Cushing’s Syndrome:

Diagnostic Challenges, Treatment

Failures, and Hope for the Future

Elizabeth E. King, M.D.

Volunteer Clinical Faculty
UT Southwestern Medical Center
August 1, 2015
 Objectives
Recognize when screening for Cushing’s
is appropriate
Utilize the appropriate diagnostic tests
when evaluating a patient with suspected
Cushing’s
Identify treatment modalities employed
when Cushing’s syndrome is diagnosed
 Classification of Disease
Exogenous (factitious or iatrogenic)
Endogenous
– ACTH Dependent (pituitary or ectopic)
– ACTH Independent (adrenal)
Cushing’s disease refers specifically to
hypercortisolism resulting from ACTH
production by a pituitary source (most
commonly an adenoma)
Specific Signs and Symptoms of
Disease

Easy bruising
Facial plethora
Proximal muscle weakness
Characteristic striae
Unexplained osteoporosis
Weight gain with
decreasing growth velocity
in children
Nieman, et al. JCEM 2008, 93(5):1526-1540.
 Other (less specific) Signs and
Symptoms
Depression
Fatigue
Weight gain
Back pain
Menstrual irregularities
Buffalo hump, moon facies, supraclavicular fullness
Skin atrophy
Hyperandrogenism in females (hirsutism, acne, etc)
HTN
PCOS
Type 2 DM
Unusual infections including cutaneous fungal infections
Nieman, et al. JCEM 2008, 93(5):1526-1540.
 Conditions Associated with
Hypercortisolism without True Cushing’s
(pseudo-Cushing’s)
Pregnancy
Depression and other psychiatric disease
Alcohol dependence
Glucocorticoid resistance
Morbid obesity
Poorly controlled DM
Physical stress
Malnutrition/anorexia nervosa
Intense chronic exercise
Hypothalamic amenorrhea
CBG excess (increases serum cortisol only, not urine
“free”)
Nieman, et al. JCEM 2008, 93(5):1526-1540.
 Who Should We Test?
Patients with unusual features for age
Patients with multiple and progressive features,
particularly those specific for Cushing’s
Children with decreasing height percentile and
increasing weight
Patients with adrenal incidentaloma c/w adenoma (these
patients are usually asymptomatic, but a signficant
fraction, up to 10%, have biochemical hypercortisolism)
Widespread testing of any other patient group is not
recommended
Before biochemical testing, a thorough history should be
taken to ensure that the patient has not be exposed to
exogenous steroids!!!!
Nieman, et al. JCEM 2008, 93(5):1526-1540.
Initial Testing

At least 2 measurements
of the following:
– 24 hour urine free cortisol
– Late-night salivary cortisol
1-mg overnight DST
Longer low dose DST
(2mg/day in divided
doses)
The above tests will not
help in determining the
cause of the Cushing’s
syndrome
Nieman, et al. JCEM 2008, 93(5):1526-1540.
24-hr Urine Free Cortisol (UFC)
Urine collected for 24 hours
– Measure free cortisol, creatinine, and volume
Advantage lies in it’s “free” cortisol measurement, unaffected by
cortisol binding globulin (CBG)
Disadvantages
– May be elevated in pseudocushing’s, including severe obesity
– Elevated with excess fluid intake
– Cannot be used in patients with renal impairment (CrCl < 60
ml/min)
– May be normal in cyclic or mild disease
– Should not be used in testing patients with adrenal
incidentaloma
Drugs that increase UFC results
– Carbamazepine, fenofibrate (if HPLC assay), some synthetic
glucocorticoids

Nieman, et al. JCEM 2008, 93(5):1526-1540.

 Late-night Salivary Cortisol
The “newest” technique in screening
Patients collect saliva using a kit between 11pm-midnight
At least 2 collections are needed, and this shouldn’t be the sole method
used in diagnosis
Preferred assay is LC-MS/MS
Specificity varies—82-100%
Sensitivity 92-100%
Advantages
– Convenient and easy to obtain
– Stable at room temperature or refrigerator for at least a week
Disdavantages
– Difficult to perform in night shift workers
– Cannot be used with tobacco products
– Can contaminate the salivette with topical steroids
– Stress prior to collection can affect results
Nieman, et al. JCEM 2008, 93(5):1526-1540.
Baid, et al. JCEM 2007, 92(8): 3102-3107.
1mg Overnight Dexamethasone
Suppression Test (DST)

Dexamethasone 1mg po given at 11pm

Blood collected at 8am the following morning
Normal is a value less than 1.8 mcg/dl
Specificity using this cutoff is only 80%
Specificity improves to 95% if using 5 mcg/dl as
cuttoff
In order to enhance sensitivity, the 1.8 level is
recommended
Nieman, et al. JCEM 2008, 93(5):1526-1540.
 Interfering Drugs
Accelerators of dex metabolism
– Phenobarbital, phenytoin, carbamezapine, primidone, rifampin,
rifapentine, ethosuximide, pioglitazone
Drugs that impair dex metabolism
– Aprepitant/fosaprepitant, itraconazole, ritonavir, fluoxetine,
diltiazem, cimetidine
Drugs that increase CBG
– Estrogens (including OCPs!!!)
– Mitotane
Repeat Testing for Patients with a
Normal First Screen

Patients with new or progressive

symptoms
Cyclical Cushing’s is suspected
Patients with discordant results
Patients with 2 negative results should not
be retested unless cyclical disease is
suspected
Testing in Special Circumstances
Pregnancy: use UFC, avoid dex testing
Epilepsy: avoid dex testing in those on
medications that interfere with its
metabolism
Renal failure: 1mg DST preferred
Cyclic: UFC or midnight salivary cortisol
Adrenal Incidentaloma: 1mg DST or late
night cortisol rather than 24 hour urine
So, you’ve diagnosed Cushing’s
syndrome—now what?

Remember that the first line tests only

establish that Cushing’s syndrome is
present
Step 1: ACTH Measurement
A suppressed ACTH indicates an adrenal
source of hypercortisolismproceed with
adrenal imaging
If the ACTH is normal or high, several
possibilities exist
– Pituitary adenoma (most common)
– Ectopic ACTH production (rare)
– Ectopic CRH production (very rare)
 Pituitary Imaging
Pituitary MRI—discrete adenoma is seen
in up to 60% of cases
Lesion must be well defined
Very small lesions may be incidental,
nonfunctional adenomas
Often, tumors are extremely small and
may not be visualized in spite of advanced
imaging techniques available today
 Bilateral Inferior Petrosal Sinus
Sampling (BIPSS)
Recommended when biochemical and imaging studies
are discordant or equivocal
Should be done in specialized centers
Procedure:
– Bilateral inferior petrosal sinuses are accessed
– Baseline ACTH levels are obtained
– Infuse 1 µg/kg or 100 µg CRH and measure ACTH 3-5-10
minutes later from both petrosal sinuses and from a peripheral
site
IPS:peripheral ratio > 2 at baseline or > 3 after CRH
indicates a pituitary source (rather than ectopic)
BIPSS use in lateralization isn’t perfect, but the goal is a
> 1.4:1 ratio from one side to the other
 Why Treat?
Mortality in patients with untreated Cushing’s
syndrome 4x higher than age/gender matched
subjects
Cardiovascular/metabolic disease contribute to
morbidity/mortality
Hypercoagulability
Osteoporosis
Metabolic syndrome
Infectious complications
Biller, et al. JCEM 2008, 93(7);2454-2462.
Arnaldi, et al. JCEM 2003, 88(12): 5593-5602.
 Treatment of Cushing’s Disease

Transsphenoidal pituitary resection is the

treatment of choice
– Ideally, an adenomectomy (rather than
hypophysectomy) is performed
Some degree of exploration at the time of
surgery may be required to locate the tumor
Remission rates for MICROadenoma in the
hands of an experienced surgeon range from
65-90%
– 5-10% recurrence at 5 years
– 10-20% recurrence at 10 years
Biller, et al. JCEM 2008, 93(7);2454-2462.
Options After Surgical Failure

