PRIMER

Adrenal insufficiency
Stefanie Hahner   1 ✉, Richard J. Ross   2, Wiebke Arlt   3,4, Irina Bancos5,
Stephanie Burger-​Stritt1, David J. Torpy6, Eystein S. Husebye7,8,9 and Marcus Quinkler10
Abstract | Adrenal insufficiency (AI) is a condition characterized by an absolute or relative
deficiency of adrenal cortisol production. Primary AI (PAI) is rare and is caused by direct adrenal
failure. Secondary AI (SAI) is more frequent and is caused by diseases affecting the pituitary,
whereas in tertiary AI (TAI), the hypothalamus is affected. The most prevalent form is TAI owing to
exogenous glucocorticoid use. Symptoms of AI are non-​specific, often overlooked or misdiagnosed,
and are related to the lack of cortisol, adrenal androgen precursors and aldosterone (especially in
PAI). Diagnosis is based on measurement of the adrenal corticosteroid hormones, their regulatory
peptide hormones and stimulation tests. The goal of therapy is to establish a hormone replacement
regimen that closely mimics the physiological diurnal cortisol secretion pattern, tailored to the
patient’s daily needs. This Primer provides insights into the epidemiology, mechanisms and
management of AI during pregnancy as well as challenges of long-​term management. In addition,
the importance of identifying life-​threatening adrenal emergencies (acute AI and adrenal crisis)
is highlighted and strategies for prevention, which include patient education, glucocorticoid
emergency cards and injection kits, are described.

Glucocorticoids
A class of corticosteroids
that are essential mediators
of the stress system and
major players in the stress
response, that regulate resting
homeostasis (metabolism
of carbohydrates, proteins
and fats) and modulate the
immune response.
Mineralocorticoids
A class of corticosteroids
involved in the maintenance
of the salt and water balance
in the body.
Immune checkpoint
inhibitors
Drugs typically used in
oncology that stimulate
antitumour immune response
by blocking checkpoint
proteins and promoting
immune-​mediated elimination
of tumour cells.
✉e-​mail: Hahner_S@ukw.de
https://doi.org/10.1038/
s41572-021-00252-7
Adrenal insufficiency (AI) is an endocrine disorder
characterized by adrenal hypofunction, leading to inad-
equate production of glucocorticoids, especially cortisol.
AI can be primary, secondary or tertiary depending on
the underlying aetiology. Accordingly, the production
of mineralocorticoids and adrenal androgens might also
be affected1 (Fig. 1). Primary adrenal insufficiency (PAI)
results from direct adrenal gland failure caused by the
destruction of or damage to the adrenal glands (Fig. 2).
Autoimmune adrenalitis, also known as Addison dis-
ease, is the most common cause of PAI, especially in
high-​income countries, whereas the proportion of
patients with PAI in whom the AI is attributable to
infectious diseases, such as tuberculosis or HIV, is high
in countries with high prevalence of these infections2–7.
Secondary adrenal insufficiency (SAI) occurs secondary
to diseases of the pituitary or the hypothalamus such as
tumours of the hypothalamus and/or pituitary and their
treatment, hypophysitis or granulomatous infiltration3.
AI caused by hypothalamic abnormalities or dysfunc-
tion, which results in reduced corticotropin-​releasing
hormone (CRH) secretion is referred to as tertiary
adrenal insufficiency (TAI). Similar to SAI, the con-
sequent lack of adrenal adrenocorticotropic hormone
(ACTH) stimulation leads to reduced cortisol and
dehydroepiandrosterone (DHEA) secretion (Fig.  2).
TAI is, therefore, frequently subsumed within the term
SAI without further differentiation between the two
entities. TAI typically results from the suppression
of the hypothalamic–pituitary–adrenal (HPA) axis
caused by the administration of supraphysiological
doses of exogenous glucocorticoids for a sustained
period of time8 (Fig. 2).
The clinical signs and symptoms of AI are related
to the respective hormone deficiency, which are often
manifested gradually over a long period of time. Major
symptoms associated specifically with cortisol deficiency
include fatigue, hypotension and weight loss; however,
these symptoms are non-​specific and often lead to diag-
nostic delays and misdiagnosis9. Unexplained hypon-
atraemia as well as hyperpigmentation or loss of pubic
and axillary hair might more specifically raise suspi-
cion of AI. AI can also manifest as an acute emergency
known as adrenal crisis. Owing to the crucial protective
role of cortisol under stressful conditions (physical and
psychological), patients with unknown AI and patients
under established replacement therapy are at risk of
developing life-​threatening adrenal crisis10–15. Thus, pre-
vention of adrenal crisis is a principal goal of long-​term
management.
Iatrogenic causes of AI are of important relevance
for many medical disciplines. Glucocorticoid phar-
macotherapy and opiates, which are known to impair
the function of the HPA axis, are broadly used to
treat multiple conditions. The more widespread use
of immune checkpoint inhibitors (ICIs), which are asso-
ciated with autoimmune hypophysitis and rarely with
auto­immune adrenalitis, has further increased the inci-
dence of AI15. Hence, knowledge of the management of
AI and the prevention and treatment of adrenal crisis

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Primer

Adrenal
gland
Kidney

Zona glomerulosa
Mineralocorticoids
• Aldosterone and corticosterone

Zona fasciculata
Glucocorticoids
• Cortisol and cortisone

Zona reticularis
Classic and 11-oxygenated
androgen precursors
• DHEA, DHEAS, androstenedione
and 11-hydroxyandrostenedione
Cortex
Medulla
Catecholamines
• Epinephrine and noreprinephrine
Peptides
• Somatostatin and substance P

Fig. 1 | Adrenal gland hormones. A schematic cross section of adrenal glands showing the different anatomical layers
and the different hormones secreted by each layer. The adrenal glands consist of two parts — an outer steroid-​secreting
adrenal cortex and an inner neuroendocrine adrenal medulla. The adrenal cortex can be further subdivided into three
zones, namely the outer zona glomerulosa, the intermediate zona fasciculata and the inner zona reticularis, which secrete
mineralocorticoids, glucocorticoids and adrenal androgen precursors, respectively. The adrenal medulla secretes the
catecholamine hormones, which include epinephrine and norepinephrine and small amounts of dopamine.
DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulfate.

is relevant for physicians across multiple disciplines.
In contrast to the rapid improvement in well-​b eing
achieved by the initiation of replacement therapy in
patients with newly diagnosed AI, long-​term manage-
ment is much more challenging. An individually tailored
glucocorticoid replacement therapy that closely mimics
Author addresses
1
Department of Medicine I, Division of Endocrinology and Diabetology, University
Hospital Wuerzburg, Wuerzburg, Germany.
2
Department of Oncology and Metabolism, The University of Sheffield, Sheffield, UK.
3
Institute for Metabolism and Systems Research, University of Birmingham,
Birmingham, UK.
4
Centre for Endocrinology, Diabetes, and Metabolism, Birmingham Health Partners,
University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK.
5
Division of Endocrinology, Metabolism and Nutrition, Department of Internal Medicine,
Mayo Clinic, Rochester, MN, USA.
6
Endocrine and Metabolic Unit, Royal Adelaide Hospital, University of Adelaide,
Adelaide, SA, Australia.
7
Department of Clinical Science, University of Bergen, Bergen, Norway.
8
K.G. Jebsen Center for Autoimmune Diseases, University of Bergen, Bergen, Norway.
9
Department of Medicine, Haukeland University Hospital, Bergen, Norway.
10
Endocrinology in Charlottenburg, Berlin, Germany.
normal physiology is important for optimal patient
management.
In this Primer, we summarize the current knowledge
of the epidemiology, pathophysiology and diagnosis of
AI and highlight the latest developments in its therapeu-
tic management. In addition, we describe the specific
challenges in current management, with a particular
focus on the prevention and treatment of adrenal crisis.
Furthermore, we discuss the outstanding questions in
the field and provide directions for future research.
Epidemiology
Primary adrenal insufficiency
The epidemiology of PAI has changed over the past
century regarding the prevalence and the spectrum
of underlying causes. PAI is rare, with a prevalence of
10–20 persons per 100,000 population and has multi-
ple aetiologies (Table 1). Although tuberculosis was one
of the predominant causes of PAI, nowadays Addison
disease and congenital adrenal hyperplasia (CAH) are
emerging as the prominent causes of PAI3,16,17. Addison
disease accounts for ~90% of non-​CAH cases in indus-
trialized countries18. By contrast, infections are the

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The hypothalamic–pituitary–adrenal axis

Primary Secondary Tertiary

PVN PVN PVN

Hypothalamus

↑ CRH ↑ CRH ↓ CRH

Pituitary

↑ ACTH ↓ ACTH ↓ ACTH

Adrenal

↓ Cortisol ↓ Cortisol ↓ Cortisol

↓ DHEA ↓ DHEA ↓ DHEA
↓ Aldosterone Normal aldosterone ↓
Normal
Aldosterone
aldosterone

Fig. 2 | Types of adrenal insufficiency. Circadian input and stress inputs converge on the paraventricular nucleus (PVN)
of the hypothalamus, inducing the release of corticotropin-​releasing hormone (CRH) and arginine vasopressin.
CRH in turn stimulates adrenocorticotropic hormone (ACTH) release into the circulation, which induces the secretion
of corticosteroids, mainly cortisol but also dehydroepiandrosterone (DHEA) and, to a minor extent, aldosterone.
The hypothalamic–pituitary–adrenal axis is regulated by cortisol via feedback regulation both in the hypothalamus and the
pituitary. In primary adrenal insufficiency, glucocorticoid deficiency leads to a loss of the negative feedback of cortisol
on the hypothalamus and pituitary, resulting in increased CRH and ACTH levels. In addition, decreased aldosterone
secretion results in increased renin release from the kidney. In secondary adrenal insufficiency (SAI), ACTH synthesis
and secretion are impaired, leading to a loss of adrenal cortisol and DHEA production; however, aldosterone production
is unimpaired as the renin–angiotensin–aldosterone system signalling cascade remains unaffected. Tertiary adrenal
insufficiency (TAI) may be caused by endogenous factors directly affecting the hypothalamic region or following the
treatment of endogenous Cushing syndrome. Most frequently, exogenous administration of glucocorticoid pharmacotherapy
results in TAI. Diminished hypothalamic CRH secretion in TAI results in reduced ACTH stimulation; similar to SAI, secretion
of cortisol and DHEA are impaired, although aldosterone secretion is preserved. Of note, often differentiation between
SAI and TAI is difficult, or mixed forms of SAI and TAI might occur (for example, by medications). As the resulting changes
in peripheral adrenocortical hormones is comparable, the term “secondary AI” is frequently used for both forms. Adapted
with permission from ref.270, Nicolaides NC, Chrousos GP, Charmandari E. Adrenal Insufficiency. 2017 Oct 14. In: Feingold
KR, Anawalt B, Boyce A, Chrousos G, de Herder WW, Dungan K, Grossman A, Hershman JM, Hofland J, Kaltsas G, Koch C,
Kopp P, Korbonits M, McLachlan R, Morley JE, New M, Purnell J, Singer F, Stratakis CA, Trence DL, Wilson DP, editors.
Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; PMID: 25905309.

21-​Hydroxylase
An enzyme involved in the
biosynthesis of cortisol
and aldosterone.
Autoimmune polyglandular
syndromes
Also known as polyglandular
autoimmune syndromes
or autoimmune polyendocrine
syndromes. These syndromes
comprise a heterogeneous
group of rare immune-​
mediated endocrinopathies
affecting more than
one endocrine organ.
Non-endocrine organs
may also be involved.
predominant cause of PAI in regions with high prev-
alence of tuberculosis, HIV infection and opportunis-
tic infections such as cytomegalovirus4–7. Overall, the
prevalence of Addison disease seems to be increasing.
For example, the prevalence has been reported to have
increased from 3.9 cases per 100,000 population in 1968
(ref.19) to 22 cases per 100,000 population in Iceland in
2016 (ref.20). The prevalence of Addison disease also dif-
fers based on the geographical location, ranging from
1.4 cases per 100,000 population in South Africa to
9–22 cases per 100,000 population in Europe2,3,17,21–24.
Addison disease usually manifests between 20–50 years
of age, but can occur at any age, although onset is rare
in children <2 years of age. PAI of any origin is more
prominent in women than in men, with a peak incidence
in the third decade of life, with higher frequencies in
individuals with other autoimmune disorders, such as
patients with type 1 diabetes mellitus, than in the gen-
eral population17,20,25–27. Other rare causes that lead to
adrenal destruction and dysfunction include bilateral
adrenal metastases, haemorrhage, infiltrative disorders
and infarction26,28.
CAH is caused by deficiency of the steroidogenic
enzyme 21-​hydroxylase and is the most common inher-
ited form of PAI29. CAH is an autosomal recessive
disorder with ~1 in 50 people harbouring a mutation in
CYP21A2 (encoding 21-​hydroxylase) The prevalence
of classic CAH varies between populations, ranging
from 0.5 to 1 person per 10,000 population30. Other less
frequent genetic causes of PAI include adrenoleukodys­
trophy, adrenal hypoplasia congenita and autoimmune
polyglandular syndrome (APS) type 1 (ref.31) (Table 1).
Autoimmune comorbidities of Addison disease. In more
than two thirds of patients, Addison disease occurs in
association with other autoimmune diseases, such as part
of APS type 1 or APS type 2 (ref.15). APS type 1 is a rare,
monogenic disorder characterized by childhood onset
with sequential manifestation of the main clinical symp-
toms, such as chronic candidiasis, hypoparathyroidism

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Table 1 | Causes of primary adrenal insufficiency

Aetiology Pathogenesis Diagnostic tools
Autoimmune T and B cell autoimmunity against adrenocortical cells 21-​Hydroxylase
autoantibodies
Infection Mycobacteria, bacteria (e.g. Neisseria meningitidis, Haemophilus influenzae, Culture, QuantiFERON
Pseudomonas aeruginosa), viruses (e.g. human immunodeficiency virus, test, PCR, adrenal CT
herpes simplex, cytomegalovirus) or fungi (e.g. Pneumocystis jirovecii)
Tumour Primary tumour (bilateral), metastasis (bilateral), adrenal lymphoma Adrenal CT
(bilateral)
Bleeding Anti-​phospholipid syndrome, anticoagulant therapy, disseminated Adrenal CT, phospholipid
intravascular coagulation autoantibodies
Surgery Bilateral adrenalectomy Patient history
Infiltrative Amyloidosis Adrenal CT,
subcutaneous fat biopsy
Haemochromatosis
Ferritin, HFE sequencing
Histiocytosis
Adrenal imaging
Genetica Congenital adrenal hyperplasia, congenital lipoid adrenal hyperplasia, Sequence of relevant
adrenoleukodystrophy (X-​linked), adrenal hypoplasia congenita, gene
autoimmune polyglandular syndrome type 1
Medicationb Enzyme inhibition (ketoconazole, fluconazole, itraconazole, etomidate, Medication and patient
aminoglutethimide, metyrapone, trilostane, osilodrostat); adrenolytic history
effect and increased cortisol metabolism (mitotane); inflammation
(checkpoint inhibitors)
a
See also Table 3. bSee also Table 4. Data from refs15,31.

Hypopituitarism
Dysfunction of the pituitary
with impaired secretion or a
lack of secretion of one or
more pituitary hormones.
and Addison disease32,33. Autoimmune comorbidities of
Addison disease include autoimmune thyroid disease
(40% of patients), premature ovarian failure (5–16%),
type 1 diabetes mellitus (11%), pernicious anaemia
(10%), vitiligo (6%), and coeliac disease (2%)3,34,35. In
contrast to APS type 1, APS type 2 is most frequently
diagnosed during adulthood.
Secondary adrenal insufficiency
SAI is more common than PAI, with a prevalence of up
to 42 cases per 100,000 population based on European
studies17,36,37. SAI typically occurs in patients with dis-
eases affecting the pituitary or hypothalamus such as
tumours, autoimmune hypophysitis or trauma, or occurs
following radiotherapy of intracranial tumours, and
only rarely has a genetic cause (for example, mutations
of the transcription factor TPIT)37–39 (Table 2). SAI will
develop in 10–62% of patients with pituitary adenoma
as a result of the mass effect of the tumour on the pitu-
itary gland; the risk increases with pituitary surgery or
radiotherapy37,39–41. The development of hypopituitarism
(also known as pituitary insufficiency) after radio-
therapy is dose-​d ependent and time-​d ependent 42.
A German study found that in patients with acromegaly
who underwent radiotherapy, the incidence of SAI
had increased from 39% to 45% at a mean of 9.1 years
after treatment43. Furthermore, SAI has been reported
in 26–57% patients with hypophysitis44,45, whereas in
pituitary stalk lesions of any kind, 23% of patients may
develop SAI46.
In addition, ICIs, which are used in various cancer
therapies, have been associated with adverse effects on
the HPA axis. ICIs were associated with an increased inci-
dence of serious grade SAI (OR 3.19, 95% CI 1.84–5.54)
and hypophysitis (OR 4.77, 95% CI 2.60–8.78)47. The
observed incidence of hypophysitis was highest in
patients receiving ICIs targeting CTLA4 and the com-
bination of CTLA4 and PD1 (up to 13% of patients)48,49.
Another form of iatrogenic SAI is opioid-​induced AI,
which has been reported in ~9–15% of patients using
chronic opioids, and has been reported at doses as
low as 20 morphine milligram equivalents per day50,51.
Nevertheless, opioid-​induced AI is poorly recognized
and is probably under-​reported52.
Tertiary adrenal insufficiency
Tertiary AI may be caused by endogenous factors such
as tumours, radiation or inflammatory processes affecting
the hypothalamic region. TAI is also observed after the
treatment of endogenous Cushing syndrome following
removal of an ACTH-​producing or cortisol-​producing
tumour.
The most common cause of TAI is chronic exoge-
nous administration of glucocorticoids. Glucocorticoid-​
induced TAI is also termed iatrogenic or exogenous
AI and is a temporary condition in most patients8. The
risk of developing TAI varies according to the route of
glucocorticoid administration owing to differences in
systemic availability. The risk of TAI is reported to be
4.2% for intranasal administration, 20% for adminis-
tration by inhalation, 49% for oral administration and
52% for intra-​articular administration8,53. The risk of
AI is lowest with short-​term, low-​dose glucocorticoid
use and highest with long-​term, high-​dose glucocorti-
coid use8. However, the correlation between TAI and
glucocorticoid dose or treatment duration is weak,
indicating that additional factors might influence indi-
vidual susceptibility8,54. Every patient on glucocorti-
coid pharmacotherapy has to be regarded as at risk of
TAI and, therefore, the dosage needs to be carefully
tapered and the patient counselled. This recommen-
dation is further supported by the increased mortality

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observed within the first 3 months following cessation
of glucocorticoid therapy55. Recovery of the function of
the HPA axis following cessation of glucocorticoid ther-
apy is observed within 24 months in most patients but
recovery may take >4 years in some patients56–58.
(for example, compounds that induce CYP3A4) has been
associated with the induction or aggravation of corti­
sol deficiency. Although 3% of all adults are using oral
glucocorticoids leading to the suppression of cortisol
secretion, the risk of adrenal crisis is generally low78.

Adrenal crisis Precipitating factors. Adrenal emergencies are the

Prevalence and mortality. In those with known AI,
adrenal crises have an incidence of 5–10 events per
100 patient-​years11,14,59–61 and are more frequent in patients
with PAI than in those with SAI10,14,61,62, presumably
owing to the lack of aldosterone and more severe hypo­
cortisolism. The mortality from adrenal crises is reported
to be 0.5 per 100 patient-​years11. Mortality from adre-
nal emergencies is rare (<1%) after hospital admis-
sion, although fatalities from undiagnosed AI may be
missed63,64. The prognosis in patients with AI is gener-
ally good if treatment is adequate. However, standard-
ized mortality rates are approximately double compared
with controls65,66. Younger patients (that is <40 years of
age) were found to be at increased risk of premature
death67. Adrenal crisis contributes to 15–40% of reported
AI-​related deaths10,65,67,68.
Risk factors. Risk factors for adrenal crisis include previ-
ous crises69, older age (>65 years of age) or younger age
(adolescence and young adulthood)70–73, and comorbidi-
ties such as diabetes mellitus, diabetes insipidus or other
non-​endocrine diseases14,69. The use of low-​dose, short-​
acting glucocorticoids70,74,75 might potentially underlie
the increased incidence of adrenal crisis75. In addition,
in patients with thyroid disease, treatment initiation with
l-​thyroxine and onset of hyperthyroidism owing to
Graves disease can precipitate a crisis through a more
rapid inactivation of cortisol than in people without
thyroid disease76,77. Treatment with drugs that reduce
cortisol production (for example, steroidogenesis inhib-
itors) or increase the metabolic clearance of cortisol
consequence of severe cortisol deficiency or relative
cortisol deficiency in the time of a major stress, in par-
ticular when associated with acute inflammation such as
sepsis10–12,69,73. Gastroenteritis is a frequent precipitant of
adrenal crisis owing to the reduced absorption of orally
administered glucocorticoids in these patients. However,
many symptoms of adrenal crisis are abdominal and,
therefore, the diagnosis of gastroenteritis as a cause may
be difficult. In any case, treatment of gastroenteritis in
AI and of adrenal crisis accompanied by gastrointestinal
symptoms is the same — timely parenteral administra-
tion of glucocorticoids. Gastroenteritis is the most com-
mon precipitating factor when a precipitant is found,
although an obvious precipitating factor is lacking in
~10% of cases11. Temporary reductions in hydrocorti-
sone availability may increase the incidence of adrenal
crises, even when alternative glucocorticoid preparations
are available79. In patients with AI, psychological stress
can also elicit an adrenal crisis under exceptional cir-
cumstances, such as bereavement. Casual dose increases
of glucocorticoid replacement because of perceived low-​
level psychological stress should, however, be avoided as
this could result in chronic over-​replacement.
Mechanisms/pathophysiology
The adrenal cortex is under the control of two different reg-
ulatory circuits, the HPA axis and the renin–angiotensin–
aldosterone system (RAAS). In PAI (except CAH),
all adrenocortical zones are affected, resulting in the
deficiency of all adrenocortical hormones. However,
in SAI, hormone secretion specifically from the zona

Table 2 | Causes of secondary adrenal insufficiency

Aetiology Pathogenesis Clinical manifestations and
diagnostic tools
Tumours Pituitary adenoma, craniopharyngioma, metastasis (carcino- Pituitary MRI, screen for hormone
mas of breast, lung, colon, prostate), chondroma, chordoma, deficiencies
germinoma, suprasellar meningioma, astrocytoma of the optic
nerve, ependymoma, pituitary carcinoma, lymphoma
Iatrogenic Pituitary surgery, radiotherapy Pituitary MRI, screen for hormone
deficiencies
Traumatic Traumatic brain injury, postpartum apoplexy (Sheehan Severe headache, visual disturbances,
and vascular syndrome), tumour apoplexy, subarachnoidal bleeding, pituitary MRI, screen for hormone
aneurysm, snake bite deficiencies
Autoimmune T and B cell autoimmunity against pituitary cells Pituitary MRI, confirmation of subtype
(hypophysitis), IgG4-​related hypophysitis by transsphenoidal biopsy, screen for
hormone deficiencies
Genetic Mutations in transcription factors, hormone and hormone Sequence of relevant gene
receptor genesa
Infiltrative Sarcoidosis, histiocytosis, haemochromatosis, amyloidosis Pituitary MRI, specific diagnostic tests
Infectious Tuberculosis, HIV infection, meningitis, actinomycosis, syphilis Pituitary MRI, specific diagnostic tests
Medication Checkpoint inhibitors, interferon-​α, opioids Check medication and patient history
See also Table 3. Table adapted from refs31,155.
a

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fasciculata and zona reticularis is impaired owing to a
lack of ACTH stimulation, whereas aldosterone secre-
tion from the zona glomerulosa remains intact (Fig. 2).
In this section, we summarize the current knowledge of
pathophysiology of the different types of AI.
Physiology of the HPA axis
The HPA axis is the anatomical unit that regulates the
physiological secretion of cortisol. The regulation of
cortisol secretion is complex and evident on multiple
levels in the HPA axis (for review see ref.80) (Fig. 2).
Circadian input from the suprachiasmatic nucleus in
the hypothalamus as well as stress stimuli from other
brain regions converge on the paraventricular nuclei of
the hypothalamus, which stimulates the release of CRH
and vasopressin80. CRH travels via the portal veins of the
median eminence to the anterior pituitary and induces
a secretory pulse of ACTH into the general circulation.
The circulating ACTH binds to and stimulates the
ACTH receptor (also known as MC2R) in the adrenal
cortex, with subsequent release of cortisol80 (Fig. 2).
Cortisol is secreted in pulses of various amplitudes
every 60–90 min creating a tightly regulated circadian
pattern with elevated secretion in the early hours of the
morning prior to waking and a nadir around bedtime
in the late evening81. Cortisol levels are lowest within
an hour of sleep and increase with a peak shortly after
awakening. Further short-​term increases in cortisol
occur subsequent to specific stimuli, such as meals
and everyday life stressors. Cortisol peaks are generally
preceded by a secretory surge of pituitary ACTH caused
by the corticotropic cells (Fig. 3). Cortisol provides a neg-
ative feedback loop by binding to glucocorticoid recep-
tors in the hypothalamus and the pituitary gland, which
inhibits ACTH secretion82.
10 mg HC 5 mg HC 2.5 mg HC
800
Night time sleep Night time sleep
700
600
Serum cortisol (nmol/l)
500
400
300
200
100
0 regulators (Fig. 4). Indeed, increases in potassium blood
1500 1900 2300 0300 0700 1100 1500 1900 2300 0300 0700
Time ( 24-h clock)
Cortisol circadian rhythm Thrice-daily hydrocortisone
Fig. 3 | The physiological rhythm of cortisol and pharmacokinetic profile of
hydrocortisone therapy. Circadian rhythm of cortisol showing early morning peak and
pulses at meal times overlaid with cortisol profile of thrice-​daily hydrocortisone (HC)
replacement therapy. Dashed lines denote oral intake of conventional hydrocortisone at
doses of 10 mg in the morning, 5 mg at noon and 2.5 mg in the afternoon. Adapted with
permission from ref.184, Oxford University Press, and ref.271, Wiley.
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Besides the circadian rhythm of cortisol secretion,
ultradian peaks of cortisol occur, which are produced
by a pituitary–adrenal feedback regulation, independent
of the CRH pulses. As cortisol is not stored but must be
synthesized upon ACTH stimulation, there is a delay
before the peak secretion of cortisol. This time delay
that occurs before the negative feedback on ACTH
production introduces the ultradian rhythmicity 83.
Oscillating glucocorticoid levels have been shown to
have an impact on the physiological regulation at the
cellular level in many organs. Hence, disruptions in
the pulsatile signal of cortisol induces changes in meta-
bolic processes, behaviours, affective state and cognitive
function84.
Functions of cortisol. Cortisol is a key modulator of
physiological processes such as energy metabolism,
stress response, reproduction, immunity and cognition,
and exerts its actions by interacting with the glucocor-
ticoid receptor and mineralocorticoid receptor85. Upon
binding, the cortisol–receptor complex translocates to
the nucleus and binds to different glucocorticoid and
mineralocorticoid response elements, thereby modulat-
ing gene transcription and repression86 to mediate the
diverse physiological functions of cortisol87. The ultra-
dian oscillation of cortisol enables cyclic glucocorticoid-​
mediated transcriptional regulation. Studies in mouse
cell lines and rat models have clearly demonstrated
markedly different transcription patterns depending
on ultradian glucocorticoid stimulation or constant
glucocorticoid stimulation, indicating that ultradian
rhythmicity is of physiological importance88. In humans,
disruption of ultradian rhythmicity of plasma cortisol
has been shown to negatively impact emotional and
cognitive responses84,89.
Most of the cortisol (>95%) is found in the circulation
bound to corticosteroid-​binding globulin (CBG). The
fraction of free bioavailable cortisol depends on the cor-
tisol binding affinity of CBG, which varies depending on
multiple factors, such as body temperature or inflamma-
tion. In the presence of fever or inflammation, decreased
CBG affinity might increase the amount of bioavailable
cortisol90,91.
Renin–angiotensin–aldosterone system
The RAAS is an important hormonal cascade, which is
a critical regulator of electrolyte balance, blood volume,
systemic vascular resistance and, consequently, blood
pressure. The RAAS is also the primary regulator of
aldosterone secretion from the adrenal cortex, with angi-
otensin II and potassium being the principal proximate
levels physiologically stimulate aldosterone secretion and
hypokalaemia results in reduced aldosterone secretion92.
The enzyme renin is released by the kidneys and cataly-
ses the conversion of angiotensinogen to angio­tensin I,
which is subsequently converted to angiotensin II by the
angiotensin-​converting enzyme. Angiotensin II binds
to angiotensin receptors and stimulates the release
of aldosterone from the adrenal cortex. The binding of
angiotensin II to its receptors induces further effects
such as vasoconstriction. Renin secretion is stimulated
 Primer

Adrenal gland
Kidney

Blood sodium concentration Blood potassium Sympathetic nerve

Macula densa mechanism concentration stimulation

Activation of Aldosterone Renal sodium retention Renal perfusion Juxtaglomerular Renin

AT1 receptor release (and potassium excretion) pressure cells release
Circulating blood volume

Vasoconstriction

Angiotensin II Angiotensin I Angiotensinogen

Angiotensin-converting enzyme

Fig. 4 | The renin–angiotensin–aldosterone system. The main stimulus of aldosterone secretion is mediated via the
renin–angiotensin–aldosterone system. Renin secretion is stimulated by decreased renal perfusion pressure (for example,
reduced blood volume, reduced sodium or increased potassium blood levels) and sympathetic nerve stimulation.
Renin catalyses the conversion of angiotensinogen to angiotensin I, which is converted to angiotensin II by the
angiotensin-converting enzyme (ACE). Binding of angiotensin II to AT1 receptor stimulates the release of aldosterone
from the adrenal cortex and induces further cardiovascular effects such as vasoconstriction. Renin release is mainly
inhibited by negative feedback of angiotensin II.

Macula densa cells
Specialized cells lining the wall
of kidney tubules that detect
changes in distal tubular fluid
composition and transmit
signals to the glomerular
vascular elements.
Juxtaglomerular cells
Specialized cells in the kidney
that synthesize, store and
secrete the enzyme renin.
Salt-​wasting syndrome
A more severe form of
congenital adrenal hyperplasia
characterized by insufficient
production and action of
aldosterone that lead to renal
sodium loss and consequent
sodium depletion of the body.
If undiagnosed, dehydration,
hypotension, failure to
thrive, hyponatraemia
and hyperkalaemia occur
within days of birth.
by decreased renal perfusion pressure, reduced blood
sodium concentrations in the body (sensed by macula
densa cells), increased blood potassium load, and sym-
pathetic nerve stimulation of juxtaglomerular cells. Renin
release is inhibited by negative feedback of angioten-
sin II or by atrial natriuretic peptide, which is released
from the cardiac muscle cells of the atria in response to
increased stretching of the atrial wall owing to increased
atrial blood volume93. ACTH acutely stimulates aldoster-
one secretion and conversely glucocorticoids suppress
aldosterone secretion94–96.
Primary adrenal insufficiency
Addison disease. In Addison disease, autoimmune
destruction of adrenocortical tissue is believed to be
caused by autoantibodies to the most frequently observed
autoantigen, 21-​hydroxylase97. These autoantibodies are
detected in most patients with Addison disease98, even
preceding overt adrenal failure by many years99 and,
therefore, are a highly specific and sensitive biomarker.
Circulating CD4+ and CD8+ T cells with autoreactivity
against 21-​hydroxylase that are found in patients are
thought to mediate the destruction of the adrenal
cor­tex100,101 (Fig. 5). Studies have shown that Addison
disease is associated with certain major histocompati-
bility complex (MHC) genotypes such as DR3-​DQ2 and
DR4-​DQ8 (refs97,102). In addition, variants in CTLA4,
PTPN22, CIITA and CLEC16A, which are also impli-
cated in other autoimmune diseases, have been shown to
increase individual susceptibility to Addison disease102.
Furthermore, heritability of Addison disease is high and
similar to that of coeliac disease. In a twin study, 97%
of disease liability was attributable to genetic factors103.
Lack of aldosterone leads to loss of sodium in
the body, with decreased intravascular fluid vol-
ume and hypotension104. The loss of negative feed-
back by cortisol in Addison disease results in
increased release of pro-opiomelanocortin and pro-
opiomelanocortin-derived peptides such as ACTH and
α-melanocyte stimulating hormone (α-​MSH). The
increase in α-MSH levels leads to skin hyperpigmen-
tation through stimulation of MSHR (also known as
melanocortin receptor 1) not only in areas of the body
exposed to sun but also in areas of increased mechanical
friction, such as palmar creases, scars, the groin and the
oral mucosa1.
Congenital adrenal hyperplasia. Congenital AI results
from mutations in genes involved in the HPA axis
(Table  3) . CAH, the most common genetic form of
PAI, comprises a group of disorders of adrenal steroid
biosynthesis. In ~95% of patients, CAH is caused by
mutations in CYP21A2 (ref.105); the resultant cortisol
deficiency stimulates increased ACTH secretion from
the pituitary, leading to adrenocortical hyperplasia and
increased secretion of adrenal androgens upstream
of the enzymatic block, driving increased androgen
production (Fig. 6).
The severity of CAH depends on the severity of the
disease-​causing mutations and the residual enzyme
activity. Neonates with <2% of the enzyme activity
will have both cortisol and aldosterone deficiency30.
In approximately two-​thirds of patients, impaired aldos-
terone synthesis leads to a potentially life-​threatening
salt-​wasting syndrome and in one-​third of patients, a mild
virilizing form.

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Adrenal cortex Local draining lymph node

Adrenal
cortex cell Antigen
Virus MHC II TCR
Dendritic Co-stimulation
cell
TH1
Necrosis cell
IFNγ
Uptake of
antigens
IL-12 Activation of
IL-2 autoreactive
Cortisol TH cells
production
Autoantibodies
Activation and
expansion of
autoreactive
TC cell TC cells B cell

BCR

Oxygen free
radicals
Activated Activation of
macrophage autoreactive B cells

Fig. 5 | Mechanisms underlying Addison disease. Addison disease is characterized by destruction of the adrenal cortex
by T cell-​mediated autoimmune mechanisms with contributions from dendritic cells and macrophages. Activation of
B cells in local draining lymph nodes leads to production of autoantibodies against the enzyme 21-​hydroxylase, which is
detected in ~90% of patients with Addison disease. Circulating CD4+ and CD8+ T cells targeting 21-​hydroxylase-​expressing
corticotrophs mediate the destruction of the adrenal cortex. The environmental triggers of Addison disease are not
completely known, but viruses might be involved. BCR, B cell receptor; IFNγ, interferon-​γ; MHC, major histocompatibility
complex; TC cell, cytotoxic T cell; TCR, T cell receptor; TH cell, helper T cell. Adapted with permission from ref.272, Elsevier.

