society for
metyrapone test to either low-dose or high-dose ACTH test. Horm Endocrinology UK. Anaesthesia 2020;75:654-63. doi:10.1111/
Res 1999;52:73-9. anae.14963 
188  Soule S, Van Zyl Smit C, Parolis G, et al. The low dose ACTH 195  Arlt W, Society for Endocrinology Clinical Committee. SOCIETY FOR
stimulation test is less sensitive than the overnight metyrapone ENDOCRINOLOGY ENDOCRINE EMERGENCY GUIDANCE: Emergency
test for the diagnosis of secondary hypoadrenalism. Clin Endocrinol management of acute adrenal insufficiency (adrenal crisis) in adult
(Oxf) 2000;53:221-7. doi:10.1046/j.1365-2265.2000.01057.x  patients. Endocr Connect 2016;5:G1-3. doi:10.1530/EC-16-0054 
189  Jamilloux Y, Liozon E, Pugnet G, et al. Recovery of adrenal function 196  Nicolaides NC, Charmandari E, Kino T, Chrousos GP. Stress-Related
after long-term glucocorticoid therapy for giant cell arteritis: a and Circadian Secretion and Target Tissue Actions of Glucocorticoids:
cohort study. PLoS One 2013;8:e68713. doi:10.1371/journal. Impact on Health. Front Endocrinol (Lausanne) 2017;8:70.
pone.0068713  doi:10.3389/fendo.2017.00070 
190  Di Dalmazi G, Berr CM, Fassnacht M, Beuschlein F, Reincke M. 197  Scherholz ML, Schlesinger N, Androulakis IP. Chronopharmacology
Adrenal function after adrenalectomy for subclinical hypercortisolism of glucocorticoids. Adv Drug Deliv Rev 2019;151-152:245-61.
and Cushing’s syndrome: a systematic review of the literature. J Clin doi:10.1016/j.addr.2019.02.004 
Endocrinol Metab 2014;99:2637-45. doi:10.1210/jc.2014-1401  198  Stewart PM. Modified-Release Hydrocortisone: Is It Time to Change
191  Bornstein SR, Allolio B, Arlt W, et al. Diagnosis and Treatment of Clinical Practice?J Endocr Soc 2019;3:1150-3. doi:10.1210/js.2019-
Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice 00046

No commercial reuse: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribe