Cushing Syndrome

Cushing syndrome
Straight to the point of care
Last updated: May 10, 2023

Table of Contents
Overview 3
Summary 3
Definition 3
Theory 4
Epidemiology 4
Aetiology 4
Pathophysiology 4
Classification 5
Case history 7
Diagnosis 9
Approach 9
History and exam 12
Risk factors 14
Investigations 16
Differentials 20
Management 21
Approach 21
Treatment algorithm overview 28
Treatment algorithm 30
Secondary prevention 70
Patient discussions 70
Follow up 71
Monitoring 71
Complications 72
Prognosis 74
Guidelines 76
Diagnostic guidelines 76
Treatment guidelines 76
Online resources 79
References 80
Images 94
Disclaimer 97
Cushing syndrome Overview
Summary
Cushing syndrome is the clinical manifestation of pathological hypercortisolism from any cause.
Exogenous corticosteroid exposure is the most common cause of Cushing syndrome. Cushing's disease,
OVERVIEW
which is hypercortisolism caused by an adrenocorticotrophic hormone (ACTH)-secreting pituitary adenoma,
is the most common cause of endogenous Cushing syndrome, and is responsible for 70% to 80% of cases.
It may be difficult to distinguish patients with mild Cushing syndrome from those with the metabolic syndrome
(central obesity with insulin resistance, and hypertension). Features more specific to Cushing syndrome
include proximal muscle weakness, supraclavicular fat pads, facial plethora, violaceous striae, easy bruising,
and premature osteoporosis.
After excluding exogenous corticosteroid use, patients with suspected Cushing syndrome should be tested
for hypercortisolism with one of three high-sensitivity tests (late-night salivary cortisol, 1 mg overnight low-
dose dexamethasone suppression testing, or 24-hour urinary free cortisol).
At least one additional test should be performed to confirm hypercortisolism in patients with a positive initial
screening test.
Once endogenous hypercortisolism is confirmed, plasma ACTH should be measured. If ACTH is

suppressed, diagnostic testing should focus on the adrenal glands. If ACTH is not suppressed, pituitary or
ectopic disease should be sought.
Surgical resection of the pituitary or adrenal adenoma that is causing hypercortisolism is the primary
treatment of choice in the vast majority of patients with endogenous Cushing syndrome.
Definition
Cushing syndrome is the clinical manifestation of pathological hypercortisolism from any cause. Patients
often display weight gain with central obesity, facial rounding and plethora, proximal muscle weakness, and
thinning of the skin. They also develop metabolic complications including diabetes mellitus, dyslipidaemia,
metabolic bone disease, and hypertension. Cushing syndrome can be caused by exogenous corticosteroid
exposure, by adrenocorticotrophic hormone (ACTH)-secreting pituitary tumours (termed Cushing's disease),
by autonomous adrenal cortisol overproduction, and, rarely, by ectopic ACTH-secreting tumours.[1]
This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 10, 2023.
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3
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Cushing syndrome Theory
Epidemiology
Cushing syndrome is relatively uncommon in the general population, with an incidence of 1.8 to 3.2
per million population per year.[11] However, studies of high-risk groups report a significantly greater
THEORY
prevalence.[8] Hypercortisolism has been reported in 0.5% to 1% of patients with hypertension, 2% to 3%

of patients with uncontrolled diabetes, 5% to 10% of patients with adrenal masses, and 11% of patients with
osteoporosis and vertebral fractures.[8] [12] [13] [14] [15] It is unclear if this increase in prevalence is due to
higher-sensitivity testing, a greater recognition of disease in high-risk groups, or variability in the diagnostic
criteria between historical and more-recent studies.
Cushing syndrome occurs 3 times more commonly in women than in men, and Cushing's disease
(adrenocorticotrophic hormone-secreting pituitary tumour) has a 3:1 to 5:1 female-to-male predominance.[1]
No ethnic disparities in prevalence have been identified. The majority of adults are diagnosed between the
ages of 20 and 50 years, although it can occur at any age. Cushing syndrome in children is unusual but well
documented.[1]
Exogenous corticosteroid exposure is the most common cause of Cushing syndrome, but no data exist as
to the exact epidemiology of exogenous disease. All currently reported statistics include only patients with
endogenous Cushing syndrome.
Aetiology
Exogenous corticosteroid exposure is the most common cause of Cushing syndrome.
The majority (70% to 80%) of patients with endogenous Cushing syndrome have adrenocorticotrophic
hormone (ACTH)-secreting pituitary adenomas; however, only 10% of all pituitary adenomas secrete
excessive ACTH.[8] [16] Silent corticotroph adenomas are immunopositive for ACTH, but clinically present
as non-functioning adenomas. However, large adenomas can rarely become ACTH secreting and cause
Cushing's disease.[17] A new gene, ubiquitin-specific protease 8, has been found to be frequently mutated in
Cushing's disease.[18]
About 10% of patients with endogenous Cushing syndrome have adrenal adenomas with unregulated
secretion of cortisol, but only 5% of all adrenal adenomas develop autonomous cortisol secretion.[8] [14]
Mutations in the cAMP/PKA pathway are the cause of most cases of primary adrenal hypercortisolism.[19]
No specific exposures or modifiable factors have been identified that cause endogenous hypercortisolism.
The aetiology of pituitary adenoma overproduction of ACTH and adrenal adenoma overproduction of cortisol
is poorly understood.
Only about 1% of patients with Cushing syndrome have adrenal carcinoma. On the other hand, adrenal
overproduction of cortisol is seen in 50% to 60% of adrenal carcinomas, resulting in ACTH-independent
Cushing syndrome.[10]
Pathophysiology
The clinical manifestations result from excess tissue exposure to cortisol. The degree to which symptoms
manifest is largely, if not entirely, based on the degree of cortisol excess. Patients with mild to moderate
hypercortisolism generally have a less prominent phenotype with glucose intolerance, dyslipidaemia,
metabolic bone disease, and abnormal weight gain, but are difficult to differentiate from other patients
4 This PDF of the BMJ Best Practice topic is based on the web version that was last updated: May 10, 2023.
with the metabolic syndrome. As the hypercortisolism increases, physical features worsen with striae,
supraclavicular fat pads, and proximal muscle weakness developing. Ectopic adrenocorticotrophic hormone
(ACTH) secretion from neuroendocrine tumours may manifest as more-severe cases with the abrupt
presentation of symptoms and greatly elevated cortisol and ACTH. These patients may also have severe
THEORY
muscle weakness and weight loss.
Classification
Aetiologies of hypercortisolism
Adrenocorticotrophic hormone (ACTH)-dependent
• Caused by conditions that have high or inappropriately normal ACTH levels stimulating adrenal cortisol
overproduction.
• ACTH-secreting pituitary adenomas (Cushing's disease) and ectopic ACTH-secreting tumours are two
forms of ACTH-dependent disease. Ectopic ACTH-secreting tumours are typically of bronchogenic or
neuroendocrine origin.
• Ectopic corticotrophin-releasing hormone can be considered in this category, but is extremely rare and
is not specifically discussed in detail here.
ACTH-independent
• ACTH-independent Cushing syndrome is caused by excessive cortisol secretion by the adrenal

glands despite a suppressed ACTH level. Included in this category are adrenal adenomas, bilateral
adrenal hyperplasia, and, rarely, adrenal carcinoma. Adrenal carcinoma is extremely rare and typically
presents as a large (>5 cm) and rapidly growing adrenal mass.
5
THEORY Cushing syndrome Theory
Abdominal computed scan showing adrenocortical tumour infiltrating the

pancreas and left kidney, and metastasised to the liver, spleen, and central nodes
From BMJ Case Reports 2010; doi:10.1136/bcr.07.2009.2100
• ACTH-independent bilateral macronodular adrenal hyperplasia (AIMAH) is a rare form of bilateral
nodular adrenal disease. The pathophysiology of AIMAH is aberrant receptor stimulation. At least
10 different aberrant receptors causing AIMAH have been identified. They include gastric inhibitory
polypeptide receptor, beta-adrenergic receptors, vasopressin receptor, serotonin receptor, angiotensin
II receptor, luteinising hormone/human chorionic gonadotrophin receptor, and leptin receptor.[2]
Stimulation of these receptors leads to inappropriate growth of bilateral, large, monoclonal and
polyclonal nodules.[3] [4] Clinically, AIMAH presents most commonly in the fifth and sixth decades of
life with excess glucocorticoid and mineralocorticoid production.[5] On imaging, bilaterally massively
enlarged adrenal glands are seen.
• Primary pigmented nodular adrenocortical disease (PPNAD), often part of Carney's complex
(a multiple endocrine neoplasia syndrome characterised by lentigines, cardiac and cutaneous
myxomas, and endocrine tumours; may be inherited in an autosomal-dominant manner), is a rare
condition caused by numerous small, autonomously functioning adrenal nodules ranging in size
from microscopic to 1 cm. On pathological examination the nodules are darkly pigmented, and the
intervening adrenal cortex is atrophic. Mutations in the protein kinase A type 1 alpha regulatory subunit
(PRKAR1A) are believed to be the causative mutations. PPNAD has a bimodal age of distribution,
with most cases being diagnosed in the second and third decades of life.[6] Patients with PPNAD
tend to be rather lean, and present without the typical central obesity seen in other causes of Cushing
syndrome. Severe osteoporosis, short stature, and severe muscle wasting are common presenting
features of patients with PPNAD.[7]
Exogenous
• Patients taking exogenous corticosteroids for any reason may develop features of Cushing syndrome.
When high-dose glucocorticosteroids are stopped, patients can develop adrenal insufficiency despite a
clinical phenotype of Cushing's.
THEORY
Case history
Case history #1
A 34-year-old woman presents with complaints of weight gain and irregular menses for the last several
years. She has gained 20 kg over the past 3 years and feels that most of the weight gain is in her
abdomen and face. She notes bruising without significant trauma, difficulty rising from a chair, and
proximal muscle wasting. She was diagnosed with type 2 diabetes and hypertension 1 year ago.
Case history #2
A 54-year-old man presents for evaluation of an incidentally discovered adrenal nodule. He underwent
a computed tomography scan of the abdomen for evaluation of abdominal pain, which was negative
except for a 2 cm well-circumscribed, low-density (2 Hounsfield units) nodule in the right adrenal gland.
He reports weight gain of 15 kg over the past 4 years. He has difficult-to-control type 2 diabetes and
hypertension. He has had two episodes of renal colic in the last 5 years.
Other presentations
Cushing syndrome presents with a variety of non-specific signs and symptoms. Several features have
higher specificity, such as violaceous striae, easy bruising, facial plethora, proximal muscle weakness,
and unexplained osteoporosis.[8] [9] Presentation largely depends on the degree of hypercortisolism.
Patients with severe and prolonged hypercortisolism develop more severe manifestations and
complications. Patients with Cushing syndrome caused by the ectopic adrenocorticotrophic hormone
syndrome generally have higher cortisol levels, and may develop severe muscle wasting, profound
hypokalaemia, excessive striae, and severe hyperglycaemia. Additionally, rapid virilisation in females
(rapid-onset or increased hirsutism, voice deepening, and clitoral enlargement) in the setting of cortisol
excess suggest adrenal carcinoma.[10] Cushing syndrome in pregnancy may be difficult to diagnose
due to overlapping features with pre-eclampsia and gestational diabetes, so it is important to have a high
index of suspicion. Pregnant patients may present with features such as weight gain, hypertension, easy
bruisability, violaceous striae, extremity oedema, and hirsutism. A common presentation in children is
growth deceleration with accompanying weight gain. Less common clinical features include multiple renal
stones, osteoporosis in younger people, or hypokalaemia without other features suggestive of Cushing
syndrome.
7
THEORY Cushing syndrome Theory
Abdominal striae in pregnancy

Cushing syndrome Diagnosis
Approach
For updates on diagnosis and management of coexisting conditions during the pandemic, see our topic
'Management of coexisting conditions in the context of COVID-19'.
The most important decision in the diagnosis of Cushing syndrome is deciding which patients need to begin
a diagnostic evaluation. With the growing epidemic of obesity and metabolic syndrome (central obesity with
hypertension and insulin resistance), many patients have a Cushingoid phenotype, but most do not have
Cushing syndrome.
Important considerations include female sex, as women have a higher proportion of Cushing syndrome,
unexplained hypertension (particularly in young patients), new onset of glucose intolerance or diabetes,
unexplained weight gain, unexplained fractures (due to premature osteoporosis), hirsutism, menstrual
irregularities, and unexplained proximal muscle weakness. Cushing syndrome creates a hypercoagulable
state and is associated with an increased risk of venous thromboembolic disease, such as deep vein
thrombosis and pulmonary embolism.[1]
History
All patients with suspected Cushing syndrome should have a complete history to exclude the use of oral,
injectable, inhaled, or topical glucocorticoids manifesting as iatrogenic disease. At a minimum, patients
with the following conditions should go on to be screened:[23] [24]
• Features unusual for age (i.e., osteoporosis or hypertension in young patients)

• Less-usual features, such as unexplained psychiatric symptoms (including depression)
• Unexplained nephrolithiasis
• Multiple or progressive symptoms
• Polycystic ovary syndrome
• Pituitary adenomas
• Adrenal adenomas.[25]
DIAGNOSIS
Physical
Clinical features suggesting Cushing syndrome include:
• Progressive proximal muscle weakness