Virilization
A condition in which a
female develops masculine
characteristics such as excess
facial and body hair, acne,
increased muscle mass and
baldness. Virilization is caused
by excess production of
endogenous androgens from
the adrenals or the ovaries or
from exogenous androgen
administration.
Precocious pseudopuberty
Partial pubertal development
that results from premature
appearance of secondary
sexual characteristics in
prepubertal boys and girls
owing to excess production
of sex steroids.
Leydig cells
Steroidogenic cells in
the testes that produce
testosterone upon stimulation
by pituitary luteinizing
hormone.
Spastic paraparesis
A group of rare hereditary
disorders that cause gradual
weakness with muscle spasms.
In the salt-​wasting form of CAH, the 46,XX female
neonate presents with virilization of the external genitalia
and both sexes may present with salt-​wasting adrenal
crisis, typically in the second and third week of life,
if steroid replacement is not initiated promptly after
birth30. Patients with less severe mutations present early
or late in childhood with signs of virilization, as well as
growth arrest and precocious pseudopuberty. Mild forms
of CAH with at least 30–50% residual enzyme function
are more prevalent and are subsumed under the term
non-​classic CAH (formerly also known as ‘late-​onset’
CAH or cryptic CAH), which is characterized by adre-
nal androgen excess, mild or absent glucocorticoid
deficiency and normal mineralocorticoid biosynthesis29.
Other congenital forms of PAI. Next to CAH, the most
prevalent genetic form of PAI is X-​linked adrenoleu-
kodystrophy. Adrenoleukodystrophy is a peroxisomal
disorder caused by mutations in ABCD1 that lead
to accumulation of very-​long-​chain fatty acids in all
tissues, especially the central nervous system, the
adrenal cortex and the Leydig cells of the testes106,107.
The incidence of adrenoleukodystrophy is 1 in 17,000
newborns (typically males and very rarely females)108.
Neurological symptoms can manifest in childhood with
central demyelination and rapid neurological decline or
in young adults with mixed motor and sensory neuro­
pathy leading to spastic paraparesis. Progressive failure
of steroid-​secreting cells occurs in adrenal and gonadal
tissues. Adrenal failure may also occur in isolation; in
one series, 8% of young boys with Addison disease had
underlying X-​linked adrenoleukodystrophy88. Other
congenital forms of PAI are typically rare in the general
population and are discussed in detail elsewhere36,109,110
(Table 3).
Secondary adrenal insufficiency
In SAI, the diminished or total lack of ACTH pulses
results in a loss of adrenal cortisol synthesis and secre-
tion. In contrast to PAI, in which loss of adrenal function
often is near complete by the time of clinical presenta-
tion, all degrees of severity of AI are observed in SAI
depending on residual ACTH secretion. Furthermore,
mineralocorticoid production is usually intact in
patients with SAI as aldosterone production is primar-
ily controlled by the RAAS hormonal cascade (which
requires a functioning adrenal gland and kidney) and
controlled only to a minor, transient degree by ACTH95.
SAI can manifest as an isolated entity, but SAI often
presents in association with the lack of other pitui-
tary hormones. In addition to pituitary tumours, the
hypothalamic–pituitary unit can also be damaged by
head trauma; up to one third of patients with traumatic
brain injury develop chronic pituitary dysfunction, most
frequently with growth hormone deficiency, followed by
gonadotrophin and ACTH deficiency111.

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Corticotroph
Cells in the anterior
pituitary that produce
pro-​opiomelanocortin, which
undergoes cleavage to form
adrenocorticotropic hormone
(ACTH) in response to
stimulation by hypothalamic
corticotropin-​releasing
hormone.
Autoimmune hypophysitis, another prominent cause
of SAI, is characterized by infiltration of lymphocytes
into the pituitary gland. It frequently develops in the
peripartum period and can lead to the development of
a mass lesion in the pituitary owing to heavy lympho-
cytic infiltration112. Isolated deficiency of single pituitary
hormones may occur, for example, as isolated ACTH
deficiency, but more often, multiple pituitary hormone
deficiencies are observed in patients. Autoimmune
hypophysitis has been reported as an important adverse
effect of ICIs, especially ipilimumab (an anti-​CTLA4
antibody)113. Besides autoimmune hypophysitis and
ICI-​induced hypophysitis, IgG4-​related disease also
leads to IgG4-​related hypophysitis owing to the infiltra-
tion of IgG4-​positive plasma cells into the pituitary gland
alongside infiltration of other organs114,115. Furthermore,
9–15% of patients on long-​term opioid therapy develop
SAI50,51,116 probably owing to blunted ACTH responses,
loss of diurnal rhythm and negative effects of opioid on
adrenal glucocorticoid production. Long-​term opioid
analgesia therapy also impairs the hypothalamic–
pituitary–gonadal axis, with secondary hypogonadism
observed in 75% of men and 21% of women50,51,117,118.
Congenital forms of SAI. Congenital SAI is very rare and
usually results from abnormalities in transcription factors
involved in the differentiation of anterior pituitary cells
(for review see refs119,120) (Table 3). For example, mutations
in PROP-1 and TPIT have been shown to result in ACTH
deficiency. Mutations in PROP-1 are the most common
cause of familial and sporadic congenital combined
pituitary hormone deficiency121. Patients with PROP-1
mutations demonstrate ACTH deficiency; however, it
is unknown whether ACTH deficiency in these patients is
a consequence of corticotroph attrition or pituitary hyper-
trophy, followed by pituitary degeneration. Congenital
forms of SAI often demonstrate atypical pheno­typic
presentation, such as post-​pubertal presentation or adult
progression of hormonal deficiencies122.
Adrenomedullary function in AI
In patients with PAI and SAI, besides a lack of cortico­
steroids, studies have found reduced adrenomedullary
epinephrine production during normal physiological
conditions and in response to stress123–129. By contrast,
norepinephrine levels were increased in the majority of
patients. Although of distinct developmental origins,
the adrenal cortex and the adrenal medulla are func-
tionally closely interconnected. For example, activity of
the enzyme PNMTase, which catalyses the conversion
of norepinephrine to epinephrine, requires high local
glucocorticoid concentrations from the adrenal cortex
through a rich blood supply130,131. These intra-​adrenal
cortisol levels cannot be achieved by standard glucocor-
ticoid replacement therapy. Nevertheless, the clinical
relevance of reduced epinephrine levels and diminished
epinephrine response under stressful conditions is yet
to be understood. High levels of norepinephrine and
respective activation of adrenergic receptors may at
least partly compensate for the epinephrine deficiency
regarding sympathomimetic effects129. Epinephrine
deficiency has been hypothesized to contribute to the

Table 3 | Genetic causes of adrenal insufficiency

Causes
Primary adrenal insufficiency
Congenital adrenal hyperplasia
Congenital lipoid adrenal hyperplasia
Adrenoleukodystrophy (X-​linked)
Adrenal hypoplasia congenita
Autoimmune polyglandular syndrome type 1
IMAGe syndrome
Kearns–Sayre syndrome
Lysosomal acid lipase deficiency
(Wolman disease)
Sitosterolaemia
Familial glucocorticoid deficiency or
corticotropin insensitivity syndromes
Triple A syndrome (Allgrove syndrome)
Secondary adrenal insufficiency
Congenital isolated corticotropin deficiency
Combined pituitary hormone deficiency
Prader–Willi syndrome
Table adapted from refs36,120,109,110.
Mechanisms
21-​Hydroxylase deficiency (>95% of patients)
Rare causes in order of prevalence: 11β-​hydroxylase deficiency,
P450 oxidoreductase deficiency, 17α-​hydroxylase deficiency,
3β-​hydroxysteroid dehydrogenase type 2 deficiency
STAR mutations
ABCD1 and ABCD2 mutations
NR0B1 (DAX1) mutations, deletion of genes linked with Duchenne
muscular dystrophy, glycerol kinase, NR5A1 mutations
AIRE mutation
CDKN1C mutations
Mitochondrial DNA deletions
LIPA mutations
ABCG5 and ABCG8 mutations
Mutations in MC2R, MRAP, MCM4 or STAR
AAAS mutations
TBX19 mutations
Mutations in GLI2, HESX1, OTX2, LHX4, LHX3, PROP1, SOX3 or POU1F1
Deletion or silencing of genes in imprinting centre for the syndrome

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Adrenarche
Maturation of the zona
reticularis of the adrenal
resulting in increased
production of adrenal
androgens.
reduced general well-​being and impaired vitality, which
might further impair resistance to stress. The effects of
epinephrine deficiency may be more pronounced in
patients with classic CAH and in patients with other con-
genital forms of AI, as cortisol deficiency may already
have affected adrenal medullary development 125,132.
Clinical studies have suggested that the lack of epi-
nephrine in patients with AI results in reduced glucose
counter-​regulatory response to hypoglycaemia and in
cognitive impairment133,134. So far, however, the exact
clinical relevance of catecholamine deficiency in patients
with AI remains to be established.
Adrenal androgens
Although highly abundant in human circulation, the
physiological role of adrenal androgens and precursors,
DHEA and dehydroepiandrosterone sulfate (DHEAS), is
still not completely understood. In contrast to glucocorti-
coid and mineralocorticoid deficiency, the lack of DHEA
or DHEAS is not life-​threatening. In PAI (except CAH),
DHEA secretion is impaired owing to the destruction
of the zona reticularis and, in SAI, owing to impaired
ACTH stimulation. The lack of DHEA results in pro-
nounced androgen deficiency in woman, whereas in
men, androgen production is preserved by testicular
testosterone secretion.
The physiological secretion of DHEA evolves over
the lifetime of an individual135,136. DHEA levels increase
in the prepubertal years, especially during adrenarche,
reaching peak levels at the end of the third decade of
life, followed by a continuous decline with advancing
age, supporting a role for DHEA in the reproductive
system137,138. A specific DHEA receptor has not yet
been identified. The various effects of DHEA can be
categorized into direct and indirect139. Indirect effects
are mediated via conversion of these major adrenal sex
steroid precursors into active androgens and oestrogens
in the placenta, gonads and peripheral target cells. The
enzymes involved in the conversion of DHEA into active
sex steroids are expressed in different tissues, enabling
local intracrine action of DHEA, independent of changes
in blood hormone levels140. DHEA has been shown to
non-​specifically bind to cell membranes or receptors.
Direct actions of DHEA include neuroprotective and
anti-​depressive effects within the brain (for example, via
binding to GABA(A) receptor subunit α-6 and GluN2A)
and immunomodulatory effects by interaction with
immune cells139,141. The observed impairment of general
well-​being in patients with AI has in part been associated
with lack of neurosteroidal stimulatory activity of DHEA
and androgens139,142.
Adrenal crisis
The pathophysiology of adrenal crisis, a potentially fatal
condition caused by acute cortisol deficiency, is not yet
well understood10. Glucocorticoids have been suggested
to influence stress by permissive, suppressive and stim-
ulating actions143. It has been hypothesized that patients
with untreated AI have a lack of permissive action of
glucocorticoids, leading to impaired responsiveness
of the cardiovascular system143–145. However, stable replace-
ment therapy in patients with chronic AI is thought to
ensure sufficient permissive actions of glucocorticoids,
such as providing sufficient sensitivity to catecholamines
in response to stress146,147. Furthermore, in patients with
PAI, the hyponatraemia and fluid retention caused by

Cholesterol DHEAS

Androgens (zona reticularis)

Pregnenolone 17-Hydroxy-pregnenolone DHEA Androstenediol

Progesterone 17-Hydroxy-progesterone Androstenedione Testosterone

21-hydroxylase deficiency
11-Deoxycorticosterone 11-Deoxycortisol
Glucocorticoids
(zona fasciculata)
Corticosterone Cortisol

18-Hydroxy-corticosterone
Mineralocorticoids
(zona glomerulosa)
Aldosterone

Fig. 6 | Adrenal steroidogenesis and 21-hydroxylase deficiency. Steroidogenesis in the adrenal cortex is catalysed by a
series of steroidogenic enzymes. Cholesterol is the basic substrate that is converted into mineralocorticoids, glucocorticoids
and sex steroids in the respective adrenocortical zones. Congenital adrenal hyperplasia is caused most frequently by
mutations in CYP21A2 (encoding the enzyme 21-​hydroxylase). This enzyme converts 17-​hydroxy-​progesterone to
11-​deoxycortisol and progesterone to 11-​deoxycorticosterone, which are precursors for cortisol and aldosterone. Impaired
cortisol synthesis leads to increased adrenocorticotropic hormone stimulation of the adrenal cortex, with accumulation
of steroid precursors upstream of the enzyme block and increased conversion to sex steroids, mainly androgens.
DHEA, dehydroepiandrosterone; DHEAS, dehydroepiandrosterone sulfate. Adapted with permission from ref.273, Elsevier.

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Adrenal gland
Stress
Medulla

Zona Zona Epinephrine deficiency

glomerulosa fasciculata
Vasodilation, impaired
effect of catecholamines

Aldosterone Cortisol
deficiency deficiency Hypotension

Capillary

Electrolyte and volume Metabolism Inflammation Increased capillary

regulation permeability

Kidney Adipose Muscle Liver Immune cells

TNF
IL-1
IL-6
Reduced sodium reabsorption
Increased potassium reabsorption Decreased Increased Glucocorticoid
gluconeogenesis inflammatory receptor insensitivity
Reduced cytokines
Hyponatraemia production of Reduced amino
Hyperkalaemia free fatty acids acid liberation Hypoglycaemia Glucocorticoid
resistance

Toxic effects of
uncontrolled Aggravation of
Hypotension Decreased energy reserves inflammation cortisol deficiency

Fig. 7 | Pathophysiological aspects of adrenal crisis. An imbalance between demand and availability of glucocorticoids
may result in adrenal crisis. This state is characterized by a modified immune response owing to the lack of glucocorticoid-​
mediated immunomodulation, leading to increased inflammatory cytokines further activating pro-​inflammatory pathways.
The cortisol deficiency is further aggravated by a cytokine-​induced glucocorticoid receptor resistance. Furthermore,
cortisol deficiency leads to reduced responsiveness to catecholamines in blood vessels, aggravating the effects of volume
depletion caused by aldosterone deficiency in primary adrenal insufficiency. Cortisol deficiency additionally results in an
impaired mobilization of energy resources owing to reduced hepatic gluconeogenesis, reduced muscular amino acid
liberation and reduced production of fatty acids.

mineralocorticoid deficiency and volume depletion
might worsen hypotension, which is further aggravated
by vomiting and diarrhoea148.
The suppressive activity of glucocorticoids pre-
vents the harmful effects of an overshooting immune
defence 143,149 , potentially primarily mediated by
pro-​inflammatory cytokines. Infections trigger the
release of cytokines such as IL-1, TNF and IL-6. These
cytokines physiologically stimulate the HPA axis and,
therefore, increase systemic cortisol concentrations150.
High cortisol levels in turn inhibit cytokine release
and action, thereby preventing their detrimental
effects151,152. In a murine model of adrenal crisis153, adre-
nalectomy increased sensitivity to the lethal inflam-
matory effects of TNF, whereas adrenalectomized
Tnfr1a-​null and Tnfr1b-​null mice and mice treated with
anti-​TNF serum were resistant to the lethal effects of
lipopolysaccharide153. Thus, studies implicate TNF as a
key mediator of adrenal crisis. In healthy individuals,
pyrexia (fever), infection and other stressful condi-
tions induce an increase in circulating cortisol levels
by increased adrenal production or reduced cortisol
breakdown owing to diminished expression or activity of
cortisol-​metabolizing enzymes154. In addition, increases
in systemic and free bioavailable cortisol are facilitated
by neutrophil elastase cleavage of CBG and pyrexia90.
Thus, it is recommended that an increase in cortisol
levels caused by stressful conditions be mimicked by
carefully adjusting the hydrocortisone dose in patients
with AI155 (Fig. 7).

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Central nervous system
• Anorexiaa
• Weight loss a
• Nausea a
• Salt craving b
• Dizzinessb
Cardiovascular system
• Hypotension and/or
dehydrationb
Haematological system
• Anaemia a
• Lymphocytosis
• Eosinophiliaa
Blood electrolytes
• Hyponatraemiaa,b
• Hyperkalaemiab
• Hypercalcaemiaa
Fig. 8 | Clinical manifestations of adrenal insufficiency. Deficiency of adrenocortical hormones affects all systems in
the human body leading to a wide range of symptoms. Frequent symptoms and their main associations with the respec-
tive deficiency of glucocorticoids, mineralocorticoids and adrenal androgens are demonstrated. PAI, primary adrenal
insufficiency; SAI, secondary adrenal insufficiency. aSymptoms specific to glucocorticoid deficiency; bSymptoms
specific to mineralocorticoid deficiency; cSymptoms specific to adrenal androgen deficiency. Adapted from ref.274,
Springer Nature Limited.
Diagnosis, screening and prevention
Presentation
Adrenal crisis may be the first presentation of AI as the
signs and symptoms of mild and advancing chronic glu-
cocorticoid deficiency are often non-​specific. Hence,
these non-​specific signs are typically not recognized
as AI by health-​care personnel, leading to diagnostic
delays or misdiagnosis. The symptoms of chronic corti-
sol deficiency include fatigue, reduced energy and appe-
tite, stomach ache or diffuse abdominal pain, pain in
joints and muscles, weight loss and increased cold sen-
sitivity (Fig. 8). Skin hyperpigmentation is a specific sign
indicative of PAI, but the severity of hyperpigmentation
differs widely between individuals. As a consequence of
the associated autoimmune disorders in PAI, additional
symptoms and signs specific to the comorbidities may be
present in patients15. Low blood pressure with increased
postural drop and salt craving might be signs of aldos-
terone deficiency in patients with PAI. DHEA deficiency
is usually associated with loss (or lack of development)
of axillary and pubic hair, dry and itchy skin, reduced
energy and loss of libido in women.
Clinical manifestations of AI in childhood include
failure to thrive, recurrent infections, family history of
neonatal deaths or early postnatal deaths, ambiguous
genitalia at birth and hepatitis156.
In routine laboratory testing, hyponatraemia, hyper-
kalaemia and hypoglycaemia specifically can increase
clinical suspicion for PAI; hypercalcaemia is rarely
observed in patients1,157.
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Neuropsychiatric system
• Depressiona,c
• Fatiguea
• Reduced libidoc
Gastrointestinal system
• Diarrhoea
• Vomitinga
• Abdominal paina
Dermatological system
• Dry skinc
• Hyperpigmentation (PAI)
• Hypopigmentation (SAI)
• Loss of pubic/axillary hairc
Musculoskeletal system
• Myalgiaa
• Joint pain
• Weaknessa
Besides the above-​mentioned symptoms of glucocor-
ticoid deficiency and androgen deficiency, in patients
with SAI, there is often complete hypopituitarism with
growth impairment, and gonadal and thyroid hormone
dysfunction, depending on the underlying aetiology. The
onset of SAI can be acute, although chronic development
might happen in certain individuals. As pituitary adeno-
mas are one of the most common causes of SAI, SAI can
be the initial clinical presentation of a pituitary tumour.
Diagnosis
Primary adrenal insufficiency. The awareness of PAI is
crucial, especially owing to the fact that most patients
are diagnosed only after years of non-​specific symptoms
such as fatigue, poor well-​being, postural dizziness, nau-
sea and weight loss, which are frequently attributed to
other causes9. Treatment of suspected acute manifesta-
tion of AI should never be delayed by performing (or
awaiting the results of ) diagnostic procedures. The
diagnostic test for suspected PAI is a paired measure-
ment of serum cortisol and plasma ACTH. A morning
serum cortisol of <140 nmol/l (5 µg/dl) in combination
with increased ACTH levels (twice the upper normal
limit) is confirmative of PAI. Cortisol concentrations
vary according to the assay used and, therefore, check-
ing the reference ranges with the relevant laboratory
is recommended158. Mass spectrometry analyses have
been shown to detect lower cortisol concentrations than
immunoassays owing to enhanced assay specificity159.
In individuals whose morning cortisol levels are

