Clinical Review & Education

JAMA | Review

Adrenal Insufficiency in Adults

A Review
Anand Vaidya, MD, MMSc; James Findling, MD; Irina Bancos, MD, MSc

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IMPORTANCE Adrenal insufficiency is a syndrome of cortisol deficiency and is categorized as CME at jamacmelookup.com
primary, secondary, or glucocorticoid induced. Although primary and secondary adrenal
insufficiency are rare, affecting less than 279 per 1 million individuals, glucocorticoid-induced
adrenal insufficiency is common.

OBSERVATIONS Primary adrenal insufficiency, which involves deficiency of all adrenocortical

hormones, is caused by autoimmune destruction, congenital adrenal hyperplasia,
pharmacological inhibition (eg, high doses of azole antifungal therapy), infection
(eg, tuberculosis, fungal infections), or surgical removal of adrenal cortical tissue.
Secondary adrenal insufficiency is caused by disorders affecting the pituitary gland, such as
tumors, hemorrhage, inflammatory or infiltrative conditions (eg, hypophysitis, sarcoidosis,
hemochromatosis), surgery, radiation therapy, or medications that suppress corticotropin
production, such as opioids. Glucocorticoid-induced adrenal insufficiency is caused by
administration of supraphysiological doses of glucocorticoids. Patients with adrenal
insufficiency typically present with nonspecific symptoms, including fatigue (50%-95%),
nausea and vomiting (20%-62%), and anorexia and weight loss (43%-73%).
Glucocorticoid-induced adrenal insufficiency should be suspected in patients who
have recently tapered or discontinued a supraphysiological dose of glucocorticoids.
Early-morning (approximately 8 AM) measurements of serum cortisol, corticotropin,
and dehydroepiandrosterone sulfate (DHEAS) are used to diagnose adrenal insufficiency.
Primary adrenal insufficiency is typically characterized by low morning cortisol levels
(<5 μg/dL), high corticotropin levels, and low DHEAS levels. Patients with secondary and
glucocorticoid-induced adrenal insufficiency typically have low or intermediate morning
cortisol levels (5-10 μg/dL) and low or low-normal corticotropin and DHEAS levels. Patients
with intermediate early-morning cortisol levels should undergo repeat early-morning cortisol
testing or corticotropin stimulation testing (measurement of cortisol before and 60 minutes
after administration of cosyntropin, 250 μg). Treatment of adrenal insufficiency involves
supplemental glucocorticoids (eg, hydrocortisone, 15-25 mg daily, or prednisone, 3-5 mg
daily). Mineralocorticoids (eg, fludrocortisone, 0.05-0.3 mg daily) should be added for
patients with primary adrenal insufficiency. Adrenal crisis, a syndrome that can cause
hypotension and shock, hyponatremia, altered mental status, and death if untreated, can
occur in patients with adrenal insufficiency who have inadequate glucocorticoid therapy,
acute illness, and physical stress. Therefore, all patients with adrenal insufficiency should be
instructed how to increase glucocorticoids during acute illness and prescribed injectable
glucocorticoids (eg, hydrocortisone, 100 mg intramuscular injection) to prevent or treat Author Affiliations: Center for
adrenal crisis. Adrenal Disorders, Brigham and
Women’s Hospital, Harvard Medical
CONCLUSIONS AND RELEVANCE Although primary and secondary adrenal insufficiency are School, Boston, Massachusetts
rare, glucocorticoid-induced adrenal insufficiency is a common condition. Diagnosis of (Vaidya); Division of Endocrinology
and Molecular Medicine, Medical
adrenal insufficiency involves early-morning measurement of cortisol, corticotropin, and
College of Wisconsin, Milwaukee
DHEAS. All patients with adrenal insufficiency should be treated with glucocorticoids (Findling); Division of Endocrinology,
and instructed how to prevent and treat adrenal crisis. Metabolism, and Nutrition, Mayo
Clinic, Rochester, Minnesota
(Bancos); Department of Laboratory
Medicine and Pathology, Mayo Clinic,
Rochester, Minnesota (Bancos).
Corresponding Author: Anand
Vaidya, MD, MMSc, Center for
Adrenal Disorders, Brigham and
Women’s Hospital, Harvard Medical
School, 221 Longwood Ave, RFB,
JAMA. 2025;334(8):714-725. doi:10.1001/jama.2025.5485 Boston, MA 02115 (anandvaidya@
Published online June 16, 2025. bwh.harvard.edu).

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 Adrenal Insufficiency in Adults: A Review Review Clinical Review & Education

P
rimary adrenal insufficiency, which is characterized by de-
ficient production of cortisol and aldosterone by the adre- Box. Commonly Asked Questions About Adrenal Insufficiency
nal gland, is most commonly caused by autoimmune
adrenalitis. Often called Addison disease, primary adrenal insuffi- What Is Adrenal Insufficiency?
ciency is rare, with global prevalence estimates ranging from 4 to Adrenal insufficiency is a syndrome of cortisol deficiency that
often presents with nonspecific symptoms such as fatigue
221 cases per 1 million.1-5 Secondary adrenal insufficiency, which is
(50%-95%), nausea and vomiting (20%-62%), and anorexia and
characterized by decreased pituitary gland production of cortico- weight loss (43%-73%). The most severe presentation of adrenal
tropin (also known as adrenocorticotropic hormone [ACTH]), may insufficiency is adrenal crisis, a life-threatening syndrome caused
be caused by pituitary gland tumors, hemorrhage, inflammation by relative cortisol insufficiency that can lead to altered mental
(such as hypophysitis and sarcoidosis), surgery, or radiation therapy, status, shock, and death if left untreated.
or by medications that suppress corticotropin production, such as How Is Adrenal Insufficiency Diagnosed?
opioids. Secondary adrenal insufficiency occurs globally in 140 to 279 An early-morning serum cortisol level of less than 5 μg/dL is
per 1 million individuals. Glucocorticoid-induced adrenal insuffi- considered highly probable for adrenal insufficiency, and morning
ciency, sometimes also known as tertiary adrenal insufficiency, is cortisol concentrations greater than 10 μg/dL indicate a very
caused by suppression of corticotropin-releasing hormone (CRH) low likelihood of adrenal insufficiency. Low or low-normal
from the hypothalamus, which prevents corticotropin release from dehydroepiandrosterone sulfate (DHEAS) levels further support
the diagnosis of adrenal insufficiency. Early-morning measurement
the pituitary. While the incidence of glucocorticoid-induced adre-
of corticotropin can help determine if adrenal insufficiency is
nal insufficiency is unknown, it is the most common form of adre- primary or secondary.
nal insufficiency globally, as up to 1% to 3% of the adult population
How Is Adrenal Insufficiency Treated?
is prescribed glucocorticoid therapy.6 Most patients with primary ad-
Patients with adrenal insufficiency require treatment with
renal insufficiency and secondary adrenal insufficiency have months
physiological doses of glucocorticoid (eg, hydrocortisone,
to years of nonspecific symptoms (such as fatigue, nausea, abdomi- 15-25 mg daily, or prednisone or prednisolone, 3-5 mg daily).
nal pain, and anorexia) before diagnosis,7-12 and up to 50% experi- Primary adrenal insufficiency also requires mineralocorticoid
ence an adrenal crisis,11,13 a life-threatening state of cortisol defi- therapy (eg, fludrocortisone, 0.05-0.3 mg daily). All patients with
ciency that can lead to hypovolemic or distributive shock that is adrenal insufficiency should be instructed about the need to
resistant to vasopressor support, severe hyponatremia with al- increase glucocorticoid dosing during illness or stress and taught
how to use injectable glucocorticoids to prevent adrenal crisis.
tered mental status, and death.
This Review summarizes the pathophysiology of adrenal insuf-
ficiency and approaches to diagnosis, treatment, and prevention of
adrenal crisis. The Box provides some common questions and an-
swers about adrenal insufficiency. variation) and stressors, such as fever, hypoglycemia, hypoten-
sion, pain, and/or acute illness. CRH induces formation and
release of corticotropin from the anterior pituitary, which stimu-
lates the adrenal cortex to produce circulating glucocorticoids,
Methods mineralocorticoids, and androgens. While the production of aldo-
A PubMed search was performed for English-language articles of ran- sterone is regulated by corticotropin, it is also independently
domized clinical trials, systematic reviews, meta-analyses, and ob- regulated by angiotensin II and extracellular potassium. There-
servational studies related to the diagnosis and treatment of adre- fore, corticotropin deficiency does not induce aldosterone defi-
nal insufficiency in adults aged 18 years or older published between ciency. Corticotropin has structural similarities to melanocyte-
January 1, 1994, and March 1, 2025. Search terms used included ad- stimulating hormone, and elevated corticotropin levels can
renal insufficiency OR Addison’s disease OR adrenal crisis. Of the 405 directly stimulate production of melanin by melanocytes, result-
studies identified, 23 were considered pertinent for this Review. ing in hyperpigmentation.
In addition, the most recent clinical practice guidelines on adrenal Once cortisol is released into the circulation, 95% is bound to
insufficiency published by the Endocrine Society,14 the Society of cortisol-binding globulin or albumin, and approximately 5% circu-
Critical Care Medicine,15 jointly by the Endocrine Society and the lates as free cortisol, which binds to intracellular glucocorticoid re-
European Society of Endocrinology,6 and the National Institute for ceptors to induce gluconeogenesis, glycogenolysis, lipolysis, and pro-
Health and Care Excellence16 were reviewed to identify 48 addi- teolysis and maintain vascular tone. Free cortisol detected by the
tional references. In total, we included 4 randomized clinical trials, hypothalamus and pituitary gland results in decreased production
23 cohort studies, 21 cross-sectional studies, 7 systematic reviews of CRH and corticotropin, which decreases cortisol synthesis, a pro-
and meta-analyses, 13 clinical practice guidelines and narrative re- cess termed negative feedback (Figure 1). Cortisol is also a miner-
views, 2 case series, and 1 nonclinical study. alocorticoid, although most of its mineralocorticoid effect in the kid-
ney is inactivated by 11β-hydroxysteroid dehydrogenase type 2,
which converts cortisol to cortisone.
Primary adrenal insufficiency results in deficiency of all adre-
Pathophysiology nocortical hormones, including low levels of cortisol, aldosterone,
Adrenocortical production of cortisol is regulated by the and the adrenal androgens dehydroepiandrosterone (DHEA) and an-
hypothalamic-pituitary-adrenal axis (Figure 1). The hypothalamus drostenedione, as well as marked elevations in corticotropin as a re-
produces CRH in response to light (typically exhibiting diurnal sult of decreased negative feedback (Figure 1).