• Bruising without obvious trauma
• Facial plethora or rounding
• Violaceous striae
• Supraclavicular fat pad
• Dorsocervical fat pad.
Children exhibiting weight gain with linear decreased growth velocity should also be considered. In
addition, many patients have increased frequency of acne on the face, back, and chest.
Rapid virilisation in females (rapid-onset or increased hirsutism, voice deepening, and clitoral
enlargement) in the setting of cortisol excess suggest adrenal carcinoma, which is associated with a 50%
to 60% chance of Cushing syndrome.[10]
9
Initial biochemical testing
One of the following three high-sensitivity tests, or a combination, should be used as a first-line diagnostic
test in patients with suspected Cushing syndrome:[23] [26] [27]
• Late-night salivary cortisol

• Overnight 1 mg dexamethasone suppression testing
• 24-hour urinary free cortisol
The 48-hour 2 mg dexamethasone suppression test is rarely used in isolation but can be used in
combination with other tests. Although all of the included diagnostic tests are highly sensitive and specific,
dexamethasone suppression testing was found to be the most sensitive while 24-hour urinary free cortisol
was less sensitive.[28]
Confirmation of biochemical testing

To increase diagnostic accuracy, the initial high-sensitivity test should be repeated.[23] For example,
late-night salivary cortisol samples should be obtained on two separate nights.[29] [30] [31] Similarly,
at least two 24-hour urinary free cortisol samples should be collected.[32] Alternatively, a second high-
sensitivity test may be performed: for example, supplementing a late-night salivary cortisol test with a 24-
hour urinary free cortisol measurement.[33] Testing of late-night salivary cortisol is more accurate at initial
diagnosis, but late-night salivary cortisol can frequently be normal in patients with recurrent/persistent
disease after pituitary surgery, requiring more samples for testing.[34]
Patients with initial normal biochemical testing are unlikely to have Cushing syndrome. If signs or
symptoms progress, or intermittent Cushing syndrome is suspected, repeat biochemical testing can be
performed after 6 months or at a time when cortisol hypersecretion is assumed.[23]
Patients with any abnormal initial biochemical testing require further investigation and referral to an
endocrinologist should be considered. Before proceeding with any further evaluation, physiological
causes of hypercortisolism should be excluded. These conditions include: psychiatric disorders including
depression, alcohol use disorder, physical stress, malnutrition, pregnancy, and perhaps class III obesity
DIAGNOSIS
(BMI 40 or above) or metabolic syndrome.[26] [35] [36] [37] Urine pregnancy testing should be considered
to exclude pregnancy, and glucose testing may reveal concomitant glucose intolerance or diabetes.
If multiple additional tests are abnormal, the patient has Cushing syndrome and differential diagnostic
testing should be undertaken. Greatly elevated dehydroepiandrosterone sulfate levels are suggestive of
adrenocortical carcinoma, but are neither sensitive nor specific.
[Algorithm for diagnosis of Cushing syndrome] (https://staticweb.bmj.com/BP/CushingSyndrome/

gr1_lrg.jpg) [26]
Initial differential diagnostic testing

Once hypercortisolism has been established, further testing to determine the aetiology should be sought.
Morning plasma adrenocorticotrophic hormone (ACTH) is the test of choice for differentiating ACTH-
dependent from ACTH-independent Cushing syndrome. Suppressed ACTH levels (<1 picomol/L [<5
picograms/mL]) suggest ACTH-independent Cushing syndrome (although assays differ between different
laboratories), and further investigations should include imaging of the adrenal glands to identify adrenal
pathology causing hypercortisolism, such as an adenoma.
Unsuppressed ACTH levels (>4 picomol/L [>20 picograms/mL]) suggest ACTH-dependent Cushing
syndrome (although assays differ between different laboratories).[1] Further investigations in such
patients should include pituitary/sellar magnetic resonance imaging (MRI) to identify an ACTH-secreting
pituitary adenoma. A spoiled-gradient echo 3D T1 sequence has been shown to have higher sensitivity
than dynamic MRI for detecting and localising pituitary micro-adenomas in patients with Cushing
syndrome.[38]
Patients with ACTH-dependent Cushing syndrome and an adenoma ≥10 mm on MRI should proceed
to treatment. Some clinicians prefer additional biochemical confirmation with high-dose dexamethasone
suppression testing before initiating surgical therapy.[39] The use of high-dose dexamethasone
suppression testing is an area of debate because of its variable sensitivity and specificity.[40]
Inferior petrosal sinus sampling

Patients with ACTH-dependent Cushing syndrome have either Cushing's disease (90% to 95%) or ectopic
ACTH production (5% to 10%). Those without definitive lesions on MRI should undergo inferior petrosal
sinus sampling (IPSS); this should be carried out in a specialised centre because of potential patient
risk.[26] Patients with adenomas 6-9 mm on MRI should have IPSS to confirm the diagnosis.[26] Up
to 40% of patients with Cushing's disease will not have visible lesions on pituitary/sellar MRI. Patients
without definitive lesions on MRI should also undergo inferior petrosal sinus sampling.[1] [41] IPSS is
the only test with sufficient diagnostic accuracy to differentiate Cushing's disease from ectopic ACTH
production.[42] [43] Patients with an IPSS central/peripheral gradient >2:1 or 3:1 after corticotrophin-
releasing hormone (CRH) stimulation have Cushing's disease and can undergo therapy. Those without a
gradient are likely to have ectopic ACTH production.[41]
Tests for ectopic ACTH syndrome

Patients without an IPSS central/peripheral gradient >2:1 or 3:1 after CRH stimulation should be
investigated for ectopic ACTH secretion. This evaluation generally includes computed tomography (CT)
scanning of the chest, abdomen, and pelvis to look for a tumour secreting ACTH. The most common
tumours that secrete ACTH are bronchial or thymic carcinoids. Other neuroendocrine tumours include
DIAGNOSIS
islet cell and medullary thyroid cancer.[43] An MRI of the chest may be helpful in selected cases; other
imaging modalities such as fluorodeoxyglucose positron emission tomography, gallium-68 DOTATATE
positron emission tomography/CT, and octreotide scanning may be considered in some patients.[44] [45]
[46] [47] [48]
Mild autonomous Cushing syndrome

These patients have an incidentally discovered adrenal adenoma producing mildly excessive cortisol
(previously known as subclinical Cushing syndrome). Mild cortisol excess requires a specialised approach
and may be more difficult to diagnose as a function of the inherent nature of the disease.[49] In patients
with incidentally discovered adrenal nodules without clinical features of Cushing syndrome, use the 1 mg
dexamethasone suppression test as the initial diagnostic test because urinary free cortisol and late-night
salivary cortisol have a lower sensitivity in these patients.[27] [50] [51][52]
One meta-analysis has shown that patients with bilateral adrenal incidentalomas present a higher
prevalence of subclinical Cushing syndrome compared with patients with unilateral adrenal
incidentalomas.[53]
11
History and exam

Key diagnostic factors
presence of risk factors (common)
• Key risk factors include exogenous corticosteroid use, pituitary or adrenal adenoma, or adrenal
carcinoma.
facial plethora (common)

• Many patients with Cushing syndrome have plethora.[23] [61]
supraclavicular fullness (common)

• Increased subcutaneous fat in the supraclavicular fossa is commonly seen in patients. It is much less
commonly seen in patients with obesity from other causes.
violaceous striae (common)

• Worsening or significant violaceous striae are commonly associated with hypercortisolism in younger
individuals.[23] [61]
absence of pregnancy (common)

• Pregnancy should be excluded as a potential physiological cause of hypercortisolism.
menstrual irregularities (common)

• Women with hypercortisolism generally have irregular menses or amenorrhoea.
absence of malnutrition (common)

• Malnutrition should be excluded as a potential physiological cause of hypercortisolism.
absence of alcoholism (common)

• Alcoholism should be excluded as a potential physiological cause of hypercortisolism.
DIAGNOSIS
absence of physiological stress (common)

• States of physiological stress should be excluded as a potential cause of hypercortisolism.
linear growth deceleration in children (common)

• Almost all children (>95%) show decreasing linear growth velocity.[62] Decreasing linear growth with
accompanying weight gain in children is suggestive of Cushing syndrome.[1]
Other diagnostic factors

female sex (common)
• Cushing syndrome has a female-to-male predominance of 3:1.[1]
hypertension (common)
• Among patients with hypertension, 0.5% to 1% have Cushing syndrome.[12] [13] However,
hypertension is common, and most patients with hypertension do not have hypercortisolism.
glucose intolerance or diabetes mellitus (common)
• Up to 70% of Cushing syndrome patients have impairment of glucose metabolism (glucose
intolerance, diabetes).[54] Patients with diabetes may have poorly controlled blood sugars. Poorly
controlled diabetes is common, and only 2% to 3% of patients with poorly controlled diabetes have
Cushing syndrome.[8] [55]
premature osteoporosis or unexplained fractures (common)

• Low bone density in younger men should raise suspicion.
• In patients with Cushing syndrome, osteoporosis occurs in over 50% and skeletal fractures in up to
76%.[56] As many as 11% of patients with osteoporosis and vertebral fractures have unsuspected
hypercortisolism.[15]
weight gain and central obesity (common)

• Nearly all patients gain weight. The degree of weight gain is based on the severity and duration of
hypercortisolism. The increasing prevalence of obesity in the general population has made weight gain
a very non-specific finding. It has also made the decision about which patients to test more difficult.
acne (common)
• Many patients have increased frequency of acne on the face, back, and chest.
psychiatric symptoms (common)

• Mood changes are common and occur in 70% of patients with Cushing syndrome. Depression is
the most common, but other psychiatric symptoms, such as anxiety and even psychosis, can also
occur.[57] [58] These symptoms improve or resolve with effective treatment of the hypercortisolism.
decreased libido (common)

• Occurs in up to 90% of patients, and true gonadal dysfunction is common.[56] Men generally complain
of decreased libido initially. As the hypercortisolism persists, erectile dysfunction may develop.
easy bruisability (common)
DIAGNOSIS
• Cushing syndrome patients have thinning of the skin and subcutaneous tissues with subsequent easy
bruising.[23] [56] Bruising without obvious trauma is a relatively specific physical finding.
weakness (common)
• Muscle weakness is very common, with proximal weakness being most prominent.[1] [23] [56]
facial rounding (common)

• Rounding of the face occurs in most if not all people who are obese, giving this finding a low specificity
for the diagnosis of Cushing syndrome. However, 90% of patients with Cushing syndrome develop
this.
dorsocervical fat pads (common)

• Increased subcutaneous fat on the back of the neck is commonly seen in Cushing syndrome, but also
in patients with obesity from other causes.
13
unexplained nephrolithiasis (uncommon)
• Some patients develop renal stones. Episodes of recurrent renal stones without other explanation
should raise suspicion.
venothrombolic event (uncommon)

• Cushing syndrome creates a hypercoagulable state and is associated with an increased risk of venous
thromboembolic disease.[1] Patients with Cushing syndrome have a 10-fold increased risk of venous
thromboembolism (deep vein thrombosis, pulmonary embolism).[59] [60]
hirsutism (uncommon)
• Rapid onset of virilisation may be a sign of adrenal carcinoma, which is associated with a 50% to 60%
chance of Cushing syndrome.[10]
Risk factors
Strong
exogenous corticosteroid use
• Patients who use any dose of exogenous glucocorticoid greater than the normal daily production
by the adrenals are at risk for developing Cushing syndrome.[20] The exact dose and the duration
needed to manifest Cushing syndrome varies among patients. Diagnosis of exogenous Cushing
syndrome is obvious in the setting of treatment with high-dose glucocorticoids, with increased risk
associated with higher daily and cumulative doses.[21] However, suspicion and detailed questioning
may be required to determine glucocorticoid delivery via alternative routes (e.g., intra-articular, inhaled,
topical therapy).[20]
pituitary adenoma
• About 70% to 80% of patients with Cushing syndrome have adrenocorticotrophic hormone-secreting
pituitary adenomas (Cushing's disease).[8] However, up to 10% of the population has incidental
DIAGNOSIS
pituitary lesions consistent with micro-adenomas.[22] The vast majority of these adenomas are non-
secretory and do not cause Cushing's disease.
adrenal adenoma
• About 15% of patients with Cushing syndrome have adrenal adenomas that overproduce cortisol.[8] A
significant proportion of patients with adrenal adenoma may have excess and inappropriate secretion
of cortisol leading to mild cortisol excess, also known as subclinical Cushing syndrome.[8] [14]
adrenal carcinoma
• A very rare disease. When it does occur, it can cause adrenal overproduction of cortisol resulting
in adrenocorticotrophic hormone-independent Cushing syndrome. About 50% to 60% of adrenal
carcinomas present with Cushing syndrome, but only 1% of Cushing syndrome cases are caused
by adrenal carcinoma.[10] Mixed Cushing and virilising syndromes are observed in the majority of
patients, and cases may present with rapid onset of virilisation in women: for example, hirsutism, voice
deepening, and clitoral enlargement.[10]
Weak
neuroendocrine tumours
• A small proportion of patients with Cushing syndrome have ectopic adrenocorticotrophic hormone
(ACTH) secretion. Neuroendocrine tumours, especially of bronchial and thymic origin, are the most
commonly reported to secrete excessive ACTH and cause ectopic ACTH syndrome.
thoracic or bronchogenic carcinoma

• These malignancies, especially small cell lung cancer, may produce adrenocorticotrophic hormone
(ACTH) and cause the ectopic ACTH syndrome.
DIAGNOSIS
15
Investigations
1st test to order
Test Result
urine pregnancy test negative
• Women of childbearing potential should always have pregnancy
excluded in the evaluation of hypercortisolism.
serum glucose elevated
• Cushing syndrome commonly leads to diabetes and glucose
intolerance.
late-night salivary cortisol elevated
• One of the first-line tests to consider in any patient with suspected
• Samples are collected by saturating a collection swab with saliva
or by passively drooling into a collection tube between 11 p.m. and
midnight.[63] [64]
• Obtaining multiple (at least two) samples may increase sensitivity,
and initial testing should be performed with sampling on two separate
nights.[23] [29] [30] [31]
• Value greater than the upper limit of normal is considered positive.
Normal values vary greatly depending on the assay and clinical
laboratory used.
• Positive results should be confirmed with dexamethasone
suppression testing or 24-hour urinary free cortisol.
• Testing of late-night salivary cortisol (LNSC) is more accurate at
initial diagnosis, but LNSC can be frequently normal in patients with
recurrent/persistent disease after pituitary surgery, thus sometimes
more samples are needed.[34]
1 mg overnight dexamethasone suppression test morning cortisol
>50 nanomol/L (>1.8
• One of the first-line tests to consider in any patient with suspected
micrograms/dL)
DIAGNOSIS
• A positive test is defined as morning cortisol >50 nanomol/L (>1.8
micrograms/dL).
• Should be a first-line test in any patient with suspected Cushing
syndrome, except those taking medications affecting dexamethasone
metabolism (phenytoin, carbamazepine, rifampin [rifampicin], and
cimetidine).
• Patient is given 1 mg of dexamethasone at 11 p.m., and a
plasma cortisol level is obtained the following morning at 8 a.m.
Dexamethasone levels are measured simultaneously with cortisol
to ensure that appropriate levels are achieved. This may help in
severely obese patients whose dexamethasone levels may be sub-
optimal.[64]
• Positive results should be confirmed with late-night salivary cortisol or
24-hour urinary free cortisol.
• In patients with incidentally discovered adrenal nodules without
clinical features of Cushing syndrome, the 1 mg dexamethasone
suppression test should be the initial diagnostic test because urinary
free cortisol and late-night salivary cortisol have a lower sensitivity in
these patients.[50] [51]
Test Result
24-hour urinary free cortisol >50 micrograms/24 hour
• Normal ranges vary by assay method.
• Should be considered as a possible first-line test in any patient with
suspected Cushing syndrome, except those with renal failure.
• Sensitivity may be lower than late-night salivary cortisol or 1 mg
overnight dexamethasone suppression testing.
• Patients need to be instructed on appropriate 24-hour urine
collection, and should avoid excessive fluid intake.[23]
• Likelihood ratio positive 10.6; likelihood ratio negative 0.16;
diagnostic odds ratio 95.4.[64]
• At least two 24-hour urinary free cortisol samples should be collected
to increase diagnostic accuracy.[32]
1 mg overnight dexamethasone suppression testing.
48-hour 2 mg (low-dose) dexamethasone suppression test morning cortisol
>50 nanomol/L (>1.8
• Rarely used in isolation; used in combination with other tests.
micrograms/dL)
• A positive test is defined as morning cortisol >50 nanomol/L (>1.8
micrograms/dL).
• May be considered as a first-line test in a patient with suspected
Cushing syndrome, except those taking medications known to affect
metabolism of dexamethasone.[23] Common examples of such
medications include phenytoin, carbamazepine, rifampin (rifampicin),
and cimetidine.
• Patients should be given 0.5 mg of dexamethasone at 9 a.m. and
at 6-hour intervals for 48 hours, with a plasma cortisol obtained at 9
a.m., 6 hours after the last dose.[39] [64]
24-hour urinary free cortisol.
DIAGNOSIS
17
Other tests to consider
Test Result
plasma dehydroepiandrosterone sulphate (DHEAS) level elevated
• Elevated plasma DHEAS level is not specific. However, in patients
with accelerated virilisation and Cushingoid features, it may point to
an adrenal carcinoma.
morning plasma adrenocorticotrophic hormone (ACTH) >4 picomol/L (>20
picograms/mL) suggests
• Exercise caution in interpretation of values as assays differ between
pituitary or ectopic
different laboratories, but typically values >4 picomol/L (>20
aetiology; <1 picomol/
picograms/mL) suggest pituitary or ectopic source of disease.[1]
L (<5 picograms/mL)
Values <1 picomol/L (<5 picograms/mL) suggest adrenal source of
suggests adrenal
disease.
aetiology
• Should be obtained only after biochemical diagnosis of
hypercortisolism (Cushing syndrome) has been established.
• If ACTH is not suppressed, ACTH-dependent Cushing's disease
due to pituitary adenoma or Cushing's disease due to ectopic ACTH
secretion is present.
• Suppressed ACTH levels indicate ACTH-independent Cushing
syndrome.
• ACTH is unstable in blood samples at room temperature, and care
must be taken to ensure appropriate handling of samples.
pituitary MRI may show pituitary
adenoma
• Should be ordered as the initial imaging test in patients with
confirmed adrenocorticotrophic hormone (ACTH)-dependent Cushing
syndrome.
• The majority of Cushing's disease adenomas measure <1 cm, and up
to 40% of patients with Cushing's disease do not have an adenoma
visible on MRI.[65]
• Patients with ACTH-dependent Cushing syndrome and an adenoma
≥10 mm on MRI may proceed to treatment. Some clinicians prefer
additional biochemical confirmation with high-dose dexamethasone
suppression testing prior to initiating surgical therapy.[39] The use
DIAGNOSIS
of high-dose dexamethasone suppression testing is an area of

debate.[40]
adrenal CT may show adrenal
adenoma, hyperplasia, or
• Should be ordered as the initial imaging test in patients with
tumour
confirmed adrenocorticotrophic hormone (ACTH)-independent
Cushing syndrome. Several adrenal abnormalities can produce
excess cortisol. However, solitary adrenal adenoma is by far the most
common.
• CT is very sensitive in detecting adrenal disease resulting in cortisol
hypersecretion.
• Patients with ACTH-independent Cushing syndrome and adrenal
abnormality seen on CT can proceed to therapy.
high-dose dexamethasone suppression test positive test is defined as
suppression of cortisol
• Rarely used in some countries. Can be considered in patients
<50% of the baseline
together with inferior petrosal sinus sampling in differentiating
value indicative of ACTH-
pituitary versus ectopic source of adrenocorticotrophic hormone
dependent Cushing
(ACTH)-dependent Cushing syndrome.
syndrome
• Patients should be given 2 mg of dexamethasone at 6-hour intervals
for 48 hours, or as an overnight test using a single dose of 8 mg
of dexamethasone at 11 p.m. Plasma cortisol should be obtained
Test Result
at the start of the test and on the following morning. A positive test
suggests a pituitary source of ACTH oversecretion. However, the use
of high-dose dexamethasone suppression testing is an area of debate
because of its variable sensitivity and specificity.[40]
inferior petrosal sinus sampling (IPSS) elevated central/
peripheral ACTH ratio
• Should be performed in patients with confirmed adrenocorticotrophic
indicates pituitary source
hormone (ACTH)-dependent Cushing syndrome without an obvious
pituitary lesion on MRI or those with adenomas 6-9 mm in size
on MRI.[1] [26][41] Should be carried out in a specialised centre
because of potential patient risk.[26] IPSS is the only test with
sufficient diagnostic accuracy to differentiate Cushing's disease from
ectopic ACTH production.[42] [43]
• Central/peripheral ACTH ratio >2:1 at baseline or >3:1 after
corticotrophin-releasing hormone (CRH) stimulation.
• Blood is sampled peripherally and in the inferior petrosal sinuses
simultaneously. If the pituitary effluent (blood in the petrosal sinuses)
has a concentration of ACTH greater than 2-fold that of peripheral
blood at baseline or greater than 3-fold after stimulation with CRH,
the source of the hypercortisolism is pituitary ACTH secretion.[41]
• If the ACTH ratio does not reach this threshold, ectopic ACTH
secretion is likely.
• This is a technically demanding study that very few centres can
perform well.
CT of chest, abdomen, and pelvis may localise tumour
• Used to determine the source of ectopic adrenocorticotrophic
hormone syndrome.
MRI chest may localise tumour
• May be helpful in selected cases of ectopic adrenocorticotrophic
hormone syndrome to localise tumour.
octreotide scanning may localise tumour
• May be helpful in selected cases of ectopic adrenocorticotrophic
DIAGNOSIS
hormone syndrome to localise tumour.
gallium-68 DOTATATE PET/CT may localise tumour
• Dotatate scans may detect small neuroendocrine tumours causing
ectopic adrenocorticotrophic hormone production.
19
Differentials
Condition Differentiating signs / Differentiating tests

symptoms
Obesity • Usually lack facial • Normal late-night salivary
plethora, unexplained cortisol, dexamethasone
bruising, proximal muscle suppression testing, or 24-
weakness, violaceous striae, hour urinary free cortisol.
supraclavicular fullness, and
osteoporotic fractures.[23]
Metabolic syndrome • Usually lack facial • Normal late-night salivary

plethora, unexplained cortisol, dexamethasone
bruising, proximal muscle suppression testing, or 24-
weakness, violaceous striae, hour urinary free cortisol.
supraclavicular fullness, and
osteoporotic fractures.[23]
DIAGNOSIS
Cushing syndrome Management
Approach
For updates on diagnosis and management of coexisting conditions during the coronavirus disease 2019
(COVID-19) pandemic, see our topic Management of coexisting conditions in the context of COVID-19 .
Do not start treatment until the diagnosis is firmly established and the source of hypercortisolism is
recognised. Give patients with moderate to severe hypercortisolism therapy directed at the underlying
cause. Resolution of cortisol excess in these cases has been shown to decrease mortality.[66] [67] Weigh
up the potential benefits and risk of therapy options in patients with only mild cortisol excess (biochemical
evidence of hypercortisolaemia but no clinical signs or symptoms of Cushing syndrome) because the benefit
of surgery has not been definitively demonstrated.[51] [52] [68]
Cushing's disease (pituitary adenoma)

Cushing's disease is caused by adrenocorticotrophic hormone (ACTH)-secreting pituitary tumours. The
ultimate goal of therapy is to remove the causative pituitary adenoma and normalise cortisol levels while
preserving pituitary function.
First-line therapy is transsphenoidal (TSS) resection of the causative pituitary adenoma performed by an
experienced surgeon.[26] [66] [69] Surgery can be done using an endoscopic or microscopic approach.
Results are comparable between both techniques for microadenomas.[70] Whether there is potential
incremental benefit with an endoscopic approach for macroadenomas remains unclear.[26] [70]
MANAGEMENT
21
Algorithm for the treatment of Cushing's disease (DST = dexamethasone suppression test. IPSS = inferior
petrosal sinus sampling. ACTH = adrenocorticotrophic hormone. *Pituitary surgery should be performed by
an experienced surgeon. †Absence of ACTH-staining adenoma. §Lifelong monitoring for hypopituitarism
and secondary neoplasia in the radiation field required. ¶On maximum tolerated dose of the drug)
Fleseriu M et al. Lancet Diabetes Endocrinol. 2021 Dec;9(12):847-75; used with permission
Many patients are supported with corticosteroids following pituitary surgery but should be assessed for
remission during the first postoperative week.[68] This is done by measuring morning cortisol at least
24 hours after the last dose of corticosteroid therapy. Patients with a postoperative morning cortisol of
<55 nanomol/L (<2 micrograms/dL) are considered to be in remission and can transition into long-term
follow-up. Patients with a postoperative morning cortisol of >138 nanomol/L (>5 micrograms/dL) require
further evaluation and possibly further therapy. Patients with a morning cortisol between 55 and 138
MANAGEMENT
nanomol/L (2 and 5 micrograms/dL) should be followed with additional measurements to detect a drop in
subsequent morning cortisol levels. Individuals with morning cortisols >55 nanomol/L (>2 micrograms/dL)
after surgery are 2.5 times more likely to have recurrences than those with cortisol levels <55 nanomol/L
(<2 micrograms/dL).[71] [72] [73]
Postoperative hypocortisolism is predictive of remission, hence some centres advocate withholding
routine corticosteroid therapy after pituitary surgery and monitoring cortisol levels every 8 hours or
if symptoms of adrenal insufficiency occur.[74] If adrenal insufficiency occurs or low cortisol levels
are documented, corticosteroid therapy is initiated. Other centres begin routine corticosteroid therapy
immediately after surgery and evaluate for remission of hypercortisolism later in the postoperative
course.[75] Corticosteroids are usually rapidly tapered to physiological doses within 1 week or less
(often by discharge from hospital). Testing to see if the hypothalamic-pituitary-adrenal (HPA) axis has
recovered can be done in follow-up by 3 months after surgery. Testing is usually a morning cortisol prior
to the patient taking the morning hydrocortisone dose, if hydrocortisone therapy had been continued.
Cortisol levels of >552 nanomol/L (>20 micrograms/dL) indicate recovery of the axis. Levels <83 nanomol/
L (<3 micrograms/dL) indicate a continued need for corticosteroids. Levels between 83 nanomol/L (3
micrograms/dL) and 552 nanomol/L (20 micrograms/dL) should prompt further testing (cosyntropin
stimulation testing, insulin tolerance testing, or metyrapone testing). Once recovery of HPA axis has been
established, patients need to undergo testing for possible recurrence. Salivary cortisol testing seems to
be a better predictor of early recurrence.[73] [76]
Additional therapy should be considered in patients with failure of initial pituitary surgery or with
recurrence of disease. The incidence of recurrence in Cushing's disease is high, with 50% of recurrences
occurring during the first 50 months after first surgery.[77] Standard therapies include repeat pituitary
surgery, radiotherapy, bilateral adrenalectomy, or medical therapy.[69] [78]
Success rates of these treatment options vary between 25% (for some of the medical therapies) and
100% (bilateral adrenalectomy). Treatment options have specific advantages, limitations, and side-effects
so treatment decisions should be individualised according to the specific needs of the patient and risk of
complications.[77] [79]
Re-operation is frequently the preferred therapy if initial surgery fails. It should be considered in all
patients with recurrence or persistence of disease. It is effective in about two-thirds of patients.[80] [81]
[82] However, the risk of pituitary deficiency after re-operation is 50%. This is significantly higher than
after initial surgical therapy.[80] If re-operation is ineffective, or if a patient is not a candidate for re-
operation, another modality should be considered.
Radiotherapy by conventional fractionated radiotherapy or stereotactic radiosurgery is most commonly

used in patients with persistent hypercortisolism after incomplete corticotroph tumour resection,
particularly if the tumour is aggressive or invasive or considered unresectable.[26] Radiotherapy allows for
control of hypercortisolism within 3 to 5 years in over half of patients.[83] [84] [85] [86] [87] This modality
is perhaps best used as part of the therapy for patients with mild residual hypercortisolism, as full effects
of therapy can take several years to be realised. Radiation of tumours located close to the optic chiasm
increases the risk of damage to the optic chiasm, and this risk should be considered prior to therapy.
Hypopituitarism can also occur following radiotherapy and is another risk to consider prior to initiating
therapy. The exact risk of hypopituitarism after conventional fractionated radiotherapy versus stereotactic
radiosurgery is unclear, but they seem similar.
Patients with unsuccessful re-operation who manifest severe hypercortisolism should be evaluated for
MANAGEMENT
therapy with medical therapy, bilateral adrenalectomy, or a combination of these therapies. The advantage
to these approaches is the rapid onset of decreased cortisol levels or blockade of cortisol action.
Medical treatment with a somatostatin analogue (pasireotide), a dopamine agonist (cabergoline), a

steroidogenesis inhibitor (osilodrostat, ketoconazole, levoketoconazole, metyrapone, mitotane, and
23
etomidate), or a glucocorticoid receptor antagonist (mifepristone) has been increasingly used in clinical
practice. Medical therapy is indicated to control cortisol secretion in patients with mild hypercortisolism,
as a short term adjunct for severe hypercortisolism before other therapies are undertaken, preoperatively
to bridge the time period until control of hypercortisolism is achieved by radiotherapy, in cases with
persistent or recurrent hypercortisolism after surgery, or where surgery is declined or not feasible (e.g.,
high surgical risk, metastatic disease).[88] [89] [90] [91] However, there is a paucity of high-quality studies
of medical therapy in Cushing's disease, and caution should be employed when comparing efficacy
rates owing to the variability in study design and quality.[91] Individualise medical therapy for patients
with Cushing's disease based on the clinical scenario, including the severity of hypercortisolism.[26] In
patients with severe disease, treat aggressively to normalise cortisol concentrations (or cortisol action).
Use multiple serial tests of both urinary free cortisol and late-night salivary cortisol to monitor treatment
outcomes.
• Pasireotide is a somatostatin analogue that selectively targets somatostatin receptors in

corticotroph adenomas and is now being used to medically treat Cushing's disease.[89] [90]
Pasireotide binds to a wide variety of somatostatin receptors, but with greater affinity to receptor
5, which is predominantly expressed in patients with corticotroph adenomas. The use of the
regular-release formulation of pasireotide has been shown to decrease cortisol levels in most
patients with Cushing's disease, but only normalises cortisol levels in 25% of patients.[92] The
long-acting formulation of pasireotide showed normalisation in approximately 40% of patients,
but hyperglycaemia was noted in up to 80% of patients.[93] In one study, tumour shrinkage was
noted in 62.5% of patients after 6 months of pasireotide treatment.[94] Salivary cortisol also
decreased after treatment; thus, salivary cortisol may be a more convenient biomarker to follow in
assessing response to treatment in patients with Cushing's disease.[95] One 10-year single-centre
experience with pasireotide reported sustained biochemical and clinical benefit in about 60% of
patients with Cushing's disease.[96] This is a pituitary-targeted therapy and should only be used in
patients with hypercortisolism due to ACTH-secreting pituitary tumours.[97] There is a high risk of
hyperglycaemia, which requires careful patient selection, and a risk of QTc prolongation.[26]
• Cabergoline, a dopamine agonist, has been used off-label in the treatment of Cushing's disease in
some countries with limited results.[89] [90] [98]
• Steroidogenesis inhibitors (agents that decrease adrenal corticosteroid production, such as
osilodrostat, ketoconazole, levoketoconazole, metyrapone, mitotane, and etomidate) can be used
(though off-label in some countries, except osilodrostat) in the treatment of Cushing syndrome.[26]
[89] [90]
• Osilodrostat is a potent oral inhibitor of steroidogenesis (inhibits steroid 11-beta-hydroxylase)

that is approved in the US for the treatment of Cushing's disease in patients where pituitary
surgery is not an option or has not been curative, and in Europe and Japan for the treatment
of endogenous Cushing syndrome.[26] [99] Osilodrostat rapidly reduces urinary free cortisol
with associated improvements in clinical signs of hypercortisolism, and is generally well
tolerated.[99] There is a risk of hypocortisolism, hypokalaemia, and QTc prolongation; careful
monitoring for hyperandrogenism is needed in women.[26]
• Ketoconazole has a relatively rapid onset of steroidogenesis inhibition. Ketoconazole may
MANAGEMENT
cause idiopathic severe liver injury and adrenal insufficiency.[90] [100] [101] If used, liver and
adrenal function should be monitored before and during treatment. Its use requires expert
guidance and is contraindicated in patients with liver disease.[101]
• Levoketoconazole is an adrenal steroidogenesis inhibitor that is approved for treatment in the
US.[102] [103] [104]
• Metyrapone provides rapid onset of inhibition and can be obtained for compassionate use in
the US.
• Mitotane has adrenostatic and adrenolytic properties, but has delayed efficacy due to slow
onset of action and a narrow therapeutic window.[90] It is rarely used for Cushing syndrome
due to causes other than adrenal carcinoma.
• Etomidate is a potent adrenostatic agent with a rapid onset of action. It is used only in
emergencies (e.g., hypercortisol-induced psychosis), and must be given intravenously.[90]
• Mifepristone, a glucocorticoid receptor antagonist, blocks the effect of cortisol at the receptor level
and should be considered in patients who have clinical and metabolic derangements of continued
hypercortisolism with hyperglycaemia and/or diabetes. The US Food and Drug Administration has
approved mifepristone for the treatment of hyperglycaemia associated with Cushing syndrome
in patients with type 2 diabetes mellitus. Cortisol and ACTH levels may increase with the use of
mifepristone due to feedback inhibition.[105] As such, cortisol levels should not be used to guide
therapy in patients treated with mifepristone.[106]
Bilateral adrenalectomy provides an immediate cure to any cause of endogenous hypercortisolism,
at the expense of causing permanent adrenal insufficiency (requiring cortisol and mineralocorticoid
replacement) and creating a risk of Nelson syndrome (corticotroph tumour growth after adrenalectomy).
This progression can cause hyperpigmentation from excessive ACTH and intracranial compressive
symptoms from growth of the tumour outside the sella. Newer laparoscopic methods of adrenalectomy
allow for more rapid recovery and tolerability.[107] One meta-analysis of 37 studies (1320 patients, 82%
with Cushing's disease, 13% with ectopic Cushing syndrome, and 5% with primary adrenal hyperplasia)
showed that bilateral adrenalectomy is relatively safe and provides adequate success.[108] Although
residual cortisol secretion due to accessory adrenal tissue or adrenal remnants was found in up to 34%
of patients, less than 2% had a relapse of Cushing syndrome. Symptoms of hypercortisolism (e.g.,
hypertension, obesity, or depression) improved in the majority of the patients after bilateral adrenalectomy.
The number of adrenal crises per 100 patient years was 9.3, and Nelson's syndrome occurred in 21% of
the patients. Excess mortality within the first year after surgery suggests that intensive clinical care for
patients after bilateral adrenalectomy is warranted.
For replacement of non-glucocorticoid pituitary hormones following pituitary surgery (any combination of
deficiencies may occur):[109]
• Levothyroxine is used to achieve a free T4 in the upper half of the normal range. A thyroid-
stimulating hormone should not be used to guide therapy.
• Testosterone therapy is used to achieve a testosterone level in the normal range.
• Women with an intact uterus taking oestrogen replacement also need 10 days of progestin each
month in addition to oestrogen replacement therapy.
• Decision to treat with growth hormone should be individualised for each patient based on
symptoms, benefits, and risk of therapy. Dose titration should occur every month to achieve clinical
response (i.e., energy level, sense of well-being, and lean body mass) and an insulin-like growth
MANAGEMENT
factor 1 (IGF-1) level in the age-adjusted mid- to upper-normal range.

• Desmopressin is titrated to control symptomatic excessive urine output. This is based on patient
preference. Serum sodium and symptoms are monitored periodically to evaluate adequacy of
treatment.
25
ACTH-independent Cushing syndrome
The most common cause of adrenal cortisol overproduction is a unilateral autonomous adrenal adenoma.
First-line therapy is almost always unilateral adrenalectomy of the affected adrenal gland. Laparoscopic
adrenalectomy is the preferred method in most cases. Removal of the affected adrenal gland is curative
in all patients with unilateral adrenal disease. Adrenalectomy has a beneficial effect on cardiovascular
risk factors in patients with subclinical Cushing syndrome overall and compared with conservative
management.[110]
Rare causes of ACTH-independent disease generally cause bilateral adrenal disease from autonomous
nodule formation or bilateral hyperplasia.[19] [89] In these cases first-line therapy generally requires
bilateral adrenalectomy. Steroidogenesis inhibitor therapy (osilodrostat, ketoconazole, levoketoconazole,
metyrapone, mitotane, and etomidate), or a glucocorticoid receptor antagonist (mifepristone) can
be used for patients who wish to avoid bilateral adrenalectomy.[19] [90] [111] Osilodrostat rapidly
reduces urinary free cortisol with associated improvements in clinical signs of hypercortisolism, and is
generally well tolerated.[26] [99] Ketoconazole has a relatively rapid onset of steroidogenesis inhibition.
Ketoconazole may cause severe liver injury and adrenal insufficiency. Its use requires expert guidance
and is contraindicated in patients with liver disease. If used, liver and adrenal function should be
monitored before and during treatment.[101] Levoketoconazole is an adrenal steroidogenesis inhibitor
that is approved for treatment in the US.[102] [103] [104] Metyrapone provides rapid onset of inhibition.
Mitotane has slow onset of action, has a narrow therapeutic window, and is generally only used in adrenal
carcinoma.[69] Etomidate, used only in emergencies, has rapid onset but must be given intravenously.[69]
Mifepristone blocks cortisol action, resulting in attenuation of cortisol effects.
Adrenal carcinoma is an exceedingly rare cause of ACTH-independent Cushing syndrome. First-line

therapy in many patients is surgical resection; however, at the time of diagnosis the disease has often
progressed beyond the point where surgical therapy is effective. The effectiveness of chemotherapy
and adjunctive therapies in both early- and late-stage disease has shown mixed results in clinical trials;
however, patients should be considered for treatment with mitotane and enrolment in clinical trials (if
available).[10]
Ectopic ACTH syndrome

The optimal first-line therapy involves locating and surgically resecting the ACTH-producing tumour. Not
infrequently, complete resection of these tumours is not possible. Where surgical resection is not possible,
second-line therapies include a glucocorticoid receptor antagonist (mifepristone), steroidogenesis inhibitor
therapy (osilodrostat, ketoconazole, levoketoconazole, metyrapone, mitotane, and etomidate), or bilateral
adrenalectomy.[89] Bilateral adrenalectomy is definitive therapy, but patients with ectopic ACTH-producing
tumours may have extremely severe hypercortisolism, and require reduction in cortisol before proceeding
to surgery. In these cases, mifepristone or steroidogenesis inhibitor therapy can be used to lower
cortisol levels in preparation for bilateral adrenalectomy. Osilodrostat rapidly reduces urinary free cortisol
with associated improvements in clinical signs of hypercortisolism, and is generally well tolerated.[26]
[99] Ketoconazole has a relatively rapid onset of steroidogenesis inhibition. Ketoconazole may cause
severe liver injury and adrenal insufficiency. Its use requires expert guidance and is contraindicated in
patients with liver disease. If used, liver and adrenal function should be monitored before and during
MANAGEMENT
treatment.[101] Levoketoconazole is an adrenal steroidogenesis inhibitor that is approved for treatment in

the US.[102] [103] [104] Metyrapone provides rapid onset of inhibition. Mitotane has slow onset of action,
has a narrow therapeutic window, and is generally only used in adrenal carcinoma.[69] Etomidate, used
only in emergencies, has rapid onset but must be given intravenously.[69] Mifepristone blocks cortisol
action, resulting in attenuation of cortisol effects.
MANAGEMENT
27
Treatment algorithm overview

Please note that formulations/routes and doses may differ between drug names and brands, drug
formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer
Ongoing ( summary )
Cushing's disease
(adrenocorticotrophic hormone
[ACTH]-secreting pituitary tumour)
1st transsphenoidal pituitary adenomectomy
adjunct medical therapy before surgery
adjunct post-surgical corticosteroid replacement

therapy
adjunct post-surgical pituitary hormone

replacement therapy
1st medical therapy alone
2nd repeat transsphenoidal pituitary

adenomectomy

therapy

replacement therapy
2nd medical therapy alone
2nd pituitary radiotherapy
adjunct medical therapy before radiotherapy
adjunct post-radiation corticosteroid replacement

therapy
adjunct post-radiation pituitary hormone

replacement therapy
2nd bilateral adrenalectomy
plus permanent post-surgical corticosteroid

and mineralocorticoid replacement
therapy
ectopic ACTH or corticotrophin-

releasing hormone (CRH) syndrome
MANAGEMENT
1st surgical resection or ablation of tumour

and metastases
Ongoing ( summary )
adjunct chemotherapy or radiotherapy for primary
tumour

therapy

tumour
3rd medical therapy only

tumour
ACTH-independent due to unilateral

adrenal carcinoma or adenoma
1st unilateral adrenalectomy or tumour

resection
adjunct chemotherapy or radiotherapy for adrenal

carcinoma
2nd medical therapy only

carcinoma
ACTH-independent due to bilateral

adrenal disease (hyperplasia or
adenoma)
1st bilateral adrenalectomy

therapy

MANAGEMENT
29
Treatment algorithm
Please note that formulations/routes and doses may differ between drug names and brands, drug
formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer
Ongoing
Cushing's disease
(adrenocorticotrophic hormone
[ACTH]-secreting pituitary tumour)
1st transsphenoidal pituitary adenomectomy
» First-line therapy is transsphenoidal resection

of the causative pituitary adenoma performed by
an experienced surgeon.[26] [69] [112] Surgery
can be done using an endoscopic or microscopic
approach. Results are comparable between both
techniques for microadenomas.[70] Whether
there is potential incremental benefit with an
endoscopic approach for macroadenomas
remains unclear.[26] [70]
» Patients with mild cortisol excess (biochemical

evidence of hypercortisolaemia but no clinical
signs or symptoms of Cushing syndrome)
should have therapy carefully weighed because
benefit of surgery has not been convincingly
demonstrated.[68]
Treatment recommended for SOME patients in
selected patient group
Primary options
» osilodrostat: 2 mg orally twice daily initially,

increase gradually according to response,
maximum 60 mg/day
OR
» metyrapone: 0.5 to 1 g/day orally given in

3-4 divided doses initially, increase gradually
according to response, maximum 6 g/day
OR
» ketoconazole: 200-600 mg/day orally

given in 2-3 divided doses initially, increase
gradually according to response, maximum
1600 mg/day given in 2-4 divided doses
MANAGEMENT
OR
» levoketoconazole: 150 mg orally twice

daily initially, increase gradually according to
response, maximum 1200 mg/day
Ongoing
OR
» pasireotide: 0.3 to 0.9 mg subcutaneously

twice daily; 10-40 mg intramuscularly every 4
weeks
OR
» cabergoline: consult specialist for guidance

on dose
OR
» mifepristone: 300 mg orally once daily

initially, increase gradually according to
Secondary options
» mitotane: consult specialist for guidance on

dose
Tertiary options
» etomidate: consult specialist for guidance

on dose
» A somatostatin analogue (pasireotide),

a dopamine agonist (cabergoline), a
steroidogenesis inhibitor (osilodrostat,
ketoconazole, levoketoconazole, metyrapone,
mitotane, etomidate), or a glucocorticoid receptor
antagonist (mifepristone) is occasionally used
short term for severe hypercortisolism before
other therapies are undertaken.[88] [89] [90] [91]
» Somatostatin analogue: pasireotide binds

to a wide array of somatostatin receptors,
with a much greater affinity for somatostatin
receptor 5, which is predominantly expressed
in corticotroph adenomas. Use of the regular-
release formulation of pasireotide decreases
cortisol in most patients, but normalises cortisol
levels in only 25% of patients.[92] The long-
acting formulation of pasireotide normalises
cortisol levels in 40% of patients.[93] It causes
hyperglycaemia in most patients. This is a
pituitary-targeted therapy and should be used
only in patients with hypercortisolism due to
ACTH-secreting pituitary tumours.[97] There is
a high risk of hyperglycaemia, which requires
MANAGEMENT
careful patient selection, and a risk of QTc

prolongation.[26]
» Dopamine agonist: cabergoline has been used

off-label in the treatment of Cushing's disease in
some countries.[98]
31
Ongoing
» Steroidogenesis inhibitors: osilodrostat,
mitotane, and etomidate decrease adrenal
corticosteroid production.[89] [90] [99] They
should only be used by physicians familiar with
their use. Osilodrostat is approved in the US
and Europe for use in Cushing's disease. It is a
potent, rapidly active steroid 11-beta-hydroxylase
inhibitor and is generally well tolerated.[99]
There is a risk of hypocortisolism, hypokalaemia,
and QTc prolongation; careful monitoring for
hyperandrogenism is needed in women.[26]
Ketoconazole and metyrapone have a relatively
rapid onset of steroidogenesis inhibition.
Ketoconazole may cause idiopathic severe
liver injury and adrenal insufficiency. Its use
requires expert guidance and is contraindicated
in patients with liver disease. If used, liver and
adrenal function should be monitored before and
during treatment.[100] [101] Levoketoconazole
is an adrenal steroidogenesis inhibitor that is
approved for treatment in the US.[102] [103]
[104] Mitotane has slow onset of action and a
narrow therapeutic window. It is rarely used for
Cushing syndrome due to causes other than
adrenal carcinoma. Etomidate is rarely used and
is reserved for emergency situations only. It has
rapid onset but must be given intravenously.[90]
» Glucocorticoid receptor antagonist:

mifepristone blocks cortisol at the receptor level
and attenuates the clinical and biochemical
effects associated with elevation of cortisol.
The US Food and Drug Administration has
approved mifepristone for the treatment of
hyperglycaemia associated with Cushing
syndrome. It may be used for all forms of
Cushing syndrome. Cortisol levels may increase
during therapy with mifepristone due to feedback
inhibition.[105] As such, cortisol levels should
not be used to guide therapy in patients treated
with mifepristone.[106]
» Patients should be monitored for development

of adrenal insufficiency.
» Dose adjustment should be based on clinical

symptoms, biochemical normalisation of 24-
hour urinary free cortisol, and late-night salivary
cortisol (with the exception of mifepristone,
where use of cortisol as a marker will not be
reliable).
MANAGEMENT

therapy
Ongoing
Primary options
» hydrocortisone: 10-25 mg per metre square

body surface area/day orally given in 2-3
divided doses; usual dose is a larger dose in
the morning (10-15 mg) and a smaller dose in
the late afternoon (5-10 mg)
» Patients who undergo pituitary adenomectomy

may become temporarily or permanently
dependent on physiological replacement
of cortisol. It is necessary to monitor blood
pressure, check for orthostatic symptoms, and
assess general sense of energy or fatigue.
» As postoperative hypocortisolism is predictive

of remission, some centres advocate withholding
routine corticosteroid therapy after pituitary
surgery and monitoring cortisol levels every 8
hours or if symptoms of adrenal insufficiency
occur. If adrenal insufficiency occurs or low
cortisol levels are documented, corticosteroid
therapy should be initiated. Other centres begin
routine corticosteroid therapy immediately
after surgery and evaluate for remission of
hypercortisolism later in the postoperative
course.[75] This is done by measuring morning
cortisol at least 24 hours after the last dose
of corticosteroid therapy. Patients with a
postoperative morning cortisol of <55 nanomol/
L (<2 micrograms/dL) are considered to be
in remission and can transition into long-term
follow-up. Patients with a postoperative morning
cortisol of >138 nanomol/L (>5 micrograms/
dL) require further evaluation and possibly
further therapy. Patients with a morning
cortisol between 55 and 138 nanomol/L (2
and 5 micrograms/dL) should be followed with
additional measurements to detect a drop in
subsequent morning cortisol levels. Individuals
with morning cortisols >55 nanomol/L (>2
micrograms/dL) after surgery are 2.5 times
more likely to have recurrences than those with
cortisol levels <55 nanomol/L (<2 micrograms/
dL).[71] [72] [73]
» Corticosteroids are usually rapidly tapered

to physiological doses within 1 week or less
(often by discharge from hospital). Testing to
see if the hypothalamic-pituitary-adrenal (HPA)
axis has recovered can be done in follow-up
MANAGEMENT
by 3 months after surgery. Testing is usually a

morning cortisol prior to the patient taking the
morning hydrocortisone dose, if hydrocortisone
therapy had been continued. Cortisol levels of
>552 nanomol/L (>20 micrograms/dL) indicate
recovery of the axis. Levels <83 nanomol/L (<3
33
Ongoing
micrograms/dL) indicate a continued need for
corticosteroids. Levels between 83 nanomol/
L (3 micrograms/dL) and 552 nanomol/L (20
micrograms/dL) should prompt further testing
(cosyntropin stimulation testing, insulin tolerance
testing, or metyrapone testing). Once recovery of
HPA axis has been established, patients need to
undergo testing for possible recurrence. Salivary
cortisol testing seems to be a better predictor of
early recurrence.[73] [76]
replacement therapy
Primary options
» levothyroxine: 1.8 micrograms/kg/day orally

--AND/OR--
» testosterone transdermal: 2.5 to 7.5 mg
once daily, titrate according to response in
men
-or-
» testosterone cipionate: 200 mg
intramuscularly every 2 weeks, titrate
according to response in men
-or-
» estradiol: 2 mg orally once daily in women
-or-
» conjugated oestrogens: 0.625 to 1.25 mg
orally once daily in women
-and-
» medroxyprogesterone: 5-10 mg orally once
daily on 10 days of each month if woman has
intact uterus and on estradiol or oestrogen
--AND/OR--
» somatropin (recombinant): dose depends
on brand used; consult specialist for guidance
on dose
--AND/OR--
» desmopressin: 0.1 mg orally once to three
times daily
» Any combination of deficiencies may occur.
» Levothyroxine is used to achieve a free T4 in

the upper half of the normal range. A thyroid-
stimulating hormone should not be used to guide
therapy.[109]
MANAGEMENT
» Testosterone therapy is used to achieve a

testosterone level in the normal range.[109]
» Women with an intact uterus taking oestrogen

replacement also need 10 days of progestin
Ongoing
each month in addition to oestrogen replacement
therapy.
» Decision to treat with growth hormone should

be individualised for each patient based on
symptoms, benefits, and risk of therapy.[109]
Dose titration should occur every month to
achieve clinical response (i.e., energy level,
sense of well-being, and lean body mass) and
an insulin-like growth factor 1 (IGF-1) level in the
age-adjusted mid- to upper-normal range.
» Desmopressin is titrated to control

symptomatic excessive urine output. This is
based on patient preference. Serum sodium and
symptoms are monitored periodically to evaluate
adequacy of treatment.[109]
1st medical therapy alone
Primary options

maximum 60 mg/day
OR

OR

OR

OR

weeks
MANAGEMENT
OR

on dose
OR
35
Ongoing

Secondary options

dose
Tertiary options

on dose
» Medical treatment alone with a somatostatin

analogue (pasireotide), a dopamine agonist
(cabergoline), a steroidogenesis inhibitor
(osilodrostat, ketoconazole, levoketoconazole,
metyrapone, mitotane, and etomidate), or a
glucocorticoid receptor antagonist (mifepristone)
has been increasingly used in clinical practice.
Medical therapy is indicated to control cortisol
secretion in patients with mild hypercortisolism
or where surgery is declined or not feasible (e.g.,
high surgical risk, metastatic disease).[88] [89]
[90] [91] However, there is a paucity of high-
quality studies of medical therapy in Cushing's
disease, and caution should be employed when
comparing efficacy rates owing to the variability
in study design and quality.[91]
» Somatostatin analogue: pasireotide binds to

a wide array of somatostatin receptors, with a
much greater affinity for somatostatin receptor
5, which is predominantly expressed in patients
with corticotroph adenomas. Use of the regular-
prolongation.[26]

MANAGEMENT
some countries.[98]

Ongoing



reliable).
2nd repeat transsphenoidal pituitary
adenomectomy
MANAGEMENT
» In patients who received transsphenoidal

pituitary adenomectomy as first-line therapy,
additional therapy should be considered in
patients with failure of initial pituitary surgery
or with recurrence of disease. The incidence of
recurrence in Cushing's disease is high, with
37
Ongoing
50% of recurrences occurring during the first 50
months after first surgery.[77] Re-operation is
frequently the preferred therapy if initial surgery
fails. It should be considered in all patients
with recurrence or persistence of disease. It is
effective in about two-thirds of patients.[80] [81]
[82] However, the risk of pituitary deficiency after
re-operation is 50%. This is significantly higher
than after initial surgical therapy.[80]

signs or symptoms of Cushing syndrome)
should have therapy carefully weighed because
benefit of surgery has not been convincingly
demonstrated.[68]
Primary options

maximum 60 mg/day
OR

OR

OR

OR

MANAGEMENT
weeks
OR

on dose
Ongoing
OR

Secondary options

dose
Tertiary options

on dose

antagonist (mifepristone) is occasionally used for
mild hypercortisolism, or short term for severe
hypercortisolism, before other therapies are
undertaken.[88] [89] [90] [91]

prolongation.[26]

some countries.[98]

MANAGEMENT

39
Ongoing



reliable).
therapy
Primary options

MANAGEMENT

» Patients who undergo pituitary adenomectomy

Ongoing
dependent on physiological replacement
of cortisol. It is necessary to monitor blood
pressure, check for orthostatic symptoms, and
assess general sense of energy or fatigue.
» As postoperative hypocortisolism is predictive

of remission, some centres advocate withholding
routine corticosteroid therapy after pituitary
surgery and monitoring cortisol levels every 8
hours or if symptoms of adrenal insufficiency
occur. If adrenal insufficiency occurs or low
cortisol levels are documented, corticosteroid
therapy should be initiated. Other centres begin
routine corticosteroid therapy immediately
after surgery and evaluate for remission of
hypercortisolism later in the postoperative
course.[75] This is done by measuring morning
cortisol at least 24 hours after the last dose
of corticosteroid therapy. Patients with a
postoperative morning cortisol of <55 nanomol/
L (<2 micrograms/dL) are considered to be
in remission and can transition into long-term
follow-up. Patients with a postoperative morning
cortisol of >138 nanomol/L (>5 micrograms/
dL) require further evaluation and possibly
further therapy. Patients with a morning
cortisol between 55 and 138 nanomol/L (2
and 5 micrograms/dL) should be followed with
additional measurements to detect a drop in
subsequent morning cortisol levels. Individuals
with morning cortisols >55 nanomol/L (>2
micrograms/dL) after surgery are 2.5 times
more likely to have recurrences than those with
cortisol levels <55 nanomol/L (<2 micrograms/
dL).[71] [72] [73]
» Corticosteroids are usually rapidly tapered

to physiological doses within 1 week or less
(often by discharge from hospital). Testing to
see if the hypothalamic-pituitary-adrenal (HPA)
axis has recovered can be done in follow-up
by 3 months after surgery. Testing is usually a
morning cortisol prior to the patient taking the
morning hydrocortisone dose, if hydrocortisone
therapy had been continued. Cortisol levels of
>552 nanomol/L (>20 micrograms/dL) indicate
recovery of the axis. Levels <83 nanomol/L (<3
micrograms/dL) indicate a continued need for
corticosteroids. Levels between 83 nanomol/
L (3 micrograms/dL) and 552 nanomol/L (20
micrograms/dL) should prompt further testing
MANAGEMENT
(cosyntropin stimulation testing, insulin tolerance

testing, or metyrapone testing). Once recovery of
HPA axis has been established, patients need to
undergo testing for possible recurrence. Salivary
cortisol testing seems to be a better predictor of
early recurrence.[73] [76]
41
Ongoing
replacement therapy
Primary options

--AND/OR--
men
-or-
-or-
-or-
-and-
--AND/OR--
on dose
--AND/OR--
times daily

The risk of pituitary deficiency after reoperation
is 50%. This is significantly higher than after
initial surgical therapy.[80]

the upper half of the normal range. A thyroid-
stimulating hormone should not be used to guide
therapy.[109]


therapy.
MANAGEMENT

Ongoing

2nd medical therapy alone
Primary options

maximum 60 mg/day
OR

OR

OR

OR

weeks
OR

on dose
OR
MANAGEMENT

Secondary options
43
Ongoing
dose
Tertiary options

on dose
» In patients who received transsphenoidal

pituitary adenomectomy as first-line therapy,
additional therapy should be considered in
months after first surgery.[77] Standard therapies
include repeat pituitary surgery, radiotherapy,
bilateral adrenalectomy, or medical therapy.[69]
[78]
» Success rates of these treatment options

vary between 25% (for some of the medical
therapies) and 100% (bilateral adrenalectomy).
Treatment options have specific advantages,
limitations, and side-effects so treatment
decisions should be individualised according
to the specific needs of the patient and risk of
» Medical treatment has been increasingly used

in clinical practice and is indicated to control
cortisol secretion in cases with persistent or
recurrent hypercortisolism after surgery, or
where surgery is declined or not feasible (e.g.,
high surgical risk, metastatic disease).[88] [89]
[90] [91]

MANAGEMENT

prolongation.[26]

some countries.[98]
Ongoing
corticosteroid production and can be used
(though off-label in most countries) in the
treatment of Cushing syndrome. They should
only be used by physicians familiar with their
use. Osilodrostat is approved in the US and
Europe for use in Cushing's disease. It is a



MANAGEMENT

reliable).
2nd pituitary radiotherapy
45
Ongoing
» Radiotherapy by conventional fractionated
radiotherapy or stereotactic radiosurgery
is most commonly used in patients with
persistent hypercortisolism after incomplete
corticotroph tumour resection, particularly if the
tumour is aggressive or invasive or considered
unresectable.[26] This modality is perhaps best
used as part of the therapy for patients with
mild residual hypercortisolism, as full effects of
therapy can take several years to be realised.
Radiation of tumours located close to the optic
chiasm increases the risk of damage to the optic
chiasm, and this risk should be considered prior
to therapy.
» After 3 to 5 years, both traditional fractionated

radiotherapy and stereotactic radiosurgery attain
remission in 50% to 60% of patients.[83] [84]
[85]
» Insufficient data exist to estimate the long-term

recurrence rates after therapy.
» Traditional fractionated radiotherapy and

stereotactic radiosurgery have similar rates of
post-therapy hypopituitarism.
adjunct medical therapy before radiotherapy
Primary options

maximum 60 mg/day
OR

OR

OR
MANAGEMENT

OR
Ongoing

weeks
OR

on dose
OR

Secondary options

dose
Tertiary options

on dose

short term for severe hypercortisolism, before

MANAGEMENT
prolongation.[26]

some countries.[98]
47
Ongoing



reliable).
MANAGEMENT
adjunct post-radiation corticosteroid replacement

therapy
Ongoing
Primary options

» Patients who undergo pituitary irradiation

dependent on physiological replacement of
cortisol. This may occur even years after
therapy. Consequently, it is necessary to
monitor for adrenal insufficiency for years after
radiotherapy (e.g., monitor blood pressure,
check for orthostatic symptoms, and assess
general sense of energy or fatigue).
» Slow taper of corticosteroid replacement may

be done over time if the pituitary axis recovers.
adjunct post-radiation pituitary hormone
replacement therapy
Primary options

--AND/OR--
men
-or-
-or-
-or-
-and-
--AND/OR--
on dose
MANAGEMENT
--AND/OR--
times daily
49
Ongoing
the upper half of the normal range. TSH should
not be used to guide therapy.[109]


therapy.


» Additional therapy should be considered in

months after first surgery.[77] Standard therapies
include repeat pituitary surgery, radiotherapy,
bilateral adrenalectomy, or medical therapy.[69]
[78]
» Success rates of these treatment options

vary between 25% (for some of the medical
therapies) and 100% (bilateral adrenalectomy).
Treatment options have specific advantages,
limitations, and side-effects so treatment
decisions should be individualised according
to the specific needs of the patient and risk of
» Bilateral adrenalectomy should be considered

in patients with severe hypercortisolism following
ineffective reoperation, or if a patient is not a
candidate for reoperation, depending on patient
preference and risk of complications.
MANAGEMENT
» Provides cure for all endogenous

hypercortisolism. A meta-analysis of 37 studies
(1320 patients, 82% with Cushing's disease,
13% with ectopic Cushing syndrome, and 5%
with primary adrenal hyperplasia) showed
Ongoing
that bilateral adrenalectomy is relatively
safe and provides adequate success.[108]
Although residual cortisol secretion due to
accessory adrenal tissue or adrenal remnants
was found in 3% to 34%, less than 2% had a
relapse of Cushing syndrome. Symptoms of
hypercortisolism (e.g., hypertension, obesity,
or depression) improved in the majority of the
patients after bilateral adrenalectomy (7 studies,
195 patients).
» Creates adrenal insufficiency with the need for

lifelong corticosteroid replacement.
» Increases the risk of Nelson syndrome,

which is progression of the ACTH-secreting
pituitary adenoma. This progression can cause
hyperpigmentation from excessive ACTH and
intracranial compressive symptoms from growth
of the tumour outside the sella.
» Newer laparoscopic methods of adrenalectomy

allow for more rapid recovery and tolerability.
therapy
Treatment recommended for ALL patients in
Primary options

-and-
» fludrocortisone: 0.05 to 0.1 mg orally once
daily
» It is necessary to monitor blood pressure,

general sense of energy or fatigue at regular
intervals.
» Replacement glucocorticoids and

mineralocorticoids are necessary in patients who
undergo bilateral adrenalectomy.
MANAGEMENT

Primary options

maximum 60 mg/day
51
Ongoing
OR

OR

OR

OR

weeks
OR

on dose
OR

Secondary options

dose
Tertiary options

on dose

MANAGEMENT

short term for severe hypercortisolism, before
Ongoing
prolongation.[26]

some countries.[98]


MANAGEMENT

53
Ongoing


reliable).
ectopic ACTH or corticotrophin-
releasing hormone (CRH) syndrome
1st surgical resection or ablation of tumour

and metastases
» Resection or ablation of ectopic tumours

producing ACTH or CRH is the preferred
mode of therapy. Many cases have severe
hypercortisolism requiring steroidogenesis
inhibition therapy in addition to surgery.
Primary options

maximum 60 mg/day
OR

OR

MANAGEMENT
OR
Ongoing
OR

Secondary options

dose
Tertiary options

on dose
» Patients with ectopic ACTH-producing tumours

may have extremely severe hypercortisolism,
and require reduction in cortisol before
proceeding to surgery. In these cases,
steroidogenesis inhibitor therapy (ketoconazole,
levoketoconazole, metyrapone, osilodrostat,
mitotane, etomidate) or a glucocorticoid receptor
antagonist (mifepristone) can be used to
block cortisol action or lower cortisol levels in
preparation before surgery.[90]
» These agents should only be used by

physicians familiar with their use. Osilodrostat is
a potent oral inhibitor of steroidogenesis (inhibits
steroid 11-beta-hydroxylase) that is approved in
the US for the treatment of Cushing's disease
in patients where pituitary surgery is not an
option or has not been curative, and in Europe
and Japan for the treatment of endogenous
Cushing syndrome.[26] [99] Ketoconazole
and metyrapone have a relatively rapid onset
of steroidogenesis inhibition. Ketoconazole
may cause idiopathic severe liver injury and
adrenal insufficiency. Its use requires expert
guidance and is contraindicated in patients
with liver disease. If used, liver and adrenal
function should be monitored before and during
treatment.[100] [101] Levoketoconazole is
an adrenal steroidogenesis inhibitor that is
MANAGEMENT

55
Ongoing
» Mifepristone blocks cortisol at the receptor
level and attenuates the clinical and biochemical


reliable).
tumour
» Depending upon the tumour source of the
ectopic ACTH or CRH syndrome, adjunctive
chemotherapy and/or radiotherapy may be
indicated.
» See local specialist protocol for dosing

guidelines.
» Should be considered if surgical resection is

not possible, depending on patient preference
and risk of complications.

hypercortisolism.
» Creates adrenal insufficiency with the need for

lifelong corticosteroid replacement.
therapy
MANAGEMENT
Primary options

Ongoing
-and-
daily

general sense of energy or fatigue.

Primary options

maximum 60 mg/day
OR

OR

OR

OR

Secondary options
MANAGEMENT

dose
Tertiary options
57
Ongoing
on dose
» Patients with ectopic ACTH-producing tumours

may have extremely severe hypercortisolism,
and require reduction in cortisol before
proceeding to surgery. In these cases,
steroidogenesis inhibitor therapy (ketoconazole,
mitotane, etomidate) or a glucocorticoid receptor
antagonist (mifepristone) can be used to
block cortisol action or lower cortisol levels in
preparation before surgery.[90]
» These agents should only be used by

physicians familiar with their use. Osilodrostat is
a potent oral inhibitor of steroidogenesis (inhibits
steroid 11-beta-hydroxylase) that is approved in
the US for the treatment of Cushing's disease
» Mifepristone blocks cortisol at the receptor

level and attenuates the clinical and biochemical
MANAGEMENT


Ongoing
reliable).
tumour
indicated.

guidelines.
3rd medical therapy only
Primary options

maximum 60 mg/day
OR

OR

OR

OR

Secondary options
MANAGEMENT

dose
Tertiary options
59
Ongoing
on dose
» There is a paucity of high-quality studies of

medical therapy in Cushing syndrome.[91] The
decision about which therapy to use should be
individualised for each patient, factoring patient
preference and risk of complications into any
decision.[90]
» Steroidogenesis inhibitors: ketoconazole,

treatment of Cushing syndrome.[90] These
agents should only be used by physicians
familiar with their use. Osilodrostat is a potent
oral inhibitor of steroidogenesis (inhibits steroid
11-beta-hydroxylase) that is approved in the
US for the treatment of Cushing's disease
function should be monitored before and
during treatment.[101] Levoketoconazole is

effects associated with elevation of cortisol. The
US Food and Drug Administration has approved
mifepristone for the treatment of hyperglycaemia
associated with Cushing syndrome. It may be
used for all forms of Cushing syndrome. It may
be used for all forms of Cushing syndrome.
Cortisol levels may increase during therapy with
MANAGEMENT
mifepristone due to feedback inhibition.[105]

As such, cortisol levels should not be used
to guide therapy in patients treated with
mifepristone.[106]
Ongoing

reliable).
tumour
indicated.

guidelines.
ACTH-independent due to unilateral
adrenal carcinoma or adenoma
1st unilateral adrenalectomy or tumour

resection
» Preferred method of therapy in patients with

unilateral cortisol-secreting adrenal adenoma.
Laparoscopic adrenalectomy is the preferred
method in most cases. Complete resection of
the adrenal gland cures hypercortisolism in all
patients without high risk of long-term adrenal
insufficiency. Adrenalectomy has a beneficial
effect on cardiovascular risk factors in patients
with subclinical Cushing syndrome overall and
compared with conservative management.[110]

signs or symptoms of Cushing syndrome) should
have therapy carefully weighed because benefit
of surgery has not been demonstrated.[51] [52]
» Adrenal carcinoma is extremely rare. First-line

therapy in many patients is surgical resection
of the tumour; however, at the time of diagnosis
the disease has often progressed beyond the
point where surgical therapy is effective. The
effectiveness of chemotherapy and adjunctive
therapies in both early- and late-stage disease
MANAGEMENT
has shown mixed results in clinical trials;

however, patients should be considered for
treatment with mitotane and enrolment in clinical
trials (if available).[10]
61
Ongoing
Primary options

maximum 60 mg/day
OR

OR

OR

OR

OR

dose
Secondary options

on dose
» Steroidogenesis inhibitors: ketoconazole,

corticosteroid production. They are generally
used short term for severe hypercortisolism,
before other therapies are undertaken.[90]
MANAGEMENT
These agents should only be used by physicians

Ongoing



reliable).
carcinoma
» Depending upon the stage of adrenal
carcinoma, adjunctive chemotherapy and/or
radiotherapy may be indicated.
MANAGEMENT

guidelines.
Primary options
63
Ongoing
maximum 60 mg/day
OR

OR

OR

OR

OR

dose
Secondary options

on dose

MANAGEMENT

Ongoing



reliable).
carcinoma
» Depending upon the stage of adrenal
carcinoma, adjunctive chemotherapy and/or
radiotherapy may be indicated.

guidelines.
ACTH-independent due to bilateral
adrenal disease (hyperplasia or
MANAGEMENT
adenoma)
1st bilateral adrenalectomy
65
Ongoing
» First-line therapy in patients with bilateral
adrenal disease from autonomous nodule
formation or bilateral hyperplasia.

hypercortisolism. Creates adrenal insufficiency
with the need for lifelong corticosteroid
replacement.
therapy
Primary options

-and-
daily

general sense of energy or fatigue.

Primary options

maximum 60 mg/day
OR

OR
MANAGEMENT

OR
Ongoing

OR

Secondary options

dose
Tertiary options

on dose

corticosteroid production. They are generally
used short term for severe hypercortisolism,
before other therapies are undertaken.[90]
These agents should only be used by physicians
MANAGEMENT

67
Ongoing


reliable).
Primary options

maximum 60 mg/day
OR

OR

OR

OR

MANAGEMENT
Secondary options

dose
Ongoing
Tertiary options

on dose

function should be monitored before and
during treatment.[101] Levoketoconazole is

effects associated with elevation of cortisol. The
US Food and Drug Administration has approved
mifepristone for the treatment of hyperglycaemia
associated with Cushing syndrome. It may be
used for all forms of Cushing syndrome. It may
be used for all forms of Cushing syndrome.
Cortisol levels may increase during therapy with
mifepristone due to feedback inhibition.[105]
As such, cortisol levels should not be used
to guide therapy in patients treated with
mifepristone.[106]
MANAGEMENT


69
Ongoing
reliable).
Secondary prevention
Exogenous Cushing syndrome may be prevented in patients who require exogenous corticosteroid
treatment, by reducing corticosteroid use to an absolute minimum required dose and frequency whenever
possible.
Standard cardiovascular screening and treatment should be applied to patients with Cushing syndrome.
Patient discussions
Care should be taken to control complications such as diabetes, hypertension, and dyslipidaemia.
Patients should be advised that adherence to medical management of these conditions can improve
quality of life and life expectancy.
MANAGEMENT
Cushing syndrome Follow up
Monitoring
Monitoring
FOLLOW UP
Recurrence of adrenocorticotrophic hormone-dependent Cushing syndrome is common, with at
least a 5% to 26% risk of recurrence at 5 years. Screen patients who have achieved remission after
hypothalamic-pituitary-adrenal (HPA) axis recovery for recurrence of disease and then annually or sooner
if there is clinical suspicion.[26] Use one of four high-sensitivity tests (late-night salivary cortisol, 1 mg
overnight dexamethasone suppression testing, 24-hour urinary free cortisol, or desmopressin testing)
to detect recurrence. Late-night salivary cortisol is the most sensitive test for detecting recurrence and
should be done annually after HPA axis recovery postoperatively and then annually.[26]
Many patients are supported with corticosteroids following pituitary surgery but should be assessed
for remission during the first postoperative week.[68] This is most easily done by measurement of
the morning cortisol at least 24 hours after the last dose of corticosteroid therapy. Patients with a
postoperative morning cortisol of <55 nanomol/L (<2 micrograms/dL) are considered to be in remission
and can transition into long-term follow-up. Patients with a postoperative morning cortisol of >138
nanomol/L (>5 micrograms/dL) require further evaluation and possibly further therapy. Patients with
a morning cortisol between 55 and 138 nanomol/L (2 and 5 micrograms/dL) should be followed with
additional morning measurements to detect a drop in subsequent cortisol levels. Individuals with morning
cortisols >55 nanomol/L (>2 micrograms/dL) after surgery are 2.5 times more likely to have recurrences
than those with cortisol levels <55 nanomol/L (<2 micrograms/dL).[72]
As postoperative hypocortisolism is predictive of remission, some centres advocate withholding

routine corticosteroid therapy after pituitary surgery and monitoring cortisol levels every 8 hours or if
symptoms of adrenal insufficiency occur.[74] If adrenal insufficiency occurs or low cortisol levels are
documented, corticosteroid therapy should be initiated. Other centres begin routine corticosteroid therapy
immediately after surgery and evaluate for remission of hypercortisolism later in the postoperative
course. Corticosteroids are usually rapidly tapered to physiological doses within 1 week or less (often
by discharge from hospital). Testing to see if the hypothalamic-pituitary-adrenal axis has recovered can
be done in follow-up by 3 months after surgery. Testing is usually a morning cortisol prior to the patient
taking the morning hydrocortisone dose, if continued. Cortisol levels of >552 nanomol/L (>20 micrograms/
dL) indicate recovery of the axis. Levels <83 nanomol/L (<3 micrograms/dL) indicate continued need for
corticosteroids. Levels between 83 nanomol/L (3 micrograms/dL) and 552 nanomol/L (20 micrograms/
dL) should prompt further testing (cosyntropin stimulation testing, insulin tolerance testing, or metyrapone
testing).
Standard testing, follow-up, and management for associated conditions of hypertension, diabetes,
and osteoporosis should be undertaken, as these conditions may persist after effective treatment of
hypercortisolism.
71
Complications
Complications Timeframe Likelihood

FOLLOW UP
adrenal insufficiency secondary to adrenal short term high

suppression
This may occur following surgery. Pathological hypercortisolism can lead to suppression of the normal
hypothalamic-pituitary-adrenal (HPA) axis. Following treatment, the normal function of the HPA axis often
remains suppressed for several months. The resultant adrenal insufficiency necessitates treatment with
glucocorticoid therapy until the HPA axis recovers normal function.
cardiovascular disease long term high
The major cause of mortality in patients with Cushing syndrome.[113] It is difficult to tell if the increase
in cardiovascular mortality is due to the development of traditional risk factors such as hypertension,
diabetes, and dyslipidaemia, or to hypercortisolism itself.[121] Risk factor modification and resolution of
hypercortisolism are the keys to lowering cardiovascular mortality. Standard cardiovascular screening and
treatment should be applied to patients with Cushing syndrome.
Adrenalectomy has a beneficial effect on cardiovascular risk factors in patients with subclinical Cushing
syndrome overall and compared with conservative management.[110]
hypertension long term high
Occurs in 70% to 80% of patients.[122] Occurs equally in adrenocorticotrophic hormone-dependent and

-independent Cushing syndrome. Generally mild to moderate but can be severe. Blood pressure usually
normalises after successful therapy, but can persist secondary to vascular remodelling. No specific class
of antihypertensive agent has been shown to have increased efficacy; standard agents for therapy of
hypertension should be used.
diabetes mellitus long term high
Occurs in 20% to 60% of patients.[122] Glycaemic control can be very difficult in patients with
hypercortisolism. No agent or combination of agents has been shown to be more effective in patients with
Cushing syndrome than in other patients with diabetes. Insulin is often needed to adequately control blood
sugars.
hypercoagulability long term high
Alterations in haemostatic parameters and in vivo endothelial dysfunction lead to increased thrombotic
events.[26] [123]
Prophylactic anticoagulation should be considered for patients at risk for venous thromboembolism,
including: history of embolism or abnormal coagulation testing; severe preoperative hypercortisolism;
current use of oestrogen or oral contraceptives; poor mobility; extended preoperative or postoperative
hospital stay; and high postoperative cortisol levels or cortisol over-replacement in patients with adrenal
insufficiency.[26]
osteoporosis long term medium
Premature osteoporosis and fracture are seen in around 50% of patients.[56] Excessive bone exposure
to glucocorticoids causes decreased osteoblast activity, and also increases osteoclast activity. It may also
interfere with calcium absorption in the gastrointestinal tract, further worsening bone disease. Patients

should have periodic bone density assessments. Patients with persistent hypercortisolism and low or
falling bone density should be treated with bisphosphonates.
FOLLOW UP
nephrolithiasis long term medium
Calcium renal stones occur in some patients.[23] The aetiology is related to altered calcium handling by
the kidney in patients with cortisol excess. The most effective therapy is treatment of hypercortisolism.
Therapies used for other patients with nephrolithiasis should also be employed.
Nelson syndrome after bilateral adrenalectomy long term low
Progression of a pituitary adenoma after bilateral adrenalectomy can result in intracranial mass effect from
increased tumour size, and elevated adrenocorticotrophic hormone (ACTH) levels. The incidence of this
complication varies depending on the exact definition used. Patients with Cushing's disease who undergo
bilateral adrenalectomy should have plasma ACTH levels and pituitary MRI 6 to 12 months after surgery.
Therapy includes repeat surgery to debulk tumour, and radiotherapy.[126]
treatment-related central hypothyroidism variable high
After pituitary surgery, patients may develop thyrotropin deficiency requiring medical replacement.[67]
[109] [128] [129]
treatment-related growth hormone deficiency variable high
Somatotropin deficiency may occur in between 53% and 93% of patients who undergo pituitary
adenomectomy.[128] [132] Deficiency of growth hormone requires replacement.[109]
treatment-related adrenal insufficiency variable medium
Transient postoperative adrenal insufficiency (defined as a morning serum cortisol of 55 nanomol/L

[<2 micrograms/dL]) in patients treated with transsphenoidal surgery is an indicator of remission or
cure. These patients generally have recovery of adrenal function within the first postoperative year.
However, repeat pituitary surgery and occasional primary surgical therapy can result in permanent adrenal
insufficiency.
Radiotherapy can cause adrenal insufficiency years after therapy, necessitating pituitary adrenal axis
evaluation periodically after therapy.
Bilateral adrenalectomy also creates an absolute cortisol deficiency, and must be treated with replacement
doses of hydrocortisone plus mineralocorticoid.
Long-term adrenal insufficiency secondary to pituitary adenomectomy occurs in 3% to 53% of patients.[67]