ACTH 1–24 stimulation test
Also known as the Synacthen
test or corticotropin-​
stimulation test. This test
is commonly used for the
assessment of adrenal
cortisol production. Cortisol
serum levels are measured
before and 30–60 min after
supraphysiological stimulation
with synthetic 1–24 ACTH.
NATURE REvIEWS | DiSeASe PriMerS | Article citation ID:
≥140 nmol/l, an ACTH 1–24 stimulation test (also known
as the short Synacthen test or corticotropin-​stimulation
test) using a 250-​μg dose of synthetic ACTH 1–24 can
be useful to assess the proper functioning of the adre-
nal glands. A peak serum cortisol concentration of
<450 nmol/l 30 min after ACTH stimulation or a peak
concentration of <500 nmol/l 60 min after ACTH stim-
ulation establishes a positive diagnosis of AI160–162. These
cut-​off values were developed using immunoassays
having high cross-​reactivity with non-​cortisol steroids,
leading to a higher response than assays with less cross-​
reactivity or with mass spectrometry. Therefore, future
research establishing criteria and cut-​off values with cur-
rent new assays and methods is warranted. Combined
plasma renin and aldosterone levels should be measured
to determine the presence of mineralocorticoid defi-
ciency, indicated by low or low–normal aldosterone in
the presence of increased levels of renin.
Once a diagnosis of PAI is established, the aetiol-
ogy should be investigated. In geographical regions
with a high prevalence of Addison disease, patients
should be evaluated for the presence of 21-​hydroxylase
autoantibodies in the serum. If patients test positive
for autoantibodies, they should be screened for con-
comitant autoimmune comorbidity. Negative testing
for 21-​hydroxylase autoantibodies does, however, not
exclude autoimmune PAI. In patients with a negative
autoantibody test, CT imaging of the adrenal region
is recommended to rule out inflammatory processes
or destruction of the adrenal glands by haemorrhage or
infiltration, for example, by bilateral metastases of
an extra-​adrenal cancer28,163,164. In men with negative
21-​hydroxylase autoantibodies, adrenoleukodystrophy
should be ruled out by measuring the levels of very long
chain fatty acids in serum. In sub-​Saharan Africa, the
most common aetiologies of PAI, such as tuberculosis
and HIV infection, should be investigated to enable
treatment of the underlying condition5.
Secondary adrenal insufficiency. The diagnostic tools
used to confirm the presence of SAI vary widely among
countries and even among different endocrine centres
in the same country165. In general, any study evaluat-
ing assay-​specific cut-​off values is limited by the lack
of a well-​established gold standard to define SAI1,166.
Assessing the stress responsivity of the HPA axis in
patients with known or suspected pituitary disease is
extremely important167. In general, besides the thyreo-
tropic axis, the corticotropic axis is one of the last ana-
tomical units to be lost in structural pituitary disease
including tumours or trauma, although autoimmune
hypophysitis may cause isolated ACTH deficiency A
history of traumatic brain injury or stroke and hypon-
atraemia with the presence of symptoms, such as con-
centration and cognitive deficits, nausea, vomiting,
confusion, headache, somnolence and seizures, should
prompt further investigation for potential SAI.
A morning serum cortisol of <100 nmol/l in com-
bination with a low or low–normal ACTH level is con-
firmative of SAI, whereas a morning serum cortisol
of >450 nmol/l excludes SAI167. The insulin tolerance
test is regarded by most clinicians as the reference
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standard test for confirming the diagnosis of SAI. The
insulin tolerance test can determine the integrity of
the HPA axis by inducing a severe hypoglycaemic state,
which activates the stress hormone axis and all insulin
counter-​regulating hormones (for example, cortisol and
growth hormone)168. The insulin tolerance test involves
the administration of an acute bolus dose of intravenous
insulin to induce symptomatic and biochemical hypo-
glycaemia (blood glucose ≤40 mg/dl or 2.2 mmol/l), with
serum cortisol and plasma ACTH measured at frequent
intervals for 120 min. Owing to hypoglycaemia, the test
is usually uncomfortable for the patient and requires
a high degree of supervision, especially as the induc-
tion of hypoglycaemia is unsafe in patients with or at
risk of epilepsy, or cerebrovascular or cardiovascular
disorders. The diagnosis of SAI is ruled out if serum
cortisol peak values in the insulin tolerance test reach
at least 550 nmol/l (ref.1) or, as stated by some authors,
>500 nmol/l (refs56,165,169,170).
Owing to the low risks and the ease of testing, the
ACTH 1–24 stimulation test described above is the most
widely performed test for SAI165,167. A peak serum cor-
tisol of >550 nmol/l is regarded as a normal response
(although assay-​dependent). The loss of adrenal cor-
tisol response subsequent to manifestation of ACTH
deficiency develops over time and, therefore, the short
ACTH 1–24 test should not be utilized in the early
postoperative period, that is <6 weeks after pituitary
surgery171,172. However, the ACTH 1–24 test can be
useful for predicting HPA axis recovery56. The stimu-
lation of the pituitary–adrenal axis with synthetic CRH
excludes the direct assessment of hypothalamic function.
Although CRH testing is used in some centres, it is not
known to be superior to the ACTH stimulation test165,167.
The metyrapone test is based on metyrapone-​
mediated inhibition of the 11β-​hydroxylase enzyme,
which catalyses the final step of cortisol synthesis,
thereby evoking an increased ACTH response by an
intact pituitary. Patients are usually given metyrapone
at midnight with a snack, and blood samples for analys-
ing ACTH, 11-​deoxycortisol and cortisol are obtained
after 8 h. An increase in plasma 11-​deoxycortisol to
>200 nmol/l suggests an intact HPA axis173. In search
of increased sensitivity and specificity of the test, other
studies have suggested the use of the sum of serum
11-​deoxycortisol and cortisol with a cut-​off value of
450 nmol/l owing to assay cross-​reactivity174 or a com-
bination of ACTH response and increase in plasma
11-​deoxycortisol levels175.
The glucagon stimulation test is rarely used but it
may also be an acceptable alternative to the insulin tol-
erance test for evaluating the HPA axis176. In the future,
measurement of basal salivary cortisol and salivary
cortisone might improve the screening of SAI, owing
to its simplicity and cost-​effectiveness and because it
is independent of binding proteins such as albumin or
CBG177,178.
Screening
Universal newborn screening for CAH has already been
implemented in most developed and many developing
countries. Timely screening is an important diagnostic
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tool, guaranteeing timely initiation of replacement
therapy179,180. As is the case for many rare diseases, it is
important to have AI as a potential differential diag-
nosis in mind; for example, patients with other auto-
immune diseases such as hypothyroidism or type 1
diabetes mellitus should be screened for PAI. Similarly,
patients with other pituitary hormonal insufficiencies
should be screened for SAI. Screening for AI should be
considered in all patients presenting with unexplained
hyponatraemia, hypotension, vomiting or diarrhoea157.
The optimal schedule for screening for associated
immune disorders in patients with Addison disease is
not established. Annual testing for thyroid disease, dia-
betes mellitus, premature ovarian failure, coeliac disease
and autoimmune gastritis with vitamin B12 deficiency
may be regarded as appropriate15.
Management
Different guidelines or consensus statements for the
management of AI exist. These guidelines includ-
ing those published by the US Endocrine Society, the
European Society of Endocrinology, and specialist soci-
eties in the UK and Japan and other countries. Although
the dosage detail might slightly vary, the goals of the
treatment remain similar across all guidelines15,155,181,182.
The most important goals of AI treatment include:
achieving the optimal glucocorticoid dosing regi-
men; improving patient quality of life and daily life
performance; avoiding the risks of over-​replacement,
Box 1 | Pregnancy and adrenal insufficiency
Pregnancy is physiologically associated with increased levels of corticotropin-​releasing
hormone, adrenocorticotropic hormone, and free and total cortisol275. Studies have found
reduced fertility rates, increased risk of preterm birth and postpartum complications
in patients with adrenal insufficiency (AI)275–279, emphasizing the need for optimal
surveillance in planned or ongoing pregnancy. Risk of premature ovarian insufficiency
has been found in 5–16% of premenopausal women with Addison disease15,67. The rate
of delivery via caesarean section is increased, partly owing to a lower threshold for
recommending caesarean section276,278,280. In women with congenital adrenal
hyperplasia (CAH), the birth rate is lower than in controls, gestational diabetes and
caesarean section are more common than in controls, but perinatal outcomes are
comparable to those in controls281. Women with secondary adrenal insufficiency (SAI)
may have infertility due to concomitant gonadotropic insufficiency and need additional
therapies including ovulation induction. In general, the majority of women with AI
experience a pregnancy with good fetal and maternal outcomes.
In pregnant women with AI, adjustment of the hydrocortisone dose is crucial15,280.
The adjustment is usually implemented in weeks 20–24 of pregnancy with further
adjustment based on clinical assessment. Given the anti-​mineralocorticoid effect
of progesterone282,283 and because its circulating concentrations increase during
pregnancy, fludrocortisone dose may need adjustment. Physicians should rely on
blood pressure and serum electrolytes to judge fludrocortisone dosing as pregnancy
increases renin concentrations284,285. Hydrocortisone dose should be increased during
stressful events in a similar manner to its adjustment in non-​pregnant patients with AI.
Placental expression of 11β-​HSD2 results in rapid cortisol inactivation and prevents
glucocorticoid over-​exposure of the fetus286. However, this inactivation does not occur
with synthetic corticosteroids (for example dexamethasone) and, therefore, synthetic
glucocorticoids should be avoided unless glucocorticoid effects on the fetus are desired.
Spontaneous delivery is the preferred way of delivery. However, in women with CAH,
vaginal delivery may be impossible as a consequence of genital corrective surgery and,
therefore, should be assessed individually by a gynaecologist. Major hydrocortisone
stress dose cover should be initiated upon entering the active stage of labour. Clear
communication with the obstetric department is necessary and should include written
instructions on hydrocortisone replacement.
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specifically metabolic syndrome, cardiovascular disease
and osteoporosis; and preventing mortality, particularly
due to adrenal crisis183.
Glucocorticoid replacement
The standard tenet in endocrinology is that hormone
replacement should aim to restore normal physiology
and health. In healthy individuals with a regular diur-
nal sleep pattern, cortisol levels rise between 2 a.m. and
4 a.m., reaching a peak shortly after waking, and decline
over the day to low levels from approximately 6 p.m.,
with slight increases at meal times184. Attaining phys-
iological cortisol profiles with existing treatments has
been unachievable so far, owing to the inability of the
medications to replicate the native circadian rhythm of
cortisol. Consequently, no markers of biological activ-
ity that predict morbidity and mortality are available to
date. Cortisol measurements are usually not useful in
monitoring the quality of replacement therapy. If hydro-
cortisone or cortisone acetate is used for replacement,
cortisol measurements are just reflective of the medica-
tion or are inaccurate in the case of prednisolone doses
owing to cross-​reactivity in immunoassays. However, in
some cases, for example, when a discrepancy between
daily doses and patient symptoms exists, measurement
of a cortisol profile might be helpful for examining the
gastrointestinal absorption of hydrocortisone. Thus, it
is suggested that the prescribing physician should titrate
the glucocorticoid dose based on patient symptoms of
cortisol deficiency and excess. Insufficient hydrocorti-
sone doses result in fatigue, weight loss and nausea, and
might lead to adrenal crisis. On the other hand, high
hydrocortisone doses can cause cortisol excess with
features of Cushing syndrome including weight gain,
increased abdominal fat, buffalo hump, thin skin, easy
bruising, hypertension and type 2 diabetes mellitus.
Many patients with AI complain of fatigue despite treat-
ment and evidence suggests that simply increasing the
glucocorticoid dose does not resolve the symptoms185.
In children with AI, monitoring of height and weight
is essential practice. In children, replacement doses are
prescribed as dose per body surface area, whereas in
adult patients treatment-​initiating doses are prescribed
according to guidelines for the specific glucocorti-
coid and adapted based on clinical follow up15,155,181,182.
In general, in patients with PAI a complete replacement
of the daily cortisol production is necessary, whereas
in SAI a near-​complete replacement dose is often suf-
ficient as patients with SAI might have residual ACTH
secretion. In pregnant patients with AI the hydrocor-
tisone doses need to be adjusted during the course of
pregnancy (Box 1).
Hydrocortisone (the pharmaceutical name for cor-
tisol) is the first-​line glucocorticoid replacement for
patients with AI. The plasma half-​life of hydrocortisone
is ~90 min and is, therefore, dosed twice or thrice daily
with the highest dose given in the morning on awaken-
ing, the next dose given early afternoon (two-​dose reg-
imen) or at lunch and afternoon (three-​dose regimen),
to replicate the circadian rhythm15. Plenadren is a dual-
release hydrocortisone drug that enables once-daily
dosing of hydrocortisone. This formulation consists of