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 Clinical Review & Education Review Adrenal Insufficiency in Adults: A Review

Figure 1. Pathophysiology of Adrenal Insufficiency

Normal hypothalamic-pituitary-adrenal axis physiology Mechanisms of adrenal insufficiency

Adrenal insufficiency is characterized by cortisol deficiency
that can manifest with nonspecific symptoms (eg, fatigue,
Light nausea, vomiting, anorexia, weight loss) and can result in
and adrenal crisis (hypotension or shock).
physiologic stressors
Glucocorticoid-induced adrenal insufficiency
HYPOTHALAMUS Suppression of entire hypothalamic-pituitary-adrenal axis

Corticotropin-releasing hormone (CRH) Decreased production of CRH

Subsequent decreased production of corticotropin,
cortisol, and dehydroepiandrosterone (DHEA)
A N T E R I O R P I T U I TA RY
Aldosterone production remains intact

Corticotropin Secondary adrenal insufficiency

Destruction or inhibition of anterior pituitary
Decreased production of corticotropin
Subsequent decreased production of cortisol and DHEA
Aldosterone production remains intact

Primary adrenal insufficiency

Destruction or inhibition of both adrenal cortices
Deficient production of cortisol, aldosterone, and DHEA
Cortisol negative feedback Subsequent increased CRH and corticotropin due to
Approximately 95% of circulating absence of cortisol negative feedback
cortisol is bound to globulins whereas
approximately 5% circulates free and
can be detected by the hypothalamus
and pituitary gland.

Corticosteroid production in
the zones of the adrenal gland

ADRENAL GLANDS CAPSULE

ZONA GLOMERULOSA
Aldosterone
Mineralocorticoid that regulates renal
sodium and potassium handling

Z O N A FA S C I C U L ATA
Corticosteroids Cortisol
DHEA Glucocorticoid and mineralocorticoid
that regulates glucose metabolism,
Aldosterone blood pressure, immune and inflammatory
mechanisms, and other metabolic processes
Cortisol
ZONA RETICULARIS
DHEA
MEDULLA Sex hormone with androgenic function

CRH is secreted by the hypothalamus in response to light and physiologic upregulation of CRH and corticotropin production. Secondary adrenal
stressors. CRH stimulates corticotropin (also known as adrenocorticotropic insufficiency is the consequence of destruction or inhibition of the anterior
hormone [ACTH]) production and secretion from the anterior pituitary gland, pituitary gland such that corticotropin production is deficient. The absence of
which in turn exerts endocrine effects on the adrenal cortex. Corticotropin corticotropin results in cortisol and DHEA deficiency; however, aldosterone
stimulates production of all adrenal steroidogenesis, including cortisol from the production remains relatively normal due to alternative stimulation by the
zona fasciculata, aldosterone from the zona glomerulosa, and DHEA from the renin-angiotensin system and extracellular potassium. Glucocorticoid-induced
zona reticularis. Circulating free cortisol exerts negative feedback on the adrenal insufficiency is sometimes referred to as secondary and/or tertiary
hypothalamus and anterior pituitary to downregulate its own production. adrenal insufficiency because it is the consequence of exogenous
Primary adrenal insufficiency is the consequence of the destruction or inhibition glucocorticoids inducing suppression of the entire hypothalamic-pituitary-
of both adrenal cortices such that the production of adrenocortical steroids is adrenal axis. Inhibition of CRH results in deficiency of corticotropin and,
diminished or deficient. The absence of negative feedback by cortisol results in consequently, cortisol production.

Secondary adrenal insufficiency occurs due to deficient pitu- drogen production are entirely dependent on the presence of cor-
itary production of corticotropin. Although cortisol and adrenal an- ticotropin, aldosterone production by the adrenal gland remains

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 Adrenal Insufficiency in Adults: A Review Review Clinical Review & Education

Table 1. Causes of Adrenal Insufficiency in Adults

Primary adrenal insufficiency Secondary adrenal insufficiency Glucocorticoid-induced adrenal insufficiency

Autoimmune (67%-90%) Tumors Exogenous glucocorticoids
• Isolated • Pituitary adenoma • Oral
• Polyglandular syndrome type 1 • Pituitary carcinoma • Intravenous
• Polyglandular syndrome type 2 • Craniopharyngioma • Inhaled
• Primary central nervous system tumor • Intranasal
• Metastatic lesions to the pituitary or sella • Intra-articular
• Topical
Congenital adrenal hyperplasia (5.4%-10%) Trauma/injury/hemorrhage
• 21-Hydroxylase deficiency • Pituitary trauma
• 11β-Hydroxylase deficiency • Central nervous system hemorrhage or trauma
• 3β-Hydroxylase deficiency • Sheehan syndrome
• 17α-Hydroxylase deficiency • Radiation
• Other
Infectious (<5%) Hypophysitis
• Tuberculosis • Primary autoimmune hypophysitis
• Fungal (histoplasmosis, cryptococcosis, • Drug-induced hypophysitis (ipilimumab, nivolumab,
coccidiomycosis, blastomycosis) pembrolizumab, atezolizumab)
• Viral (cytomegalovirus, HIV)
Infiltrative (<5%) Infiltrative
• Metastases from extra-adrenal • Langerhans cell histiocytosis
malignancy • Amyloidosis
• Adrenal lymphoma • Hemochromatosis
• Sarcoidosis • Sarcoidosis
• Amyloidosis
Medications (<5%) Medications
• Antifungals (ketoconazole, • Opioids
levoketoconazole, itraconazole, • Megesterol acetate
fluconazole, posaconazole)
• Mitotane
• Abiraterone acetate
• Metyrapone
• Osilodrostat
• Mifepristone
• Immunotherapies (ipilimumab,
nivolumab, pembrolizumab)
• Heparin
• Etomidate
Other Other
• Hemorrhage • Hemorrhage
• Surgical resection • Surgical resection

normal because it is regulated by angiotensin II and potassium lion, ascertained between 2000 and 2014).4 The most common
(Figure 1 and Table 1). Prolonged corticotropin deficiency results causes of primary adrenal insufficiency are autoimmune adrenal-
in atrophy of the adrenal cortex and decreased ability to produce itis (90% of all cases in North American and Europe) and inherited
cortisol. disorders of adrenal steroidogenesis, such as congenital adrenal hy-
Use of exogenous glucocorticoids in supraphysiological doses perplasia due to 21-hydroxylase deficiency (approximately 1 in 15 000
(eg, prednisone, >5 mg daily) induces negative feedback to sup- live births).20 However, infectious adrenalitis may be the leading
press CRH and corticotropin production, resulting in decreased en- cause of primary adrenal insufficiency in areas of the world with high
dogenous adrenal production of cortisol and androgens (Figure 1). rates of tuberculous and/or HIV infection (Table 1).21 Primary adre-
With prolonged exposure to supraphysiological doses of glucocor- nal insufficiency can occur at any age; however, most cases occur
ticoids, atrophy occurs in both the pituitary corticotrophs that pro- between ages 20 and 50 years.22 Accurate prevalence statistics for
duce corticotropin and the adrenal cortex. In addition, opioids such the causes of secondary adrenal insufficiency are not available, but
as morphine, oxycodone, and fentanyl can suppress hypothalamic the best available estimates indicate that it is rare, ranging from 140
CRH and induce adrenal insufficiency, although how much each opi- to 279 per 1 million individuals (Table 1).23-25
oid analogue induces hypothalamic-pituitary-adrenal suppression Use of immune checkpoint inhibitor therapies can cause irre-
is not predictable or consistent.17-19 versible primary or secondary adrenal insufficiency. Most affected
individuals have secondary adrenal insufficiency from hypophysi-
tis, with incidence rates of 3.2% for ipilimumab, 0.4% for nivolumab
or pembrolizumab, less than 0.1% for atezolizumab, and 6.4% for
Epidemiology
the combination of nivolumab plus ipilimumab.26 Immune check-
Primary adrenal insufficiency is rare, with prevalence estimates in point inhibitor–induced adrenal insufficiency typically occurs 2
Europe of 117 cases per 1 million (ascertained in Italy in 1996),1 144 months to 8 months after initiation of treatment.27,28 Approxi-
cases per 1 million (ascertained in Norway between 1993 and 2007),2 mately 5% of patients with immune checkpoint inhibitor–induced
and 221 cases per 1 million (ascertained in Iceland in 2012),3 with adrenal insufficiency have primary adrenal insufficiency due to au-
slightly higher prevalence among women compared with men.1 In toimmune adrenalitis.29,30
other areas of the world, such as South Korea, prevalence esti- Although the exact incidence of glucocorticoid-induced adre-
mates of primary adrenal insufficiency are lower (4 cases per mil- nal insufficiency is unknown, it is the most common form of adrenal

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 Clinical Review & Education Review Adrenal Insufficiency in Adults: A Review

Table 2. Diagnosis and Treatment of Adrenal Insufficiency

Primary adrenal insufficiency Secondary adrenal insufficiency Glucocorticoid-induced adrenal insufficiency

Ascertaining the pretest probability of adrenal insufficiency
Symptoms suggestive • Fatigue (95%) • Fatigue (50%-76%) • With supraphysiological glucocorticoid use
of adrenal • Nausea, vomiting, abdominal discomfort • Nausea, vomiting, abdominal discomfort (about 10% to 100%): weight gain, muscle
insufficiency (62%) (20%-48%) mass loss, weakness
• Anorexia and weight loss (67%-73%) • Anorexia and weight loss (29%-43%) • When reducing glucocorticoids to below
• Hyperpigmentation (74%) physiological doses (about 10% to 100%):
• Orthostatic hypotension (68%) fatigue, nausea, abdominal discomfort,
• Muscle and/or joint pain (40%) arthralgias, myalgias
• Salt craving (12%-19%)
General laboratory
studies
Basic metabolic Hyponatremia or hyperkalemia (35%) Hyponatremia (4%-10%)
panel
Complete blood cell • Anemia (13%) • Eosinophilia (rare) • Eosinopenia
count • Eosinophilia (rare) • Lymphocytosis • Lymphopenia
• Lymphocytosis
Diagnostic tests for adrenal insufficiency
Testing in the morning • Low cortisol • Low cortisol • Low cortisol
• High corticotropin • Low or low-normal corticotropin • Low or low-normal corticotropin
• Low or low-normal DHEAS • Low or low-normal DHEAS • Low or low-normal DHEAS
• Low aldosterone
• High renin
Dynamic testing Cosyntropin stimulation test (not needed • Cosyntropin stimulation testa Usually not necessary
(if needed) if baseline cortisol is low and corticotropin • Overnight metyrapone test
is high)a • Insulin tolerance test
Ascertaining the subtype of adrenal insufficiency
Laboratory • 21-Hydroxylase antibodies Consider tests for pituitary target gland Not needed
• Very long-chain fatty acids deficiencies (eg, thyrotropin, thyroxine,
• 17-Hydroxyprogesterone prolactin, growth hormone, insulin-like
growth factor 1, follicle-stimulating
hormone, luteinizing hormone)
Imaging Computed tomography of the abdomen Pituitary magnetic resonance imaging Not needed
(needed only if etiology not established by
laboratory assessments)
Treatment and management
Glucocorticoid therapy Hydrocortisone, 15-25 mg daily (eg, 15 mg Hydrocortisone, 15-25 mg daily (eg, 15 mg Hydrocortisone, 15-25 mg daily (eg, 15 mg
on waking, 5 mg 6-8 hours later), or on waking, 5 mg 6-8 hours later), or on waking, 5 mg 6-8 hours later), or
prednisone, 3-5 mg each morning prednisone, 3-5 mg each morning prednisone, 3-5 mg each morning
Mineralocorticoid Fludrocortisone, 0.05-0.3 mg daily (usual Not needed Not needed
therapy daily dose, 0.1 mg)
Education Reasoning for the dosing/timing of Reasoning for the dosing/timing of Reasoning for the dosing/timing of
glucocorticoids, approach to special glucocorticoids, approach to special glucocorticoids, approach to special
situations, management during sickness/ situations, management during sickness/ situations, management during sickness/
stress dosing, medical alert system stress dosing, medical alert system stress dosing, medical alert system (eg,
(eg, necklace, bracelet), how to use (eg, necklace, bracelet), how to use necklace, bracelet), how to use injectable
injectable glucocorticoids injectable glucocorticoids glucocorticoids
Monitoring • Symptoms, circumstances around stress • Symptoms, circumstances around stress • Symptoms, circumstances around stress
dosing dosing dosing
• Yearly monitoring for autoimmune • Physical examination (features of • Physical examination (features of
conditions glucocorticoid deficiency/excess) glucocorticoid deficiency/excess)
• Physical examination (features of • Monitoring for recovery of adrenal function
glucocorticoid and mineralocorticoid (morning cortisol measurement after
deficiency/excess) withholding glucocorticoids for 24 hours)
• Mineralocorticoid replacement:
electrolytes, renin plasma activity,
blood pressure

Abbreviation: DHEAS, dehydroepiandrosterone sulfate.

a
Measure serum cortisol before and 60 minutes after administration of 250 μg of intravenous or intramuscular cosyntropin.

insufficiency. A daily dose of 5 mg or greater of prednisone (or its A cross-sectional study of 213 patients with primary or second-
equivalent)for3to4weeksorlongercaninduceadrenalinsufficiency.6 ary adrenal insufficiency showed that 20% reported such nonspe-
cific symptoms for more than 5 years prior to diagnosis.7 In addition,
less than 30% of women and less than 50% of men in this study were
diagnosedwithadrenalinsufficiencywithinthefirst6monthsofsymp-
Clinical Presentation and Causes
tom onset.7 In another cross-sectional study of 696 patients, me-
Patients with adrenal insufficiency commonly experience fatigue dian symptom duration was 1 year prior to initiation of therapy.12
(50%-95%); nausea, vomiting, and abdominal pain (20%-62%); Most patients with primary adrenal insufficiency develop hy-
muscle or joint paint (40%-53%); and anorexia and weight loss (43%- perpigmentation (74%).2 They may also report salt cravings (12%-
73%) (Table 2).2,7-11 19%) and have orthostatic hypotension (68%) due to concomitant

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 Adrenal Insufficiency in Adults: A Review Review Clinical Review & Education

Figure 2. Suggested Approach to Diagnosing Adrenal Insufficiency

Patient presents with signs and symptoms of adrenal insufficiency

• Fatigue • Vomiting • Abdominal pain • Hyperpigmentation • Orthostatic hypotension
• Nausea • Anorexia and weight loss • Muscle or joint pain • Salt cravings • Hyponatremia

Assess for hemodynamic instability Hemodynamic instability present Initiate high-dose parenteral glucocorticoids

No hemodynamic instability

Evaluate early-morning cortisol, corticotropin, and dehydroepiandrosterone sulfate (DHEAS)

Cortisol <5 μg/dL Cortisol 5-10 μg/dL Cortisol >10 μg/dL

Corticotropin low or Corticotropin low or within reference range Corticotropin mid to high end of reference range Corticotropin within
Corticotropin elevated
within reference range reference range
DHEAS low or low end of reference range DHEAS mid to high end of reference range
DHEAS low or low end DHEAS low or low end DHEAS within
of reference range of reference range reference range
Clinical Repeat early-morning cortisol, corticotropin, Clinical
judgment and DHEAS judgment
or
Perform corticotropin stimulation testa
Primary adrenal Secondary adrenal insufficiency Cortisol ≤5 μg/dL Cortisol >10 μg/dL Very low probability of clinically
insufficiency or or or relevant adrenal insufficiency
Glucocorticoid-induced Inadequate stimulation Adequate stimulation
adrenal insufficiency

When adrenal insufficiency is suspected in a critically ill or hemodynamically during the day and work at night, testing should be performed in the morning
unstable patient, high-dose parenteral glucocorticoids should be administered after normalization of the circadian rhythm (for example, while on vacation, on
without delay. If random serum cortisol, corticotropin, and DHEAS weekends, or during long stretches of return to normal sleep-wake cycles), or
measurements can be obtained before administration of glucocorticoids, they use dynamic testing such as corticotropin stimulation tests.
may have diagnostic value; however, laboratory testing should not delay a
Measurement of cortisol before and 60 minutes after intravenous or
treatment. For stable, ambulatory patients with suspected adrenal intramuscular administration of 250 μg of cosyntropin; cortisol levels >18 μg/dL
insufficiency, a morning (approximately 8 AM) blood test to measure serum after cosyntropin administration indicate adequate stimulation.
cortisol, corticotropin, and DHEAS should be performed. In patients who sleep

mineralocorticoid deficiency, which may cause hyperkalemia and hy-

ponatremia (35%).2 Patients with secondary adrenal insufficiency Assessment and Diagnosis
may present with hyponatremia (4%-10%).31
Patients with glucocorticoid-induced adrenal insufficiency In the absence of a serious illness, early-morning testing of cortisol,
may initially develop signs and symptoms of Cushing syndrome, such corticotropin, and dehydroepiandrosterone sulfate (DHEAS) usu-
as weight gain, central obesity, sarcopenia with proximal muscle ally provides sufficient evidence to diagnose adrenal insufficiency
weakness, skin fragility, and easy bruising6 due to treatment with (Figure 2). The evaluation of morning cortisol concentrations as-
supraphysiological doses of glucocorticoids. These patients may then sumes that a patient follows a pattern of sleeping at night and being
develop symptoms of adrenal insufficiency when their daily gluco- awake during the day such that peak cortisol levels are expected in
corticoid dose is reduced below physiological supplemental doses, the morning and trough levels close to midnight.
typically defined as 15 to 25 mg daily of hydrocortisone or 3 to 5 mg
daily of prednisone or prednisolone. Cortisol
Cortisol and corticotropin production follow a circadian rhythm. Peak
levels occur in the early morning, just before waking, according to
an individual’s sleep cycle, followed by a gradual decline through-
Adrenal Crisis
out the day, and nadir overnight when sleeping.34,35 Early-morning
Although there is no universally accepted definition of adrenal crisis, evaluation of serum cortisol (at approximately 8 AM) is the recom-
this term is typically used to describe cortisol insufficiency that causes mended initial test to evaluate for adrenal insufficiency6,14; how-
hypotension, hypovolemic or distributive shock that is resistant to ever, its interpretation may be limited by variability of cortisol pro-
vasopressor support, and severe hyponatremia with altered men- duction as a function of each individual’s circadian rhythm and the
tal status and/or somnolence or altered consciousness. Adrenal cri- time of the blood draw.36 In a retrospective cohort of 804 patients
sis has a mortality rate of 0.5%. While adrenal crisis is reported by being evaluated for adrenal insufficiency (46.7% prevalence of ad-
5% to 8% of patients with all types of adrenal insufficiency,32 up to renal insufficiency), an early-morning cortisol level greater than 16
50% of patients with primary adrenal insufficiency experience at μg/dL had a negative predictive value for the diagnosis of adrenal
least 1 adrenal crisis prior to diagnosis of adrenal insufficiency.11,13 Ad- insufficiency of 98.7%; a basal cortisol level of less than 3.6 μg/dL
renal crisis is the cause of death in 15% of persons with Addison had a positive predictive value of 93.2% to diagnose adrenal
disease.33 insufficiency.37 In a retrospective study of 1135 patients being

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 Clinical Review & Education Review Adrenal Insufficiency in Adults: A Review

evaluated for adrenal insufficiency, a basal cortisol level of 10 μg/dL ates cortisol before and 60 minutes after intravenous (or intramus-
or greater excluded adrenal insufficiency in 98.8% of patients.38 cular) administration of 250 μg of cosyntropin (corticotropin[1-
Among 416 patients in a retrospective study, a cortisol value of less 24]). The expected peak cortisol level following administration of
than 3.0 μg/dL was 99.7% specific for adrenal insufficiency while a cosyntropin is 18 μg/dL or greater at 60 minutes.43 A systematic re-
cortisol value greater than 12.7 μg/dL was 98.9% sensitive; values view and meta-analysis that included 28 studies with 1437 patients
between 3 μg/dL and 12.7 μg/dL were considered intermediate.39 who had secondary adrenal insufficiency reported that a cortisol level
Guidelines from the European Society of Endocrinology and the of less than 18 to 20 μg/dL at 30 or 60 minutes after administra-
Endocrine Society state that an early-morning cortisol measure- tion of cosyntropin, 250 μg, had a sensitivity of 64% and a speci-
ment greater than 10 μg/dL very likely indicates relatively normal ficity of 93% for diagnosis of adrenal insufficiency.44 Thus, some pa-
hypothalamic-pituitary-adrenal axis function and therefore has a very tients with secondary adrenal insufficiency may have a normal
low probability of clinically relevant adrenal insufficiency.6 Con- corticotropin stimulation test finding, especially those in whom cor-
versely, an early-morning serum cortisol level of less than 5 μg/dL ticotropin deficiency has been of short duration (days to weeks).
in patients with clinical features concerning for adrenal insuffi- Other dynamic diagnostic tests include the overnight metyra-
ciency is considered highly probable of adrenal insufficiency.6 The pone test, insulin-induced hypoglycemia, and glucagon stimula-
use of early-morning salivary free cortisol as a method to test for ad- tion test, which are reserved for patients considered likely to have
renal insufficiency with samples collected at home has recently been secondary adrenal insufficiency but who had a normal or equivocal
investigated, and a salivary free cortisol level greater than 180 ng/dL cosyntropin stimulation test finding. Insulin-induced hypoglyce-
(5 nmol/L) excluded adrenal insufficiency with a sensitivity of 95%.40 mia and glucagon stimulation tests are resource intensive and may
not be readily available outside of specialized centers. The over-
Corticotropin night metyrapone test has high accuracy for identifying secondary
When combined with an early-morning cortisol measurement, adrenal insufficiency,45 but metyrapone is typically not readily avail-
corticotropin concentrations help determine the type of adrenal in- able, so this test is rarely used.
sufficiency. Nearly all patients with primary adrenal insufficiency have
elevated plasma corticotropin (usually >100 pg/mL; reference range,
15-65 pg/mL). In contrast, patients with secondary and glucocorti-
Treatment
coid-induced adrenal insufficiency have corticotropin concentra-
tions that are below or at the lower end of the reference range Management of adrenal insufficiency involves determining the ap-
(usually <20 pg/mL) (Figure 2 and Table 2).14,22 propriate physiological supplemental dose of glucocorticoid (and
mineralocorticoid, if applicable), patient education about glucocor-
Dehydroepiandrosterone Sulfate ticoid dosing, and management of glucocorticoid therapy during ill-
In primary adrenal insufficiency, all adrenocortical steroid levels are ness or stress to prevent adrenal crisis (Table 2).
low (including DHEA and its stable sulfated metabolite, DHEAS).
In secondary and glucocorticoid-induced adrenal insufficiency, the Glucocorticoid Therapy
insufficiency or deficiency of corticotropin results in low or low- Physiological glucocorticoid therapy should be initiated in all pa-
normal levels of DHEAS.41 Because DHEAS circulates in high con- tients with adrenal insufficiency. Physiological dosing refers to
centrations (3-6 orders of magnitude higher than cortisol) and has therapy given to mimic the amount and timing of the body’s natu-
a long half-life (7-10 hours), DHEAS serves as an accurate predic- ral production of cortisol.
tive marker of hypothalamic-pituitary-adrenal axis impairment. In Hydrocortisone, which is bioidentical to cortisol, is a short-
a study of 1135 patients, DHEAS concentrations demonstrated good acting oral glucocorticoid (peak concentrations 2-3 hours after in-
diagnostic accuracy for adrenal insufficiency, especially in patients gestion), and a dose of approximately 15 to 25 mg daily (approxi-
without a history of glucocorticoid use (area under the curve of 0.83); mately 12 mg/m2 daily) is generally sufficient for most adult patients
when cortisol concentrations were in the indeterminate range of 5 with adrenal insufficiency; the daily dose can be divided into 2 doses,
to 9.9 μg/dL and when DHEAS was greater than 60 μg/dL, adrenal with the first and larger dose taken on waking (eg, two-thirds of the
insufficiency was excluded in 98.7% of patients.38 daily dose taken on waking) and the second and smaller dose no later
than 6 hours prior to sleep (eg, one-third of the daily dose taken in
Adrenal Antibodies the early afternoon).12,21 Prednisone or prednisolone is a longer-
More than 90% of patients with primary adrenal insufficiency have acting oral glucocorticoid that is commonly used and can be admin-
circulating 21-hydroxylase antibodies, which confirms the diagno- istered once daily, typically at doses of 3 to 5 mg.6 Because there is
sis of autoimmune adrenalitis.42 The absence of these antibodies no clear evidence indicating improved outcomes with one gluco-
does not exclude primary adrenal insufficiency but should lead to corticoid compared with the others, the decision to use supplemen-
evaluation for other, nonautoimmune causes of primary adrenal in- tal hydrocortisone, prednisone, or prednisolone is based on pa-
sufficiency (Table 1). tient and clinician preferences. Other glucocorticoids (such as
methylprednisolone or dexamethasone) are not recommended for
Dynamic Testing daily treatment of adrenal insufficiency given their long half-life
Dynamic assessment of adrenal function may be useful when early- (which does not replicate the normal circadian pattern of cortisol),
morning testing is equivocal (eg, morning serum cortisol level of high potency, and risk of inducing Cushing syndrome.
5-10 μg/dL) in patients considered likely to have adrenal insuffi- After treatment initiation, the steroid dose must be individual-
ciency. Dynamic testing with the corticotropin stimulation test evalu- ized because serum cortisol and plasma corticotropin are not helpful

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 Adrenal Insufficiency in Adults: A Review Review Clinical Review & Education

Table 3. Guidelines for Prescribing Stress-Dose Glucocorticoid Treatment for Adults With Adrenal Insufficiencya

Suggested regimen
Minor stress
Illness requiring bed rest; illness with fever (out of • Hydrocortisone: increase to 40-mg total daily dose, to be given in 3 divided doses (eg, 20 mg on
hospital); illness requiring treatment with antibiotics rising, 10 mg at midday, and 10 mg in mid-afternoon); continue for 2-5 days until well (or for
(out of hospital); significant emotional stress duration of antibiotic treatment)
(eg, bereavement, major psychiatric episode) • Prednisone: increase to 10-mg total daily dose, to be given in 1 or 2 divided doses; continue for 2-5
days until well (or for duration of antibiotic treatment)
Minor surgery, including any procedure requiring local • Hydrocortisone: increase to 40-mg total daily dose, to be given in 3 divided doses (eg, 20 mg 1 hour
anesthesia prior to procedure, 10 mg 6 hours after procedure, and 10 mg after a further 6 hours); continue
increased dose in patients who remain unwell after procedure until clinically stable
• Prednisone: increase to 10-mg total daily dose, to be given 1 hour prior to procedure; continue
increased dose in patients who remain unwell after procedure until clinically stable
Bowel procedures not carried out under general Continue usual or double glucocorticoid dose on day of procedure; give an equivalent intravenous
anesthesia dose if prolonged nil by mouth
Major stress/adrenal crisis
Severe or critical illness, for example: persistent vomiting • For patients with persistent vomiting or diarrhea: hydrocortisone, 100-mg intramuscular injection
or diarrhea from gastrointestinal illness; infection immediately; patients should be seen at a health care facility for intravenous fluids
requiring hospital admission or intravenous antibiotics • For patients requiring hospital admission: hydrocortisone, 100-mg intravenous bolus or
(eg, sepsis); acute trauma, pain, or significant blood loss; intramuscular injection immediately, followed by hydrocortisone, 50-mg intravenous boluses every
unexplained hemodynamic compromise, hypotension, 6 hours, or, alternatively, a continuous infusion of hydrocortisone, 200 mg, over 24 hours; the
shock, or critical illness duration and dose of the glucocorticoid regimen thereafter must be individualized based on the
stressor type and patient’s clinical status
Surgery or any procedure requiring general or regional • Intraoperative regimen: hydrocortisone, 100-mg intravenous bolus at induction, followed by
anesthesia with anticipated short recovery time and no nil hydrocortisone, 50-mg intravenous boluses every 6 hours, or, alternatively, a continuous infusion
by mouth of hydrocortisone, 200 mg, over 24 hours
• Postoperative regimen: resume oral glucocorticoids at an increased dose for 48 hours and then
resume presurgical dose; in case of postoperative complications (eg, significant pain, infections),
maintain an increased oral dose or give stress-dose glucocorticoids intravenous as clinically
appropriate
Surgery (including cesarean delivery) or any procedure • Intraoperative regimen: hydrocortisone, 100-mg intravenous bolus at induction, followed by
requiring general or regional anesthesia with nil by mouth hydrocortisone, 50-mg intravenous boluses every 6 hours, or, alternatively, a continuous infusion
or expected long recovery time of hydrocortisone, 200 mg, over 24 hours
• Postoperative regimen: if the postoperative period is uncomplicated and once the patient can eat,
resume oral glucocorticoids at 2-3 times the basal dose, then transition to presurgical dose; in case
of postoperative complications (eg, significant pain, infections), maintain an increased oral dose or
give stress-dose glucocorticoids intravenous as clinically appropriate
Labor and vaginal delivery Hydrocortisone, 100-mg intravenous bolus at onset of labor, followed by hydrocortisone, 50-mg
intravenous boluses every 6 hours, or, alternatively, a continuous infusion of hydrocortisone, 200 mg
over 24 hours
a
Table adapted with permission from the European Society of Endocrinology and Endocrine Society joint clinical guideline.6

to guide treatment due to their variability throughout the day. The Adrenal Crisis
daily dose and frequency of administration should be subse- Adrenal crisis is a life-threatening emergency and should be treated
quently determined by a patient’s general well-being and function- promptly with high-dose intravenous glucocorticoid therapy and
ality, with the goal of using the lowest steroid dose to achieve sub- other supportive care such as intravenous fluids and vasopressors
jective well-being. (doses and duration are dependent on the clinical situation)
(Table 3).6
Steroid Dosing During Acute Illness or Stress
To accommodate the increased physiological need for glucocorti- Mineralocorticoid Therapy
coids during stress, all patients with adrenal insufficiency should Although patients with secondary and glucocorticoid-induced
receive higher doses of glucocorticoids during stressors, such as adrenal insufficiency do not develop mineralocorticoid deficiency,
infections and surgeries requiring general anesthesia. Increased most patients with primary adrenal insufficiency have mineralo-
steroid dosing may also be considered for patients during times of corticoid deficiency that requires replacement with fludrocorti-
intense mental or emotional stress, such as bereavement and sone. The usual starting dose of fludrocortisone is 0.1 mg daily,
intense grief (Table 3). Specific glucocorticoid medications and with down- or up-titration to 0.05 mg and 0.3 mg daily.47 Monitor-
dosing recommendations for patients with adrenal insufficiency ing of mineralocorticoid replacement therapy includes clinical
and in acute illness or stress are outlined in Table 3. These recom- assessment of energy level and general well-being, physical
mendations should also be applied for patients considered at high examination for volume depletion or peripheral edema, and labo-
likelihood of having adrenal insufficiency but before adrenal insuffi- ratory measurements to assess sodium and potassium.47,48 Signs
ciency is confirmed.6,46 of mineralocorticoid underreplacement include salt craving, ortho-
Hemodynamically unstable or critically ill patients known or sus- static hypotension, elevated serum potassium, hyponatremia, and
pected to have adrenal insufficiency should receive urgent treat- elevated renin. Signs of mineralocorticoid overreplacement
ment with parenteral high-dose glucocorticoids (ie, 1 intravenous ad- include edema, hypertension, hypokalemia, and suppressed renin.
ministration of hydrocortisone, 100 mg) (Figure 2). Although some studies have shown that plasma renin levels can

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 Clinical Review & Education Review Adrenal Insufficiency in Adults: A Review

guide fludrocortisone dosing, others have not48-51; therefore, rou- Unlike most patients with primary or secondary adrenal insuf-
tine monitoring of plasma renin in patients with primary adrenal ficiency, patients with glucocorticoid-induced adrenal insuffi-
insufficiency is not recommended. ciency can recover normal adrenocortical function and discontinue
use of glucocorticoids. The process of tapering glucocorticoids with
Androgen Therapy normalization of the hypothalamic-pituitary-adrenal axis may take
Several studies have shown that DHEA replacement in both women months, and in some cases, years.6 Monitoring of this tapering pro-
and men with primary adrenal insufficiency and secondary adrenal cess involves checking morning serum cortisol levels 24 hours af-
insufficiency may improve quality of life, mood, and sex drive.52-55 ter the most recent glucocorticoid dose to avoid measurement of
However, a systematic review and meta-analysis that included exogenous glucocorticoid metabolites. Recent clinical practice guide-
10 randomized clinical trials with 264 patients reported only a lines recommend discontinuing glucocorticoids in patients with glu-
small overall clinical benefit (for general quality of life, a pooled cocorticoid-induced insufficiency when morning serum cortisol is
standardized mean difference of 0.21 [95% CI, 0.08-0.33]); for de- 10 μg/dL or higher.6
pression, a pooled standardized mean difference of 0.23 [95% CI, Patients with glucocorticoid-induced adrenal insufficiency
0.04-0.42]).56 Clinical practice guidelines recommend DHEA re- can develop adrenal crisis if their steroid treatments are stopped
placement therapy in women with adrenal insufficiency who have suddenly or weaned too rapidly; studies have reported that 37% of
low libido, fatigue, and symptoms of depression.14 The recom- patients with glucocorticoid-induced adrenal insufficiency devel-
mended starting dose is typically 25 mg daily, with a goal of titrat- oped at least 1 adrenal crisis and had more adrenal crises per person-
ing the dose to a mid-normal serum DHEAS concentration.14 If no year compared with patients with primary and secondary adrenal
symptomatic benefit is seen after 6 months of therapy, DHEA can insufficiency.12,21 However, patients with glucocorticoid-induced ad-
be discontinued. Signs of androgen overreplacement include acne renal insufficiency are less likely to be prescribed injectable gluco-
and hirsutism. corticoids for emergencies or to wear a medical alert identifier, and
these patients report substantially more difficulty managing stress
Management Considerations in Patients With glucocorticoid dosing compared with patients with primary adre-
Glucocorticoid-Induced Adrenal Insufficiency nal insufficiency or secondary adrenal insufficiency.12,21 This phe-
Although glucocorticoid-induced adrenal insufficiency is typically nomenon reflects less education for patients with glucocorticoid-
due to oral glucocorticoid use, systemic absorption of nonoral glu- induced adrenal insufficiency about how to increase steroid dosing
cocorticoid formulations can induce durable suppression of CRH and during emergency situations, possibly due to the expectation that
corticotropin relative to the duration and dose exposure. For ex- their adrenal insufficiency is temporary and because they are less
ample, inhaled fluticasone can induce glucocorticoid-induced ad- likely to be treated by endocrinologists.21
renal insufficiency in a dose-dependent manner.57-59 The preva-
lence of glucocorticoid-induced adrenal insufficiency in people who
use inhaled glucocorticoids is 7.8% (95% CI, 4.2%-13.9%), but the
Prognosis
prevalence increases with higher doses, such as fluticasone propio-
nate, 500 μg or greater daily, for which the prevalence may be 21% After being diagnosed with adrenal insufficiency, starting steroid
(95% CI, 12%-35.5%), or a duration longer than 12 months, for which treatment, and being informed about the risk of and treatment for
the prevalence may be 27.4% (95% CI, 17.7-39.8).6 Similarly, intra- adrenal crisis, patients with adrenal insufficiency generally have very
articular glucocorticoid injections repeated within 3 months can good quality of life and are capable of working, participating in sports,
cause hypothalamic-pituitary-adrenal axis suppression.6 and traveling.12,21 However, adrenal crisis can occur unexpectedly
Most patients with glucocorticoid-induced adrenal insuffi- with concurrent illness or trauma and can lead to critical illness or
ciency have been treated with supraphysiological glucocorticoids for death if not promptly treated with high doses of glucocorticoids and
months to years, which may lead to development of iatrogenic other supportive therapy (Table 3).
Cushing syndrome and glucocorticoid tolerance. When glucocorti-
coid therapy is no longer needed to treat a medical condition, the
dose is tapered. During this process, patients frequently develop
Special Considerations
glucocorticoid withdrawal syndrome,60,61 which usually occurs with
supraphysiological glucocorticoid doses62 (for example, when pred- Because 95% of cortisol is bound to corticosteroid-binding globu-
nisone is decreased from 10 mg to 7.5 mg daily). Symptoms of glu- lin or albumin, alterations in these proteins should be considered
cocorticoid withdrawal syndrome, which include myalgias, arthral- when assessing patients for adrenal insufficiency.
gias, fatigue, weakness, and mood changes, can be reduced by
slowing the pace of the taper (eg, decreasing the dose every 2 weeks High Estrogen States
instead of weekly) or by using a taper that has smaller decrements Estrogen markedly raises hepatic globulin production, including
in the daily glucocorticoid dose (eg, reducing prednisone by 1 mg corticosteroid-binding globulin. Therefore, use of estrogen-
instead of 2.5 mg or tapering to every-other-day regimens). It containing oral contraceptives, hormone therapies, and preg-
may be difficult to differentiate glucocorticoid withdrawal syn- nancy result in higher levels of total cortisol but relatively un-
drome from adrenal insufficiency because their symptoms are changed free cortisol fractions.63-66 As a result, patients with high
similar. However, generally, glucocorticoid withdrawal syndrome is estrogen states may have the diagnosis of adrenal insufficiency er-
more likely than adrenal insufficiency if the glucocorticoid dose roneously excluded due to seemingly normal total cortisol levels. For
is supraphysiological. these patients, measurement of total cortisol levels 1 month after

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 Adrenal Insufficiency in Adults: A Review Review Clinical Review & Education

the high estrogen state has resolved may provide more accurate di- In the US, most ambulances and emergency medical services per-
agnostic information. Alternatively, measurement of free serum cor- sonnel do not carry hydrocortisone.71
tisol levels can be performed, although this test may be available only
at specialized laboratories.

Limitations
Low Serum Albumin or Protein Levels
Conversely, patients with very low protein levels (eg, albumin), such This Review has limitations. First, it is limited by the small number
as with cirrhosis and chronic illness, may have much lower than nor- of randomized clinical trials that have evaluated the best approach
mal total cortisol levels, although their free cortisol levels may be to diagnosis and treatment. Second, there are no standardized
normal.67 Therefore, patients with low albumin levels may be incor- definitions for adrenal insufficiency and adrenal crisis. Third, some
rectly diagnosed with adrenal insufficiency based on low total relevant studies may have been missed. Fourth, the quality of in-
cortisol levels. For these patients, testing of serum free cortisol test- cluded studies was not formally evaluated.
ing or salivary cortisol should be considered.68-70

Conclusions
Practical Considerations
Although primary and secondary adrenal insufficiency are rare,
Patient education about stress dosing of glucocorticoids should be glucocorticoid-induced adrenal insufficiency is a common condi-
reviewed at every clinic visit. Patients should be instructed to carry tion. Diagnosis of adrenal insufficiency involves early-morning mea-
medical identification (such as an identification bracelet) and inject- surement of cortisol, corticotropin, and DHEAS. All patients with ad-
able glucocorticoids (eg, intramuscular or subcutaneous hydrocor- renal insufficiency should be treated with glucocorticoids and
tisone, 100 mg) and trained how to use injectable glucocorticoids.6,46 instructed about how to prevent and treat adrenal crisis.

ARTICLE INFORMATION Endocrinol Metab (Seoul). 2017;32(4):466-474. 13. Hahner S, Loeffler M, Bleicken B, et al.
Accepted for Publication: March 28, 2025. doi:10.3803/EnM.2017.32.4.466 Epidemiology of adrenal crisis in chronic adrenal
5. Løvås K, Husebye ES. High prevalence and insufficiency: the need for new prevention
Published Online: June 16, 2025. strategies. Eur J Endocrinol. 2010;162(3):597-602.
doi:10.1001/jama.2025.5485 increasing incidence of Addison’s disease in
western Norway. Clin Endocrinol (Oxf). 2002;56(6): doi:10.1530/EJE-09-0884
Conflict of Interest Disclosures: Dr Vaidya 787-791. doi:10.1046/j.1365-2265.2002.t01-1- 14. Bornstein SR, Allolio B, Arlt W, et al. Diagnosis
reported receipt of consulting fees from Corcept 01552.x and treatment of primary adrenal insufficiency: an
Therapeutics, Mineralys, and HRA Pharma. Endocrine Society clinical practice guideline. J Clin
Dr Findling reported receipt of consulting fees from 6. Beuschlein F, Else T, Bancos I, et al. European
Society of Endocrinology and Endocrine Society Endocrinol Metab. 2016;101(2):364-389. doi:10.
Corcept Therapeutics and Diurnal and research 1210/jc.2015-1710
funding (to institution) from Recordati. Dr Bancos joint clinical guideline: diagnosis and therapy of
reported receipt of consulting fees (to institution) glucocorticoid-induced adrenal insufficiency. Eur J 15. Annane D, Pastores SM, Rochwerg B, et al.
from Diurnal, Neurocrine, Adrenas, Spruce, Endocrinol. 2024;190(5):G25-G51. doi:10.1093/ Guidelines for the diagnosis and management of
Sparrow, Corcept Therapeutics, HRA Pharma, ejendo/lvae029 critical illness-related corticosteroid insufficiency
Camurus, Crinetics, Recordati, Xeris, Novo Nordisk, 7. Bleicken B, Hahner S, Ventz M, Quinkler M. (CIRCI) in critically ill patients (part I): Society of
and AstraZeneca and research funding Delayed diagnosis of adrenal insufficiency is Critical Care Medicine (SCCM) and European
(to institution) from Recordati and HRA Pharma. common: a cross-sectional study in 216 patients. Society of Intensive Care Medicine (ESICM) 2017.
Am J Med Sci. 2010;339(6):525-531. doi:10.1097/ Intensive Care Med. 2017;43(12):1751-1763. doi:10.
Submissions: We encourage authors to submit 1007/s00134-017-4919-5
papers for consideration as a Review. Please MAJ.0b013e3181db6b7a
contact Kristin Walter, MD, at kristin.walter@ 8. Ben-Shlomo A, Mirocha J, Gwin SM, et al. Clinical 16. National Institute for Health and Care
jamanetwork.org. factors associated with biochemical adrenal-cortisol Excellence. Adrenal insufficiency: identification and
insufficiency in hospitalized patients. Am J Med. management. Published August 28, 2024.
REFERENCES 2014;127(8):754-762. doi:10.1016/j.amjmed.2014.03. Accessed December 2024. https://www.nice.org.
002 uk/guidance/ng243
1. Laureti S, Vecchi L, Santeusanio F, Falorni A.
Is the prevalence of Addison’s disease 9. Li T, Donegan D, Hooten WM, Bancos I. Clinical 17. de Vries F, Bruin M, Lobatto DJ, et al. Opioids
underestimated? J Clin Endocrinol Metab. 1999;84 presentation and outcomes of opioid-induced and their endocrine effects: a systematic review
(5):1762. doi:10.1210/jcem.84.5.5677-7 adrenal insufficiency. Endocr Pract. 2020;26(11): and meta-analysis. J Clin Endocrinol Metab. 2020;
1291-1297. doi:10.4158/EP-2020-0297 105(3):1020-1029. doi:10.1210/clinem/dgz022
2. Erichsen MM, Løvås K, Skinningsrud B, et al.
Clinical, immunological, and genetic features of 10. Jang W, Sohn Y, Park JH, Pai H, Kim DS, Kim B. 18. Karavitaki N, Bettinger JJ, Biermasz N, et al.
autoimmune primary adrenal insufficiency: Clinical characteristics of patients with adrenal Exogenous opioids and the human endocrine
observations from a Norwegian registry. J Clin insufficiency and fever. J Korean Med Sci. 2021;36 system: an Endocrine Society scientific statement.
Endocrinol Metab. 2009;94(12):4882-4890. (23):e152. doi:10.3346/jkms.2021.36.e152 Endocr Rev. 2024;45(6):773-794. doi:10.1210/
doi:10.1210/jc.2009-1368 endrev/bnae023
11. Papierska L, Rabijewski M. Delay in diagnosis of
3. Olafsson AS, Sigurjonsdottir HA. Increasing adrenal insufficiency is a frequent cause of adrenal 19. Li T, Cunningham JL, Gilliam WP, Loukianova L,
prevalence of Addison disease: results from a crisis. Int J Endocrinol. 2013;2013:482370. doi:10. Donegan DM, Bancos I. Prevalence of
nationwide study. Endocr Pract. 2016;22(1):30-35. 1155/2013/482370 opioid-induced adrenal insufficiency in patients
doi:10.4158/EP15754.OR taking chronic opioids. J Clin Endocrinol Metab.
12. Li D, Genere N, Behnken E, et al. Determinants 2020;105(10):e3766-e3775. doi:10.1210/clinem/
4. Hong AR, Ryu OH, Kim SY, Kim SW; Korean of self-reported health outcomes in adrenal dgaa499
Adrenal Gland and Endocrine Hypertension Study insufficiency: a multisite survey study. J Clin
Group, Korean Endocrine Society. Characteristics of Endocrinol Metab. 2021;106(3):e1408-e1419. 20. Therrell BL. Newborn screening for congenital
Korean patients with primary adrenal insufficiency: doi:10.1210/clinem/dgaa668 adrenal hyperplasia. Endocrinol Metab Clin North Am.
a registry-based nationwide survey in Korea.

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 Clinical Review & Education Review Adrenal Insufficiency in Adults: A Review

2001;30(1):15-30. doi:10.1016/S0889-8529(08) 34. Bhake R, Russell GM, Kershaw Y, et al. 48. Pofi R, Prete A, Thornton-Jones V, et al. Plasma
70017-3 Continuous free cortisol profiles in healthy men. renin measurements are unrelated to
21. Li D, Brand S, Hamidi O, et al. Quality of life and J Clin Endocrinol Metab. 2020;105(4):dgz002. mineralocorticoid replacement dose in patients
its determinants in patients with adrenal doi:10.1210/clinem/dgz002 with primary adrenal insufficiency. J Clin Endocrinol
insufficiency: a survey study at 3 centers in the 35. Upton TJ, Zavala E, Methlie P, et al. Metab. 2020;105(1):dgz055. doi:10.1210/clinem/
United States. J Clin Endocrinol Metab. 2022;107(7): High-resolution daily profiles of tissue adrenal dgz055
e2851-e2861. doi:10.1210/clinem/dgac175 steroids by portable automated collection. Sci 49. Ceccato F, Torchio M, Tizianel I, et al. Renin and
22. Øksnes M, Husebye ES. Approach to the Transl Med. 2023;15(701):eadg8464. doi:10.1126/ electrolytes indicate the mineralocorticoid activity
patient: diagnosis of primary adrenal insufficiency scitranslmed.adg8464 of fludrocortisone: a 6 year study in primary adrenal
in adults. J Clin Endocrinol Metab. 2023;109(1):269- 36. Brown S, Hadlow N, Badshah I, Henley D. insufficiency. J Endocrinol Invest. 2023;46(1):111-122.
278. doi:10.1210/clinem/dgad402 A time-adjusted cortisol cut-off can reduce referral doi:10.1007/s40618-022-01889-1

23. Chabre O, Goichot B, Zenaty D, Bertherat J. rate for synacthen stimulation test whilst 50. Jadoul M, Ferrant A, De Plaen JF, Crabbé J.
Epidemiology of primary and secondary adrenal maintaining diagnostic performance. Clin Mineralocorticoids in the management of primary
insufficiency: prevalence and incidence, acute Endocrinol (Oxf). 2017;87(5):418-424. doi:10.1111/ adrenocortical insufficiency. J Endocrinol Invest.
adrenal insufficiency, long-term morbidity and cen.13405 1991;14(2):87-91. doi:10.1007/BF03350272
mortality. Ann Endocrinol (Paris). 2017;78(6):490- 37. Struja T, Briner L, Meier A, et al. Diagnostic 51. Piazzola C, Dreves B, Albarel F, et al. Plasma
494. doi:10.1016/j.ando.2017.10.010 accuracy of basal cortisol level to predict adrenal renin: a useful marker for mineralocorticoid
24. Regal M, Páramo C, Sierra SM, Garcia-Mayor RV. insufficiency in cosyntropin testing: results from an adjustment in patients with primary adrenal
Prevalence and incidence of hypopituitarism in an observational cohort study with 804 patients. insufficiency. J Endocr Soc. 2024;8(11):bvae174.
adult Caucasian population in northwestern Spain. Endocr Pract. 2017;23(8):949-961. doi:10.4158/ doi:10.1210/jendso/bvae174
Clin Endocrinol (Oxf). 2001;55(6):735-740. doi:10. EP171861.OR 52. Arlt W, Callies F, van Vlijmen JC, et al.
1046/j.1365-2265.2001.01406.x 38. Han AJ, Suresh M, Gruber L, et al. Performance Dehydroepiandrosterone replacement in women
25. Tomlinson JW, Holden N, Hills RK, et al; West of dehydroepiandrosterone sulfate and baseline with adrenal insufficiency. N Engl J Med. 1999;341
Midlands Prospective Hypopituitary Study Group. cortisol in assessing adrenal insufficiency. J Clin (14):1013-1020. doi:10.1056/NEJM199909303411401
Association between premature mortality and Endocrinol Metab. Published online December 9, 53. Callies F, Fassnacht M, van Vlijmen JC, et al.
hypopituitarism. Lancet. 2001;357(9254):425-431. 2024. doi:10.1210/clinem/dgae855 Dehydroepiandrosterone replacement in women
doi:10.1016/S0140-6736(00)04006-X 39. Manosroi W, Phimphilai M, Khorana J, with adrenal insufficiency: effects on body
26. Barroso-Sousa R, Barry WT, Garrido-Castro AC, Atthakomol P. Diagnostic performance of basal composition, serum leptin, bone turnover, and
et al. Incidence of endocrine dysfunction following cortisol level at 0900-1300h in adrenal exercise capacity. J Clin Endocrinol Metab. 2001;86
the use of different immune checkpoint inhibitor insufficiency. PLoS One. 2019;14(11):e0225255. (5):1968-1972. doi:10.1210/jcem.86.5.7483
regimens: a systematic review and meta-analysis. doi:10.1371/journal.pone.0225255 54. Gurnell EM, Hunt PJ, Curran SE, et al.
JAMA Oncol. 2018;4(2):173-182. doi:10.1001/ 40. Debono M, Elder CJ, Lewis J, et al. Home Long-term DHEA replacement in primary adrenal
jamaoncol.2017.3064 waking salivary cortisone to screen for adrenal insufficiency: a randomized, controlled trial. J Clin
27. Cui K, Wang Z, Zhang Q, Zhang X. Immune insufficiency. NEJM Evid. 2023;2(2):a2200182. Endocrinol Metab. 2008;93(2):400-409. doi:10.
checkpoint inhibitors and adrenal insufficiency: doi:10.1056/EVIDoa2200182 1210/jc.2007-1134
a large-sample case series study. Ann Transl Med. 41. Neunzig J, Bernhardt R. Dehydroepiandros- 55. Hunt PJ, Gurnell EM, Huppert FA, et al.
2022;10(5):251. doi:10.21037/atm-21-7006 terone sulfate (DHEAS) stimulates the first step in Improvement in mood and fatigue after
28. Min L, Vaidya A, Becker C. Association of the biosynthesis of steroid hormones. PLoS One. dehydroepiandrosterone replacement in Addison’s
ipilimumab therapy for advanced melanoma with 2014;9(2):e89727. doi:10.1371/journal.pone.0089727 disease in a randomized, double blind trial. J Clin
secondary adrenal insufficiency: a case series. 42. Wolff AB, Breivik L, Hufthammer KO, et al. The Endocrinol Metab. 2000;85(12):4650-4656.
Endocr Pract. 2012;18(3):351-355. doi:10.4158/ natural history of 21-hydroxylase autoantibodies in doi:10.1210/jcem.85.12.7022
EP11273.OR autoimmune Addison’s disease. Eur J Endocrinol. 56. Alkatib AA, Cosma M, Elamin MB, et al.
29. Shi Y, Shen M, Zheng X, Yang T. Immune 2021;184(4):607-615. doi:10.1530/EJE-20-1268 A systematic review and meta-analysis of
checkpoint inhibitor-induced adrenalitis and 43. Husni H, Abusamaan MS, Dinparastisaleh R, randomized placebo-controlled trials of DHEA
primary adrenal insufficiency: systematic review Sokoll L, Salvatori R, Hamrahian AH. Cortisol values treatment effects on quality of life in women with
and optimal management. Endocr Pract. 2021;27 during the standard-dose cosyntropin stimulation adrenal insufficiency. J Clin Endocrinol Metab.
(2):165-169. doi:10.1016/j.eprac.2020.09.016 test: personal experience with Elecsys cortisol II 2009;94(10):3676-3681. doi:10.1210/jc.2009-0672