Repeat surgery
Radiotherapy
Bilateral adrenalectomy
Medical therapy
Options for Persistence/Recurrence—
Surgery
Success rates (50-70%) are lower than
those seen after the initial surgery
Remission rates improve if adenoma is
localized
Increased risk of panhypopituitarism,
especially if hypophysectomy is required
Should be done asap after the initial
surgery

Biller, et al. JCEM 2008, 93(7);2454-2462.

Options for Persistence/Recurrence—
Radiation
XRT vs. stereotactic radiosurgery
50-60% success at 3-5 years after
treatment
Requires long term f/u
Panhypopituitarism often results
1-2% risk of second tumor formation after
radiotherapy

Biller, et al. JCEM 2008, 93(7);2454-2462.

Options for Persistence/Recurrence—
Bilateral Adrenalectomy
Definitive treatment resulting in immediate
control of hypercortisolism
Always results in permanent need for
glucocorticoid and mineralocorticoid
replacement
Must perform regular MRI and ACTH
levels to monitor for tumor progression
(Nelson’s syndrome)

Biller, et al. JCEM 2008, 93(7);2454-2462.

Options for Persistence/Recurrence—
Consensus Recommendation in 2008

Repeat transsphenoidal surgery should be done

initially
Radiotherapy should generally be second line
– Bilateral adrenalectomy can also be considered
– choice should be individualized
Medical therapy can be considered in some
circumstances but is not usually recommended
in lieu of surgery or radiotherapy

Biller, et al. JCEM 2008, 93(7);2454-2462.

What Are the Medical Options?
Anticorticotroph drugs
– Dopamine agonists
– Somatostatin analogues
Adrenal steroidogenesis inhibitors
– Ketoconazole
– Metyrapone
– Etomidate
– LCI 699
Adrenolytic agent
– mitotane
Glucocorticoid receptor antagonist
– mifepristone
 Dopamine Agonists—
cabergoline
Only cabergoline found to have efficacy
– D2 receptor agonist
D2 receptor found to be expressed in 75% of ACTH-
producing tumors
Advantages:
– Well tolerated
– Easy to administer
Disadvantages:
– Effective in limited number of patients (30-40% patients over
long-term)
– Escape phenomenon noted
– Relatively high doses required, so long term safety is a concern
– No FDA approval for CD Pivonello, et al. JCEM 2009, 94(1); 223-230.
Godbout A et al. Eur J Endocrinol 2010;163:709-716
Somatostatin Analogue—Pasireotide

FDA approved in 2012 for patients with

Cushing’s disease with persistent or recurrent
disease despite surgery or for nonsurgical
candidates/those who refused surgery
Compared with octreotide, carries a higher
affinity for the type 5 somatostatin receptor, the
one most prominent in corticotroph adenomas

Colao A et al. N Engl J Med 2012;366:914-924

 Pasireotide
Advantages
– Works at the “root of the problem”
– Improves not only biochemical parameters but
tumor size as well
– FDA approved
Disadvantages
– Significant number of adverse events to
include hyperglycemia and diabetes
– Injectable route of administration twice a day
 Steroidogenesis Inhibitors
Often effective
Does not treat the underlying issue for
Cushing’s disease (i.e. no effect on tumor)
None are FDA approved for use in
Cushing’s syndrome
 Ketoconazole
Advantages
– Rapid onset of action
– Decreases UFC in 70% of CD patients
– Administered orally
Disadvantages
– Severe hepatotoxicity has been seen
FDA black box warning in 2013 due to this, the
potential for adrenal insufficiency, and drug-drug
interactions
– GI upset
– Headache and sedation
– Potent inhibitor of cytochrome P450 enzymes
Tritos and Biller. Discovery Medicine 2012, 13(69); 171-179.
 Metyrapone

Inhibits 11-β
hydroxylase

Side effects
related to
accumulation of
androgens and
mineralocorticoid
precursors

Not widely
available in U.S.