a coated outer layer that provides immediate release
of the drug and an extended-​release inner core186.
However, Plenadren has ~20% less bioavailability than
immediate release hydrocortisone187. Open-​label studies
of Plenadren have shown reductions in BMI in adults
with AI after changing from hydrocortisone and these
changes were sustained after 12 months of treatment
with improvements in lipid profile. However, whether
this finding was a consequence of lower overall expo-
sure to hydrocortisone owing to reduced bioavailabi­
lity or related to the pattern of hydrocortisone release
is unclear188,189. One new study demonstrated improved
immune cell profiles and reduced susceptibility to
infections in patients after switching to Plenadren190.
Prednisolone, a synthetic glucocorticoid, is more
potent with a longer duration of action with an elim­
ination half-​life of 150 min. Prednisolone has less
mineralocorticoid activity than hydrocortisone and is
reco­mmended in patients with poor compliance15. In some
countries, cortisone acetate is used for replace­ment
therapy. Prednisone and cortisone acetate are precur­sors
of prednisolone and cortisol, respectively, and require
activation by hepatic 11β-​hydroxysteroid dehydro­genase
type 1 to show biological activity. Dexamethasone, a
potent, albeit difficult to titrate glucocorticoid is gen-
erally not recommended for replacement therapy in
AI owing to its complete lack of mineralocorticoid
activity and its association with poor health outcomes
in patients with CAH105,191. In addition, dexametha-
sone does not exert any mineralocorticoid activity, as
opposed to cortisol, where a 40-​mg dose of hydrocor-
tisone exerts mineralocorticoid activity equivalent to
100 µg of fludrocortisone. Findings from studies using
continuous subcutaneous infusions of hydrocortisone in
small subsets of patients with PAI are inconsistent, with a
few studies showing improved quality of life192 and a few
reporting otherwise193. In addition, continuous subcuta-
neous infusions of hydrocortisone have been shown to
improve symptoms of CAH194, although skin reactions
are common. The treatment of CAH has the additional
challenge of controlling excess androgens in addition to
replacing cortisol. Current oral therapies with hydro-
cortisone, prednisolone and even dexamethasone can-
not control androgen excess despite following dosing
in a reverse circadian fashion with a dose just before
bedtime105,191. Chronocort, a modified-​release hydro-
cortisone under development, differs from Plenadren
by having a delayed and sustained absorption profile
rather than an immediate-​release and sustained-​release
profile195. Chronocort aims to mimic the physiological
cortisol levels such that the night-​time dose releases
hydrocortisone in the early hours of the morning,
providing physiological waking hour cortisol levels195.
A phase II open-​label study of Chronocort in 16 adults
with CAH showed improved biochemical control of
CAH196. Furthermore, a phase III study of Chronocort
showed improved morning control of adrenal androgens
compared with standard therapy197. A newly developed
CRFR1 antagonist has been shown to offer an additional
strategy to reduce ACTH production without increasing
glucocorticoid therapy above physiological replacement
doses in patients with CAH198.
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Mineralocorticoid replacement
Patients with PAI, in particular those with Addison
disease or the salt-​wasting form of CAH, and patients
after bilateral adrenalectomy require mineralocorti-
coid replacement if aldosterone production is impaired.
However, residual aldosterone production was found
in ~13% of patients with Addison disease199. The goal
of therapy is to achieve general well-​being, prevent salt
craving, and restore normal blood pressure and normal
serum electrolyte levels15,200.
Aldosterone by itself is not used in replacement
therapy owing to its short half-​life and rapid hepatic
metabolism after oral ingestion. The preferred min-
eralocorticoid preparation for replacement therapy is
9α-​fluorocortisol (also known as fludrocortisone) which
has a 200–400-​fold higher mineralocorticoid potency
than hydrocortisone201. Its introduction into clinical
practice ended the use of deoxycorticosterone, which
had been used since the 1960s. Fludrocortisone is more
stable, available in tablet form and can be better titrated
to regulate its biological effects. Fludrocortisone also
balances the other well-​known symptoms of aldosterone
deficiency, such as electrolyte imbalance (hyperkalaemia
and hyponatraemia), hypovolaemia and hypotension.
However, the fact that the mineralocorticoid receptor
is also expressed in several brain regions might explain
the effect of fludrocortisone on cognitive function
and mood, with better performance in patients with
high mineralocorticoid receptor occupancy following
fludrocortisone uptake202.
Children and young adults may require higher doses
of fludrocortisone than most adult patients with PAI201
as the mineralocorticoid receptor is less sensitive in chil-
dren and, therefore, mineralocorticoid requirements
should be re-​assessed during late adolescence or early
adulthood. Additionally, patients on prednisolone or
dexamethasone might require higher fludrocortisone
doses, owing to their lower mineralocorticoid activity
than hydrocortisone. In patients who develop essential
hypertension during their lifetime, hydrocortisone dose
should be re-​e valuated and the fludrocortisone
dose may be reduced depending on plasma renin and
electrolyte levels but should not be discontinued. A direct
vasodilator (for example, calcium antagonist) is prob-
ably the best choice of anti-​hypertensive treatment in
patients with PAI. Diuretics, especially aldosterone anta­
gonists, such as spironolactone or eplerenone, should
be avoided203. In patients with PAI and heart failure,
angiotensin-​converting enzyme inhibitors, angiotensin II
antagonists or β-​blockers are recommended, and the use
of mineralocorticoid receptor antagonists and/or dis-
continuation of fludrocortisone should be decided on an
individual basis203. The effects of fludrocortisone might
not last for 24 hours because of faster elimination rates in
some patients; in these patients, twice-​daily fludrocorti-
sone is recommended. Patients with mineralocorticoid
deficiency are allowed to consume sodium salt and salty
foods without restriction.
Monitoring of mineralocorticoid replacement ther-
apy is performed by questioning the patient about salt
craving, light-​headedness or orthostatic dysregula-
tion, by measuring blood pressure, by examining for
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the presence of peripheral oedema148 and by measur-
ing serum potassium and sodium levels. The meas-
urement of plasma renin levels might potentially be
useful200,204, especially in determining mineralocorticoid
under-​replacement205. However, plasma renin levels
might be high in women using hormonal contraceptives,
owing to the stimulation of plasma renin substrate by
oestrogen and, therefore, should be used with caution
for monitoring purposes. Fludrocortisone-​mediated
regulation of the extracellular fluid volume and blood
pressure changes following dose changes are only seen
after several days or weeks. Therefore, fludrocortisone
dose changes should not be monitored earlier than
2–4 weeks after changing the dose201,206,207. Rapid weight
gain, high blood pressure, oedema and hypokalaemia
indicate an excessive dose of fludrocortisone148.
Phenytoin, phenobarbital, rifampicin and mitotane
induce hepatic 6β-​hydroxylation via CYP3A4, one of
the major 9α-​fluorocortisol metabolic pathways. Patients
with PAI on these drugs need increased doses of fludro-
cortisone and also of hydrocortisone as drug-​mediated
CYP3A4 induction results in more rapid inactivation
of cortisol208. In situations of increased salt loss such
as sweating in a hot climate, transiently increasing the
fludrocortisone dose and/or the salt intake might be
useful148. This dosing is often routinely followed during
the summer months in countries with a hot climate.
Patients with PAI receiving high doses of hydrocortisone
(>50 mg per day) do not need an additional fludrocor-
tisone dose as such high hydrocortisone doses provide
sufficient mineralocorticoid activity.
DHEA replacement
Most, but not all trials investigating the effect of DHEA
replacement in patients with AI have demonstrated a
positive influence on mood and subjective health status
and on libido (particularly in women)142,209–212. These
effects were generally moderate and showed marked
inter-​individual variability, with the most significant
effects observed in women. However, large-​scale out-
come studies of chronic DHEA supplementation are
lacking and, therefore, DHEA replacement is not a
mandatory part of the standard replacement regimen in
patients with AI. Nevertheless, clinical signs of andro-
gen deficiency in women with AI may be successfully
treated by DHEA replacement. Evidence shows a role for
DHEA in immunomodulation; for instance, oral DHEA
replacement has been shown to restore normal levels of
regulatory T cells in patients with Addison disease213.
In addition, rodent-​based studies have suggested that
DHEA enhances natural killer cell function213. However,
another study that documented highly decreased natu-
ral killer cell cytotoxicity in patients with PAI did not
find any improvement of natural killer cell cytotoxicity
in patients with established DHEA replacement. This
finding implies that the decreased natural killer cell cyto-
toxicity might rather be due to glucocorticoid-​induced
alterations in clock gene regulation in natural killer cells.
Although increased IGF1 levels have been docu-
mented following initiation of DHEA replacement
(which may be of relevance for patients receiving growth
hormone replacement therapy), only minor effects on
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body composition, bone composition or turnover
markers, metabolic or cardiovascular parameters were
observed in patients with AI receiving DHEA replace-
ment, indicating no relevant anabolic activity212,214–217.
A meta-​analysis of DHEA trials in women with PAI or
SAI focusing on quality of life, depression, anxiety and
sexual well-​being revealed only minor effects of DHEA
and the data were not sufficiently compelling to support
routine use of DHEA218. The decision to initiate DHEA
replacement is made on an individual basis, with a focus
on women with impaired well-​being associated with
signs and symptoms of androgen deficiency, such as
dry skin and reduced libido219. A single oral morning
dose of 25–50 mg DHEA, with evaluation of beneficial
effects and adverse effects after 6 months of replacement,
is recommended15,139. Patients need to be informed that
it may take several months for beneficial effects to occur.
Monitoring of treatment includes clinical evaluation of
androgenic effects and the measurement of morning
serum DHEAS, androstenedione, testosterone and sex
hormone binding globulin prior to the intake of the daily
DHEA dose, aiming at a mid-​normal reference range.
Adverse effects
Osteoporosis. Until 2009, studies investigating bone min-
eral density (BMD) in patients with AI included only a
small number of patients (<30) and found contradictory
results. A two-​cohort cross-​sectional study in Norway, UK
and New Zealand (in 292 patients), showed that patients
on an average daily hydrocortisone dose of 30 mg per day
had a significantly lower BMD than population-​based
controls, and BMD decreased further with increasing daily
glucocorticoid doses220. By contrast, patients with AI who
received lower daily doses of hydrocortisone than typi-
cally used in replacement therapy (mean 12.0 ± 2.7 mg/m2)
had BMD values within the normal reference range221.
In addition, a prospective, longitudinal study demon-
strated that cautious reduction of glucocorticoid doses
led to increases in BMD, whereas dose increments
reduced BMD in patients with PAI222. A population-​based
cohort study found a nearly doubled risk of hip fracture
in patients with PAI compared with controls (HR 1.8,
95% CI 1.6–2.1; P < 0.001)223. A cross-​sectional study in
365 patients with SAI showed an association between
glucocorticoid replacement and reduced BMD, inde-
pendent of other known risk factors such as patient age224.
However, evidence shows that growth hormone deficiency
is the main determinant of skeletal fragility in patients
with hypopituitarism, and growth hormone replacement
therapy normalized fracture risk in these patients225,226.
Among different glucocorticoids used for replacement,
prednisolone use was associated with the worst BMD in
patients with PAI221,222 and in patients with CAH227.
Cardiovascular morbidity and metabolic syndrome.
Although glucocorticoid excess is a well-​known risk fac-
tor for adverse cardiovascular and metabolic outcome,
the question arises as to whether non-​physiological
cortisol profiles achieved by standard replacement
can also contribute to such adverse effects. In general,
cardiovascular mortality was found to be increased in
patients with AI compared with the general population65.

A study utilizing the US-​based national payer database
including 10,383 patients with AI (1,014 patients with
PAI, 8,818 patients with SAI and 551 patients with
CAH) revealed that the odds ratios for diabetes melli-
tus, hypertension and hyperlipidaemia were significantly
higher in patients with AI than in matched controls
from the same database23. By contrast, the prevalence of
these cardiovascular risk factors did not differ between
549 Swedish patients with Addison disease and controls34.
Several analyses have indicated that discrepancies in
cardiovascular risk might be due to dose differences
in and the timing of glucocorticoid replacement. For
example, hydrocortisone doses in the late afternoon or
evening impaired insulin sensitivity more than morn-
ing doses134,228,229. In addition, patients with SAI with
daily hydrocortisone-​equivalent doses of >20 mg were
at increased risk of developing signs and symptoms of
the metabolic syndrome230. Another Swedish analysis
involving 1,500 patients with PAI found an increased
risk of ischaemic heart disease but not cerebro­vascular
disease, particularly in women, compared with the
general population231. This study showed a significant
positive correlation between the prevalence of ischae-
mic heart disease and the doses of glucocorticoid and
Box 2 | Sick day rules for stress dosing with glucocorticoids
Cortisol levels increase in response to stress to cover the body’s increased need for
protective stress hormones. Accordingly, extra doses of glucocorticoids must be
given under respective circumstances in patients with AI. Sick day rules are a set of
recommendations for glucocorticoid dose adjustment under specific circumstances
to prevent adrenal crisis10,15.
Conditions
• Management of illness with fever at home (sick day rule 1) should include doubling
(if fever >38 °C) or tripling (if fever >39 °C) of oral hydrocortisone replacement dosing
until recovery (usually after 2–3 days).
• If the patient is unable to tolerate oral medication owing to vomiting and/or
diarrhoea, trauma, high fever and clinical deterioration (sick day rule 2), 100 mg
parenteral (intramuscular or subcutaneous) hydrocortisone should be given and
health professionals contacted in case of initial self-​treatment.
Medical procedures
• For minor or moderate surgical stress and major dental procedures, 100 mg
hydrocortisone as a subcutaneous bolus before anaesthesia or as an intravenous
infusion for the duration of surgery should be given.
• For major surgery with general anaesthesia, trauma, delivery or disease that requires
intensive care, 100 mg hydrocortisone as an intravenous injection followed by
continuous intravenous infusion of 200 mg hydrocortisone over 24 h is recommended;
alternatively, if continuous administration is not possible or feasible, an intravenous or
intramuscular bolus of 50 mg hydrocortisone every 6 h should be administereda.
Acute adrenal crisis
• 100 mg hydrocortisone as an intravenous bolus injection followed by 200 mg
hydrocortisone as a continuous infusion over 24 h should be administered;
subsequently, dosing should be tapered and switched to oral administration
according to the patient’s clinical condition.
• Fluid resuscitation should be tightly monitored and should involve administration of
up to 1,000 ml isotonic saline within the first hour, followed by continuous intravenous
isotonic saline guided by individual patient needs, particularly taking into consideration
plasma sodium levels and urinary excretion.
a
Different glucocorticoid supplementation schemes for surgical procedures exist that are
tailored to the severity of the surgery287; of note, one study showed that continuous intravenous
infusion is the best scheme for surgical procedures146.
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mineralocorticoid used. Another study involving
588 patients with CAH and 58,800 matched controls
showed that morbidity associated with cardiovascular
disorders (hypertension, atrial fibrillation and venous
thromboembolism) and metabolic disorders (dys-
lipidaemia, obesity, diabetes mellitus and obstructive
sleep disorder) was increased in patients with CAH232,
with women being generally more affected than men.
Furthermore, the specific glucocorticoid preparation
seems to play a part; for example, longer-​acting pre­
dnisolone was associated with a worse lipid profile than
hydrocortisone in patients with PAI and SAI233. Similarly,
dexamethasone caused a more adverse metabolic
risk profile in patients with CAH than shorter-​acting
glucocorticoids191,234,235.
Hypertension may occur in PAI and SAI, although it is
less frequently observed than in the general population34.
Patients with PAI with hypertension have to be assessed
for signs of mineralocorticoid over-​replacement, such
as low renin levels; however, in most patients the min-
eralocorticoid dose may be maintained. High doses of
hydrocortisone can cause hypertension, but might also
promote the progression of atheromatous vascular dis-
ease and may contribute to the increased number of pre-
mature cardiovascular deaths among patients with AI65.
An open crossover study in ten men with SAI who
were randomized to three hydrocortisone dose regi-
mens (each over 6 weeks), demonstrated that the lowest
dose regimen (10 mg–5 mg–0 mg) was associated with
the greatest lowering of blood pressure, and this was
supported by the findings of another study236,237. Thus,
mineralocorticoid dose as well as glucocorticoid replace-
ment dose needs to be carefully evaluated in patients
with hypertension.
Adrenal crisis
The management of adrenal crisis or acute AI is straight-
forward and, if delivered promptly, highly successful.
An initial intravenous or intramuscular bolus injection
of 100 mg hydrocortisone should be followed prefer-
ably by continuous intravenous infusion of 200 mg of
hydrocortisone per 24 hours, or alternatively, by intra-
venous or intramuscular bolus injections of 50 mg of
hydrocortisone every 6 hours. A pharmacokinetic study
demonstrated that continuous intravenous infusion can
prevent the intermittent troughs in circulating corti-
sol observed with intramuscular or intravenous bolus
injections146. After the initial treatment period and
with recovery of the patient, the hydrocortisone dose
should be tapered in line with the clinical response of
the patient, with close monitoring of blood pressure
and clinical symptoms. Intravenous glucose may be
needed, in particular in children, in whom concomi-
tant hypoglycaemia is much more frequently observed
than in adults238. Transfer to oral hydrocortisone within
24 hours is possible if there is no ongoing underlying
inflammatory precipitant. Intravenous fluids, gener-
ally isotonic saline, should be given generously, albeit
under tight monitoring to avoid either exacerbation
or too-​rapid correction of hyponatraemia10,239 (Box 2).
Treatment of the precipitating cause of the crisis is essen-
tial. After fluid resuscitation, it is advisable to consider
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Box 3 | Patient education and prevention of adrenal crisis
Patient education pursues several goals, including: improving quality of life and daily
life performance by providing a better understanding of the disease and knowledge on
options for action by the patient; reducing morbidity from chronic over-​replacement or
under-​replacement; and reducing mortality by prevention or optimal management of
emergency situations.
Education is key for preventing adrenal crisis. One study showed that only 30–66% of
patients were equipped with glucocorticoids for emergency use11,69,288. In patients with
AI, rapid situational dose adaptation is frequently required to adapt the corticosteroid
supply to the body’s need. Glucocorticoid administration by health professionals in
case of emergencies can be delayed265; a well-​trained patient (or relative) is therefore
crucial for optimal management. Education in dose adjustment and self-​injection of
glucocorticoids enables patients to manage daily challenges more independently267.
All patients with AI have to be equipped with a steroid emergency card and
prescription for an additional supply of oral glucocorticoids as well as a hydrocortisone
self-​injection kit for emergency management. Patients require education to recognize
signs and symptoms of adrenal crisis and on the correct behaviour in the event of
an emergency, which includes explanation of sick day rules and training in hydrocortisone
emergency self-​injection10,15. Patients need written instructions on glucocorticoid dose
adaptation in case of medical interventions. Clinical data on correct stress dosing are
limited and many recommendations are based on expert opinion and may show slight
variations.
Studies have demonstrated the benefit of structured education strategies, revealing
a significant increase in knowledge on AI and its management as well as improved
subjective self-​assurance of patients to deal with their disease265–267,289,290. Nevertheless,
assurance in correct handling of emergencies declined after several months267,
indicating that at least bi-​annual repetition of education is necessary for patient
empowerment.
causes and triggers of adrenal crises that may recur and
review preventative measures. Patients should be edu-
cated about the potential seriousness of such events, with
the advice that adequate self-​management makes events
rare and adverse consequences unlikely so that excessive
anxiety is minimized. Delayed treatment of adrenal
emergencies risks death. Delays may be owing to concern
about hydrocortisone-​induced adverse effects. Physician
training and awareness may be insufficient owing to the
rare incidence of adrenal crisis240,241. Improved patient
self-​treatment, particularly with self-​directed delivery
of intramuscular hydrocortisone will help circumvent
these delays. Subcutaneous hydrocortisone may be used
as an alternative to intramuscular hydrocortisone for
prevention of adrenal crisis, as subcutaneous delivery
showed satisfactory and minimally delayed absorption
in volunteers with PAI242. However, its use is off-​label
and it is not clear whether absorption of hydrocortisone
is diminished in the presence of severe clinical deteri-
oration with peripheral vasoconstriction in patients
with hypotension or shock. Parenteral hydrocortisone
administration seems to be superior to rectal supposi-
tories (prednisone), which are used in some patients as
an alternative for crisis prevention15,243. However, the key
strategy for prevention of adrenal emergencies is patient
education and early response to potential risks (Box 3).
Quality of life
The general well-​being of an individual and the expecta-
tions for a good quality of life are influenced by somatic
and mental symptoms. Health-​related quality of life,
assessed by disease-​specific and general questionnaires,
is frequently impaired in patients with PAI and SAI
according to data from several countries, irrespective
18 | Article citation ID: (2021) 7:19 www.nature.com/nrdp
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of the origin of the AI or concomitant disease185,244,245.
Studies have found impairment of physical and emo-
tional health with reduced vitality and increased fatigue
and anxiety3,246–250. In addition, affective and depressive
disorders are highly prevalent in patients with AI23,142,185.
Multiple studies have found high inter-​individual vari-
ation in the quality of life scores, indicating that some
subgroups of patients are more vulnerable than others251.
This difference is also reflected by variable daily perfor-
mance of patients. In general, 40–80% of patients with
AI report disruption of their daily life activities owing
to the disease. Several studies have found occupational
changes in AI, with disability pensions received up to
four times more frequently among patients than among
the general population185,245,252. Interestingly, patients in
whom the diagnosis of AI was delayed had a significantly
worse quality of life than those in whom the diagnosis
was not delayed9.
The underlying causes of impaired quality of life in
patients with AI remain to be elucidated. The effects of
the chronic disease in combination with a lack of DHEA
and epinephrine, and the complexities associated with
non-​physiological mineralocorticoid and glucocorti-
coid replacement discussed above, could all contribute
to the impaired quality of life in patients251. The lack of
circadian and ultradian cortisol tissue exposure is par-
ticularly regarded as a factor contributing to the reduced
quality of life. A cross-​sectional study demonstrated no
differences in the quality of life based on the type of glu-
cocorticoid prescribed252. However, high daily hydro-
cortisone doses were associated with a worse quality of
life status185,244,253, although these studies do not provide
any information about causality. For instance, patients
with hypercortisolism exhibit functional damage in
brain regions involved in stress reactivity and emotional
processing. Patients reporting reduced quality of life are
more likely to receive increased doses of hydrocortisone,
which might further impair quality of life244. Thus, a dose
increase based on a patient-​reported impaired quality
of life always needs re-​evaluation. Non-​blinded stud-
ies have shown that hydrocortisone formulations that
closely mimic the physiological cortisol profile seem to
improve quality of life186,254.
Outlook
Mechanisms and diagnosis
AI is receiving increasing attention, particularly owing
to its association with the use of novel drugs (Table 4).
Timely diagnosis of AI is crucial to prevent negative
long-​term consequences and adrenal crisis. Bearing
in mind that AI is a potential differential diagnosis,
particularly in patients with unexplained hyponatrae-
mia, fatigue, hypotension and weight loss, is key for
timely identification and treatment of patients with
AI. Diagnostic evaluation often remains challenging
in patients with SAI and the optimum diagnostic tests
and cut-​off values remain to be established by large pro-
spective studies. Several open questions remain to be
addressed including the mechanisms associated with
the onset of Addison disease. Future research facilitat-
ing the translation of genetic susceptibility into potential
pathogenetic mechanisms of autoimmune inflammation
 Primer