30. Grouthier V, Lebrun-Vignes B, Moey M, et al. assay. Front Endocrinol (Lausanne). 2022;13:978238. 57. Kachroo P, Stewart ID, Kelly RS, et al.
Immune checkpoint inhibitor-associated primary doi:10.3389/fendo.2022.978238 Metabolomic profiling reveals extensive adrenal
adrenal insufficiency: WHO VigiBase report 44. Ospina NS, Al Nofal A, Bancos I, et al. ACTH suppression due to inhaled corticosteroid therapy
analysis. Oncologist. 2020;25(8):696-701. doi:10. stimulation tests for the diagnosis of adrenal in asthma. Nat Med. 2022;28(4):814-822. doi:10.
1634/theoncologist.2019-0555 insufficiency: systematic review and meta-analysis. 1038/s41591-022-01714-5

31. Miljic D, Doknic M, Stojanovic M, et al. Impact of J Clin Endocrinol Metab. 2016;101(2):427-434. doi: 58. Dluhy RG. Clinical relevance of inhaled
etiology, age and gender on onset and severity of 10.1210/jc.2015-1700 corticosteroids and HPA axis suppression. J Allergy
hyponatremia in patients with hypopituitarism: 45. Saini J, Garcia RG, Herndon J, Erickson D, Clin Immunol. 1998;101(4 pt 2):S447-S450. doi:10.
retrospective analysis in a specialised endocrine Gruber L, Bancos I. Use of overnight metyrapone 1016/S0091-6749(98)70157-5
unit. Endocrine. 2017;58(2):312-319. doi:10.1007/ test in suspected secondary adrenal insufficiency: 59. Lipworth BJ. Systemic adverse effects of
s12020-017-1415-1 a retrospective single centre-study. Clin Endocrinol inhaled corticosteroid therapy: a systematic review
32. Hahner S, Spinnler C, Fassnacht M, et al. High (Oxf). 2024;100(3):203-211. doi:10.1111/cen.14989 and meta-analysis. Arch Intern Med. 1999;159(9):
incidence of adrenal crisis in educated patients with 46. Simpson H, Tomlinson J, Wass J, Dean J, Arlt W. 941-955. doi:10.1001/archinte.159.9.941
chronic adrenal insufficiency: a prospective study. Guidance for the prevention and emergency 60. Prete A, Bancos I. Glucocorticoid induced
J Clin Endocrinol Metab. 2015;100(2):407-416. doi: management of adult patients with adrenal adrenal insufficiency. BMJ. 2021;374(1380):n1380.
10.1210/jc.2014-3191 insufficiency. Clin Med (Lond). 2020;20(4):371-378. doi:10.1136/bmj.n1380
33. Erichsen MM, Løvås K, Fougner KJ, et al. doi:10.7861/clinmed.2019-0324 61. Hansen SB, Dreyer AF, Jørgensen NT, et al.
Normal overall mortality rate in Addison’s disease, 47. Esposito D, Pasquali D, Johannsson G. Primary Changes in adrenal function and insufficiency
but young patients are at risk of premature death. adrenal insufficiency: managing mineralocorticoid symptoms after cessation of prednisolone. JAMA
Eur J Endocrinol. 2009;160(2):233-237. doi:10. replacement therapy. J Clin Endocrinol Metab. 2018; Netw Open. 2025;8(3):e251029. doi:10.1001/
1530/EJE-08-0550 103(2):376-387. doi:10.1210/jc.2017-01928 jamanetworkopen.2025.1029

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 Adrenal Insufficiency in Adults: A Review Review Clinical Review & Education

62. Zhang CD, Li D, Singh S, et al. Glucocorticoid 65. Lebbe M, Arlt W. What is the best diagnostic insufficiency. J Clin Endocrinol Metab. 2025;110(5):
withdrawal syndrome following surgical remission and therapeutic management strategy for an 1218-1223. doi:10.1210/clinem/dgae486
of endogenous hypercortisolism: a longitudinal Addison patient during pregnancy? Clin Endocrinol 69. Raff H, Brock S, Findling JW. Cosyntropin-
observational study. Eur J Endocrinol. 2023;188(7): (Oxf). 2013;78(4):497-502. doi:10.1111/cen.12097 stimulated salivary cortisol in hospitalized patients
592-602. doi:10.1093/ejendo/lvad073 66. Bancos I, Erickson D, Bryant S, et al. with hypoproteinemia. Endocrine. 2008;34(1-3):
63. Suri D, Moran J, Hibbard JU, Kasza K, Weiss RE. Performance of free versus total cortisol following 68-74. doi:10.1007/s12020-008-9101-y
Assessment of adrenal reserve in pregnancy: cosyntropin stimulation testing in an outpatient 70. El-Farhan N, Tennant S, Rees SE, Evans C,
defining the normal response to the setting. Endocr Pract. 2015;21(12):1353-1363. doi:10. Rees DA. Salivary cortisol response to ACTH
adrenocorticotropin stimulation test. J Clin 4158/EP15820.OR stimulation is a reliable alternative to serum cortisol
Endocrinol Metab. 2006;91(10):3866-3872. doi:10. 67. Hamrahian AH, Oseni TS, Arafah BM. in evaluating hypoadrenalism. J Clin Endocrinol Metab.
1210/jc.2006-1049 Measurements of serum free cortisol in critically ill 2024;109(2):e579-e588. doi:10.1210/clinem/dgad576
64. Jung C, Ho JT, Torpy DJ, et al. A longitudinal patients. N Engl J Med. 2004;350(16):1629-1638. 71. Miller BS, Spencer SP, Geffner ME, et al.
study of plasma and urinary cortisol in pregnancy doi:10.1056/NEJMoa020266 Emergency management of adrenal insufficiency in
and postpartum. J Clin Endocrinol Metab. 2011;96 68. Kvam Hellan K, Lyngstad M, Methlie P, Løvås K, children: advocating for treatment options in
(5):1533-1540. doi:10.1210/jc.2010-2395 Husebye ES, Ueland GA. Utility of salivary cortisol outpatient and field settings. J Investig Med. 2020;
and cortisone in the diagnostics of adrenal 68(1):16-25. doi:10.1136/jim-2019-000999

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