Tritos and Biller. Discovery Medicine 2012, 13(69); 171-

Other Steroidogenesis Inhibitors
Etomidate
– Used in emergency situations in order to gain
rapid control over cortisol levels
LCI699
– Investigational with study ongoing
Adrenolytic Agent—Mitotane
Studied extensively in adrenal cortical
carcinoma and is FDA approved for this purpose
Not FDA approved for Cushing’s syndrome
Inhibits several steps in steroidogenesis and is
cytotoxic to the adrenal cortex
Effective in 80% of patients but onset of action is
slow (at least 2 weeks)
Side effects mitigate use (GI, neuro, teratogenic)
Close monitoring required

Tritos and Biller. Discovery Medicine 2012, 13(69); 171-179.

Bertagna and Guignat. JCEM 2013, 98(4); 1307-1318.
 Glucocorticoid Receptor
Antagonist—mifepristone
FDA approved in 2012 for hyperglycemia in
adults with endogenous cushing’s syndrome,
who are not surgical candidates or have failed
surgery
Initially used as a progesterone receptor
antagonist—RU 486
Also has affinity for glucocorticoid receptor when
used in higher doses

Fleseriu, et al. JCEM 2012, 97(6); 2039-2049.

 Mifepristone
Significant improvement noted in:
– Glycemic control
– Weight
– Mood and cognition

Fleseriu, et al. JCEM 2012, 97(6); 2039-2049.

 Mifepristone
Advantages
– FDA approved
– Easy route of administration
– Significant improvement in many of the features of
hypercortisolism
Disadvantages
– Cannot monitor measures of cortisol/ACTH
– Potential for tumor growth
– Very close monitoring required during initiation and
titration of the drug
 Cushing’s Therapy—Timeline
???—
1981—cabergoline discovered LCI699
1996—FDA approved for
1960s—metyrapone
prolactin related disease 2012—
used in ACC
2004—series published in CD mifepristone
1977—series published
FDA approved
in CD
for use in CD

1950s—Bilateral 1964—etomidate discovered

adrenalectomy 1990—series of 6 patients in
CD reported
1980—mitotane
series published

1976-ketoconazole 2012—pasireotide FDA

discovered; series approved for use in CD
published in CD in
1985
 Case 1
58 y/o male with a 3.5cm adrenal incidentaloma
Previously evaluated (2 years ago) for hormone
hypersecretion by an endocrinologist with reportedly
normal results—a 24 hour UFC was done measuring
45mcg/dL (creatinine not available)
Reports central weight gain, new HTN, and newly
diagnosed hypogonadism
Repeat testing performed:
– 24 hour UFC: 247mcg/24 hours (did this first, as pt is night shift
worker), repeated it and the result was 356mcg/24 hours
– 1mg overnight DST: 4.9mcg/dl
– Midnight salivary cortisol x 3: 2/3 elevated
Patient is diagnosed with Cushing’s syndrome and has a
known adrenal mass
Case 1 CT Abdomen
 Case 1
Additional labs are done:
– ACTH <5 pg/mL (normal 10-60)
Outcome
– Laparoscopic left adrenalectomy in 9/12
– Off steroids in 6/13
 Case 2
18 y/o morbidly obese female presents with weight gain,
striae, and facial plethora in 2008
She also has depression, previously with suidical
ideation
24 hour UFC was performed
– 218 mcg/24 hours (normal < 45 mcg)
– 174 mcg/24 hours
DST was performed, and her cortisol suppressed to 0.8
mcg/dL
 Case 2—Additional Testing
ACTH 17 pg/mL
Pituitary MRI completed
Midnight salivary cortisol:
– 0.096 mcg/dL (normal < 0.010- 0.090)
– 0.086 mcg/dL
– 0.190 mcg/dL
Repeat 24 hour UFC 24 mcg
– Creatinine 1.6g
– Volume 1150cc
Case 2 MRI
 Case 2
She is noncompliant with follow up for 3 years and then
returns in 2012
Notes continued weight gain (BMI 51 kg/m2) but no other
new symptoms
No longer on medication for depression but is on OCPs
Repeat testing completed, as symptoms have perhaps
progressed
– UFC 57 mcg with creatinine 1.52g and volume
1400cc (normal < 45 mcg)
– Midnight salivary cortisol normal x 3
Diagnosis?
Plan?
 Case 3
18 y/o female with an extensive history to include obesity, HTN, DM,
and amenorrhea
Initially dx’d and treated for PCOS
Found to have increasing insulin requirement, further weight gain,
worsening HTN
Cushing’s w/u pursued
24 hour urinary free cortisol 71 mcg initially
Repeat UFC also increased
ACTH 45 pg/mL
Case 3 MRI
 Case 3
Proceeded with petrosal sinus sampling
– Central source of ACTH confirmed
– Right to left gradient
Pituitary exploration completed with tumor seen
and resected
– Path report +ACTH
Initially did well with weight loss, decreasing
insulin requirements, and spontaneous
resumption of menstrual cycles
 Case 3
Noncompliant with follow up for several months
Returned to clinic about 10 months later, still on
physiologic replacement hydrocortisone
Noted worsening glycemic control, weight gain
Hydrocortisone was stopped and UFC was done
2 weeks later which was elevated x 2
Midnight salivary cortisol also elevated
MRI 3 mos post op vs now
What can we offer this patient?
Repeat transphenoidal surgery
Radiation (stereotactic vs conventional)
Medical therapy
Bilateral adrenalectomy
 Progress
A multidisciplinary approach was taken
She was given the option of bilateral
adrenalectomy vs medication vs radiation
vs combination
Result: stereotactic radiation and medical
therapy with mifepristone while awaiting
the effects of gamma knife
 Case 4
62 y/o woman found to have a large sellar
mass when she presented to her
community ER with a severe headache
She reported a 30 pound weight gain, new
onset diabetes, and moon facies
Biochemical w/u consistent with Cushing’s
disease
Surgical resection attempted
Medical therapy with ketoconazole was
initiated
Case 4 CT Scan
 Case 4
She was sent to our facility for another
opinion
An endoscopic evaluation of her sphenoid
sinus reveals a pulsatile mass in the
posterior aspect of the sphenoid sinus,
presumably her internal carotid artery
Surgery is not offered, but she is
interested in our opinion regarding medical
therapy
 Case 4
Repeat UFC (off therapy) was 212mcg/24 hours
Did not suppress with dexamethasone 1mg
Discussed medical options
Pt elected to resume ketoconazole
6 weeks later, complained of arthralgias,
dizziness, generalized weakness, and nausea
Repeat UFC only 8.7mcg/24 hours
What now???
 Summary and Conclusions
Cushing’s syndrome refers to the state of cortisol excess
and results in significant morbidity and mortality
Etiologies of disease include ACTH dependent and
ACTH independent sources, with Cushing’s disease
being the most common
Screening of appropriate patients should be conducted
using 24 hour UFC, low dose DST, or midnight salivary
cortisol in the majority of cases
To determine the etiology of disease, a serum ACTH is
collected
– If suppressed, adrenal disease is suspected
– If normal or elevated, either pituitary or ectopic disease is the
culprit
 Summary and Conclusions
Pituitary MRI can confirm disease in 60% of cases
Additional testing with BIPSS can be used if needed, and
additional imaging may be needed to find ectopic
sources
For all etiologies of Cushing’s syndrome, surgery is the
mainstay of treatment
In cases of recurrent/persistent pituitary disease, repeat
surgery, radiotherapy, bilateral adrenalectomy, and
medical therapy may be considered based on the
individual case and patient preferences
Goals of treatment, in order to prevent the morbidity and
mortality associated with the disease, are to normalize
the biochemical parameters and alleviate the clinical
features of Cushing’s
Questions?