[124] [125]
Steroidogenesis inhibitors can also sometimes cause adrenal insufficiency.
surgery- or radiation-related hypopituitarism variable medium
Therapy for Cushing's disease, either surgery or radiotherapy, can damage normal pituitary tissue. If
hypopituitarism is the result of surgical therapy, deficits generally manifest immediately after surgery.
Hypopituitarism after radiotherapy can occur many years after therapy. Individuals who have received
73

radiotherapy should have periodic evaluation of pituitary function to monitor for development of
recurrences.
FOLLOW UP
Pituitary surgery may lead to deficiencies of hormones other than the adrenocorticotrophic hormone,
requiring replacement with thyroid hormones, androgens or oestrogens, growth hormone, or
desmopressin.[109]
surgery-related hyponatraemia variable medium
Hyponatraemia is a known complication of pituitary surgery. Age, sex, tumour size, rate of decline of blood
sodium, and Cushing syndrome are potential predictors of delayed symptomatic hyponatraemia.[127]
treatment-related hypogonadism variable medium
Occurs in between 3% and 48% of patients undergoing pituitary adenomectomy.[67] [128] [129] [130]
[131] Pituitary surgery may lead to deficiencies of hormones other than the adrenocorticotrophic
hormone, requiring replacement with thyroid hormones, androgens or oestrogens, growth hormone, or
desmopressin.[109]
treatment-related diabetes insipidus variable medium
More than one quarter of patients who undergo surgery will develop vasopressin deficiency and rates are
higher after the second surgery.[69] [133] [134]
Pituitary surgery may lead to deficiencies of hormones other than the adrenocorticotrophic hormone,
requiring replacement with thyroid hormones, androgens or oestrogens, growth hormone, or
desmopressin.[109]
Over 50% of patients with Cushing's disease treated with pasireotide develop hyperglycaemia that must be
promptly managed.[92] [97]
Prognosis
Without treatment, hypercortisolism persists and in many patients worsens. Untreated disease carries a
dismal survival rate of 50% at 5 years.[113] This leads to worsening of the Cushing phenotype and increased
mortality, mainly from cardiovascular disease. With therapy to normalise cortisol levels, patients have a
mortality rate similar to the general population.[66] [67] Within the first year of effective therapy, many of
the characteristic features such as facial plethora, striae, and supraclavicular fat pads will resolve or show
marked improvement. Patients lose a significant amount of weight with improved control or resolution
of diabetes and hypertension. Bone density steadily improves after hypercortisolism resolves. Despite
improvement of complications in most patients, cardiovascular risk, hypertension, obesity, and decreased
quality of life may persist in some patients even after biochemical cure.[11] [114] [115]
Patient-reported outcomes are scarce, but they show that decreased quality of life persists even in
patients with biochemical normalisation and they are worse in Cushing's disease compared with Cushing
syndrome.[116]
Pituitary adenomectomy
Outcomes are largely based on the size of the initial tumour in patients with Cushing's disease. Micro-
adenomas (size <1 cm) have superior outcomes with remission rates quoted as 48% to 100% of patients.
An average of approximately 32% of Cushing's disease patients, and up to 75% of Cushing's disease
patients initially submitted to pituitary surgery, will require a second-line treatment during the disease course.
The long-term failure of pituitary surgery is evidently higher in patients with macro-adenomas (range, 0
to 71.4; mean, 48.8; median, 52.2) than in patients with micro-adenomas (range, 0 to 55.5; mean, 25;
median, 21.2).[69] [73] [117] Patients with macro-adenomas (size >1 cm) have remission rates <65%
FOLLOW UP
after surgery and show recurrence rates of 12% to 45% at about 16 months.[67] [113] [118] Patients may
require temporary or prolonged treatment for deficiencies of thyrotropin, gonadotrophin, growth hormone, or
antidiuretic hormone and corticosteroids.
A 2018 study did not find significant differences between endoscopic and microscopic pituitary surgery in
remission percentage. Although the short term recurrence was lower for endoscopic surgery, both groups
had a recurrence rate of approximately 4% per person/year.[119] A 2021 study in young people with pituitary
tumours found favourable outcomes and lower re-treatment rates with endonasal endoscopic surgery
compared with microscopic transsphenoidal surgery.[120]
Adrenocorticotrophic hormone (ACTH)-independent Cushing

syndrome
Patients who undergo unilateral adrenalectomy for a causative adrenal adenoma are uniformly cured of
their disease. Recurrence in the contralateral adrenal gland is exceedingly rare. Patients with bilateral
adrenalectomy will need monitoring and corticosteroid and mineralocorticoid replacement. Outlook for
patients with adrenal carcinoma depends upon the stage at which it is diagnosed. Beyond surgical resection,
benefit of additional treatments is debated and should be patient-specific.
Ectopic ACTH production

Encompasses a diverse group. The nature of the tumour secreting ACTH largely determines the outcomes.
Many ACTH-secreting tumours are aggressive and grow rapidly. In these cases, complete resection of the
tumour is difficult, and patients generally succumb to tumour-related complications. Individuals with indolent
ACTH-secreting tumours often have complete tumour resection with resolution of hypercortisolism as well as
symptoms.
75
Cushing syndrome Guidelines
Diagnostic guidelines
North America
Diagnosis, management, and followup of the incidentally discovered adrenal

mass (ht tps://www.cua.org/guidelines)
Published by: Canadian Urological Association Last published: 2023
Consensus on diagnosis and management of Cushing's disease: a guideline

update (ht tps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8743006)
Published by: The Pituitary Society Last published: 2021
ACR appropriateness criteria: adrenal mass evaluation (ht tps://www.acr.org/

Clinical-Resources/ACR-Appropriateness-Criteria)
Published by: American College of Rheumatology Last published: 2021
GUIDELINES
The diagnosis of Cushing's syndrome (ht tps://www.endocrine.org/clinical-

practice-guidelines)
Published by: The Endocrine Society Last published: 2008
Asia
Clinical guidelines for the diagnosis and treatment of Cushing's disease in

Korea (ht tps://www.e-enm.org/journal/view.php?doi=10.3803/EnM.2015.30.1.7)
Published by: Korean Endocrinology Society Last published: 2015
Treatment guidelines
United Kingdom
Endoscopic transsphenoidal pituitary adenoma resection (ht tps://

www.nice.org.uk/guidance/IPG32)
Published by: National Institute for Health and Care Excellence Last published: 2003
Europe
Clinical practice guidelines on the management of adrenocortical carcinoma

in adults (ht tps://www.ese-hormones.org/publications/guidelines)
Published by: European Society of Endocrinology, European Network Last published: 2018
for the Study of Adrenal Tumors
Management of adrenal incidentalomas (ht tps://www.ese-hormones.org/

publications/guidelines)
Published by: European Society of Endocrinology; European Network Last published: 2016
for the Study of Adrenal Tumors
Treatment of Cushing's syndrome (ht tps://www.endocrine.org/clinical-

practice-guidelines)
Published by: The Endocrine Society; European Society for Last published: 2015
Endocrinology
GUIDELINES
International
Treatment of adrenocorticotropin-dependent Cushing's syndrome:

a consensus statement (ht tps://academic.oup.com/jcem/
article/93/7/2454/2598289)
Published by: Pituitary Society; European Neuroendocrine Association Last published: 2008
77
North America
Diagnosis, management, and followup of the incidentally discovered adrenal

mass (ht tps://www.cua.org/guidelines)
Published by: Canadian Urological Association Last published: 2023
NCCN clinical practice guidelines in oncology: neuroendocrine and adrenal

tumors (ht tps://www.nccn.org/guidelines)
Published by: National Comprehensive Cancer Network Last published: 2022
American Association of Endocrine Surgeons guidelines for

adrenalectomy (ht tps://collectedmed.com/index.php/article/article/
demo_article_display/8449/82/1/1)
Published by: American Association of Endocrine Surgeons Last published: 2022
Consensus on diagnosis and management of Cushing's disease: a guideline

GUIDELINES
update (ht tps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8743006)

Published by: The Pituitary Society Last published: 2021
Medical guidelines for the management of adrenal incidentalomas

(ht tps://pro.aace.com/clinical-guidance/pituitary-gonad-adrenal-and-
neuroendocrine)
Published by: American Association of Clinical Endocrinologists; Last published: 2009
American Association of Endocrine Surgeons
Asia
Clinical guidelines for the diagnosis and treatment of Cushing's disease in

Korea (ht tps://www.e-enm.org/journal/view.php?doi=10.3803/EnM.2015.30.1.7)
Published by: Korean Endocrinology Society Last published: 2015
Cushing syndrome Online resources
Online resources
1. Algorithm for diagnosis of Cushing syndrome (https://staticweb.bmj.com/BP/CushingSyndrome/
gr1_lrg.jpg) (external link)
ONLINE RESOURCES
79
Cushing syndrome References
Key articles
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reviewed-fulltext-article-CLEP) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/25945066?
tool=bestpractice.bmj.com)
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disease: a guideline update. Lancet Diabetes Endocrinol. 2021 Dec;9(12):847-75. Full text
(https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8743006) Abstract (http://www.ncbi.nlm.nih.gov/
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doi/10.1177/2042018816687240) Abstract (http://www.ncbi.nlm.nih.gov/pubmed/28377801?
93
Cushing syndrome Images
Images
IMAGES
Figure 1: Abdominal computed scan showing adrenocortical tumour infiltrating the pancreas and left kidney,
and metastasised to the liver, spleen, and central nodes
Cushing syndrome Images
IMAGES
Figure 2: Abdominal striae in pregnancy
95
IMAGES Cushing syndrome Images
Figure 3: Algorithm for the treatment of Cushing's disease (DST = dexamethasone suppression test. IPSS
= inferior petrosal sinus sampling. ACTH = adrenocorticotrophic hormone. *Pituitary surgery should be
performed by an experienced surgeon. †Absence of ACTH-staining adenoma. §Lifelong monitoring for
hypopituitarism and secondary neoplasia in the radiation field required. ¶On maximum tolerated dose of the
drug)
Fleseriu M et al. Lancet Diabetes Endocrinol. 2021 Dec;9(12):847-75; used with permission
Cushing syndrome Disclaimer
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DISCLAIMER
Contributors:
// Authors:
Maria Fleseriu, MD, FACE

Professor of Medicine (Endocrinology) and Neurological Surgery
Director, Pituitary Center, Oregon Health & Science University, Portland, OR
DISCLOSURES: MF is on the Pituitary Society's Board of Directors. She holds a research grant to the
University for Clinical Studies as Principal Investigator for Recordati and Strongbridge, and is an occasional
Scientific Consultant for Recordati, HRA Pharma, and Sparrow. MF is an author of several references cited
in this topic.
// Acknowledgements:
Dr Maria Fleseriu would like to gratefully acknowledge Dr Ty Carroll and Dr James Findling, previous
contributors to this topic.
DISCLOSURES: TC is an author of a number of references cited in this topic. He is an investigator in
clinical trials sponsored by Corcept. JF is an author of a number of references cited in this topic. He is a
consultant for, and investigator in, clinical trials sponsored by Corcept and Novartis.
// Peer Reviewers:
Paul M. Stewart, FRCP FMedSci

Professor of Medicine
Director of Research, College of Medical and Dental Sciences, University of Birmingham, Honorary
Consultant Physician, Queen Elizabeth Hospital, Birmingham, UK
DISCLOSURES: PMS declares that he has no competing interests.
Antoine Tabarin, MD
Head
Department of Endocrinology, University Hospital of Bordeaux, Pessac, France
DISCLOSURES: AT declares that he has no competing interests.
Liliana Contrersas, MD
Chief
Endocrine Research Department, Instituto de Investigaciones Médicas A. Lanari, University of Buenos Aires
and IDIM-CONICET, Buenos Aires, Argentina
DISCLOSURES: LC declares that she has no competing interests.
Philip R. Orlander, MD
Professor of Medicine
Director, Division of Endocrinology, Diabetes & Metabolism, University of Texas Medical School, Houston,
TX
DISCLOSURES: PRO declares that he has no competing interests.
Mouhammed Amir Habra, MD, FACP, FACE

Assistant Professor
Contributors:
Department of Endocrine Neoplasia and Hormonal Disorders, Division of Internal Medicine, University of
Texas MD Anderson Cancer Center, Houston, TX
DISCLOSURES: MAH declares that he has no competing interests.

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Cushing syndrome

Straight to the point of care

Last updated: May 10, 2023

Once endogenous hypercortisolism is confirmed, plasma ACTH should be measured. If ACTH is

prevalence.[8] Hypercortisolism has been reported in 0.5% to 1% of patients with hypertension, 2% to 3%

• ACTH-independent Cushing syndrome is caused by excessive cortisol secretion by the adrenal

Abdominal computed scan showing adrenocortical tumour infiltrating the

Abdominal striae in pregnancy

• Features unusual for age (i.e., osteoporosis or hypertension in young patients)

• Progressive proximal muscle weakness

• Late-night salivary cortisol

Confirmation of biochemical testing

[Algorithm for diagnosis of Cushing syndrome] (https://staticweb.bmj.com/BP/CushingSyndrome/

Initial differential diagnostic testing

Inferior petrosal sinus sampling

Tests for ectopic ACTH syndrome

Mild autonomous Cushing syndrome

History and exam

facial plethora (common)

supraclavicular fullness (common)

violaceous striae (common)

absence of pregnancy (common)

menstrual irregularities (common)

absence of malnutrition (common)

absence of alcoholism (common)

absence of physiological stress (common)

linear growth deceleration in children (common)

Other diagnostic factors

premature osteoporosis or unexplained fractures (common)

weight gain and central obesity (common)

psychiatric symptoms (common)

decreased libido (common)

easy bruisability (common)

facial rounding (common)

dorsocervical fat pads (common)

venothrombolic event (uncommon)

thoracic or bronchogenic carcinoma

Other tests to consider

of high-dose dexamethasone suppression testing is an area of

Condition Differentiating signs / Differentiating tests

Metabolic syndrome • Usually lack facial • Normal late-night salivary

Cushing's disease (pituitary adenoma)

Radiotherapy by conventional fractionated radiotherapy or stereotactic radiosurgery is most commonly

Medical treatment with a somatostatin analogue (pasireotide), a dopamine agonist (cabergoline), a

• Pasireotide is a somatostatin analogue that selectively targets somatostatin receptors in

• Osilodrostat is a potent oral inhibitor of steroidogenesis (inhibits steroid 11-beta-hydroxylase)

factor 1 (IGF-1) level in the age-adjusted mid- to upper-normal range.

Adrenal carcinoma is an exceedingly rare cause of ACTH-independent Cushing syndrome. First-line

Ectopic ACTH syndrome

treatment.[101] Levoketoconazole is an adrenal steroidogenesis inhibitor that is approved for treatment in

Treatment algorithm overview

1st transsphenoidal pituitary adenomectomy

adjunct medical therapy before surgery

adjunct post-surgical corticosteroid replacement

adjunct post-surgical pituitary hormone

1st medical therapy alone

2nd repeat transsphenoidal pituitary

adjunct medical therapy before surgery

adjunct post-surgical corticosteroid replacement