Table 4 | Drugs inducing adrenal insufficiency

Compounds
Supraphysiological treatment with
glucocorticoid hormones, e.g. prednisone,
prednisolone, dexamethasone, triamcinolone
Opioids, e.g. morphine, fentanyl, tramadol,
methadone or mixed opioids
Mifepristone
Adrenostatic agents, e.g. etomidate,
metyrapone, ketoconazole, osilodrostat
Mitotane
Rifampicin, phenytoin, troglitazone,
phenobarbital
IFNα
Immune checkpoint inhibitors, e.g. avelumab,
ipilimumab, nivolumab, pembrolizumab
ACTH, adrenocorticotropic hormone; HPA, hypothalamic–pituitary–adrenal; IFNα, interferon-​α. Table adapted from refs31,269.
Mechanism
Suppression of the HPA axis through negative feedback on the
hypothalamus and pituitary and induction of tertiary adrenal
insufficiency in case of long-​term treatment
Inhibition of the HPA axis by blocking release of hypothalamic
corticotropin-​releasing hormone; also affect adrenal steroid
production
Glucocorticoid receptor antagonist; adrenal insufficiency occurs
in overdosing
Inhibition of corticosteroid synthesis by inhibition of steroidogenic
enzymes, mainly 11β-​hydroxylase (CYP11B1) and aldosterone
synthase (CYP11B2), side-​chain cleavage enzyme (CYP11A1).
Destruction of adrenocortical tissue (adrenolytic effect); strong
induction of the cortisol-​metabolizing enzyme CYP3A4
Increased cortisol metabolism by induction of CYP3A4
Induction of hypophysitis
Hypophysitis due to lymphocytic pituitary infiltration of lymphocytes
leading to ACTH deficiency; less common, adrenalitis and direct
impairment of adrenal cortex function (new immune checkpoint
inhibitors seem to cause hypophysitis less frequently)

is warranted. Understanding the as-​yet largely unclear
pathophysiology of adrenal crisis is of high importance
for the prevention and management of such emergen-
cies. In addition, the precise mechanisms underlying
ICI-​induced hypophysitis require further investigation.
Management
Given the persistent disease burden (for example,
reduced vitality) and the increased mortality observed
in patients with established replacement therapy, ther-
apeutic concepts are currently changing. In addition
to standard hydrocortisone therapy, new formulations
and modes of administration designed to best mimic
the physiological cortisol circadian rhythm are being
evaluated in clinical trials193,195,254,255. Preliminary results
indicate that easier dose reduction and optimization of
glucocorticoid exposure over the day can be achieved,
and may reduce adverse effects. The extent to which
these new formulations can improve the long-​term
outcomes in patients with AI will be revealed by future
study results. The relevance of the pulsatile ultradian
activity of the HPA axis in addition to the circadian
pattern of cortisol secretion is of additional scientific
interest and probably also of clinical importance. A pilot
study investigating the effects of pulsatility on cognition,
emotion and sleep in young cortisol-​suppressed men
demonstrated that pulsatility is important for intact neu-
rological physiology, optimal quality of sleep and perfor-
mance of working memory compared with continuous
cortisol infusions89. Existing glucocorticoid replace-
ment regimens could furthermore adversely impact the
CLOCK-​mediated regulation of the immune system
including natural killer cell function. A decreased natu-
ral killer cell cytotoxicity was observed in patients with
PAI256, which might underlie the observed increased rate
of infections21,257,258 and the reported increased mortality
owing to respiratory infections in patients with PAI65.
Restored immune function might therefore help pre-
vent adrenal crisis and associated mortality. Ongoing
and future trials are expected to elucidate these aspects
in patients with AI.
Regenerative medicine. Regenerative medicine
approaches have attempted to restore endogenous
adrenocortical steroid production with the aim of mim-
icking the pulsatility of cortisol259. In preclinical studies,
a bioartificial adrenal could be established by encapsu-
lation of bovine adrenocortical cells in alginate260. The
adrenal cortex generally shows high plasticity and regen-
erative capacity. The adrenocortical progenitor cells are
located in the subcapsular region of the adrenal cortex,
which is assumed to contribute to rapid regeneration.
Indeed, residual adrenal function has been observed in
up to 30% of patients with Addison disease199, provid-
ing a basis for subsequent studies aiming at restoring
endogenous steroid production. Long-​term treatment
with 1–24 ACTH or B cell depletion therapy was able to
restore endogenous cortisol secretion, although only in
few patients261–263. Nevertheless, stem cell-​based regen-
erative medicine and adeno-​associated virus-​mediated
gene therapy (particularly for CAH) may be promising
approaches to the treatment of AI in the future.
The backbone of optimal therapy, especially in
rare diseases such as AI, is a well-​informed patient
and environment, as emergency management is not
always known to health-​care professionals but often
requires timely interventions240,264,265. The establishment
and continuous improvement of structured training
programmes266,267 and the development and homogeni-
zation of international guidelines and emergency tools268
will make an important contribution to the long-​term
outcomes in patients.
Published online xx xx xxxx

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Acknowledgements
S.H. is supported by the Deutsche Forschungsgemeinschaft
(DFG) (within the CRC/Transregio 205/1 “The Adrenal: Central
Relay in Health and Disease” and HA 6931/3-1). W.A. is sup-
ported by the Medical Research Council UK (programme
grant G0900567). I.B. is supported by the National Institute
of Diabetes and Digestive and Kidney Diseases (NIDDK) of
the National Institutes of Health (NIH) USA under award
K23DK121888. The views expressed are those of the
author(s) and not necessarily those of the National Institutes
of Health, USA. E.S.H. is supported by K.G. Jebsen Center of
Autoimmune Disorders, The Novonordisk Foundation, The
Norwegian Research Council. The authors thank S. Aslaksen
for her input in creating the figure on mechanisms underlying
Addison disease.
Author contributions
Introduction (S.H. and M.Q.); Epidemiology (I.B. and E.S.H.);
Mechanisms/pathophysiology (S.H., E.S.H., R.J.R. and M.Q.);
Diagnosis, screening and prevention (W.A. and M.Q.);
Management (W.A., S.H., M.Q., R.J.R., S.B.-​S. and D.J.T.);
Quality of life (S.H.); Outlook (S.H., M.Q. and R.J.R.);
Overview of Primer (S.H.).
Competing interests
R.J.R. is a Director of Diurnal group PLC. W.A. served as con-
sultant and clinical investigator for Diurnal Ltd. All other
authors declare no competing interests.
Peer review information
Nature Reviews Disease Primers thanks L. Chan,
G. Johannsson, L. Nieman and the other, anonymous,
reviewer(s) for their contribution to the peer review of this work.
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