AUA Update Series

Lesson 4 Volume 29 2010

Adrenal Incidentalomas
Learning Objective: At the conclusion of this continuing medical education activity, the
participant will understand the basic evaluation required for assessing incidentally
detected adrenal lesions and the indications for observation, biopsy, surgical resection or
medical management in this cohort of patients.
Jessica Mandeville, M.D.
Disclosures: Nothing to disclose
Chief Resident
Lahey Clinic Institute of Urology
and
Ali Moinzadeh, M.D.
Disclosures: Intuitive Surgical: Consultant/Advisor
Director of Robotic Surgery
Urologic Oncology
Lahey Clinic Institute of Urology
Assistant Professor
Tufts University Medical School
Boston, Massachusetts
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AUA.
Publication date: January 2010
Expiration date: January 2013
2010 American Urological Association, Education and Research Inc., Linthicum, MD
KEY WORDS: adrenal, adrenal gland neoplasms, pheochromocytoma,
Cushing syndrome
INCIDENCE AND EPIDEMIOLOGY
Adrenal masses are among the most common tumors in humans.
The prevalence of incidental adrenal masses in various autopsy
series ranges between 1% and 8.7%, and this incidence increases
with age.
1, 2
Up to 7%of patients older than 70 years can be expected
to harbor an adrenal mass. The term adrenal incidentaloma refers
to those adrenal lesions larger than 1 cm found serendipitously
during imaging studies performed for reasons other than evalu-
ation of adrenal disease.
3, 4
With the widespread use of imaging
technologies such as ultrasound, computerized tomography and
magnetic resonance imaging, AIs are now being detected more
often. In fact, recent studies have determined the prevalence of
adrenal lesions to be approximately 4% in patients undergoing
abdominal CT.
1-4
Despite increased rates of detection associated
with high resolution imaging techniques, no definitive algorithm
exists for managing AIs. Key elements in determining the appro-
priate treatment of these incidentalomas include size of the lesion,
likelihood of malignancy, appearance on cross-sectional imaging
and functionality of the mass.
The majority of incidentally detected adrenal lesions are benign,
non-secretory and clinically silent adrenocortical adenomas. Up to
20% of these lesions can be expected to have endocrine function
with resultant conditions such as Cushings syndrome (sub-clinical
or clinical), primary hyperaldosteronism or pheochromocytoma.
1-4
In patients with no known history of malignancy greater than
70% of these lesions will be benign. However, in patients with
a history of malignant disease 50% to 75% of adrenal masses
will be categorized as metastases.
3, 5
Finally, <5% of patients
with adrenal masses will be diagnosed with primary adrenocortical
carcinoma, a rare malignancy affecting only 1 to 2 per million
persons per year.
3
For all patients with AIs, a careful history,
physical examination and biochemical evaluation are mandatory to
assess for functionality and malignant potential, and to determine
if there is a need for medical/surgical intervention or long-term
follow-up.
HISTORY AND PHYSICAL EXAMINIATION
The main goal of history taking in patients with AIs is to
determine if the patient has signs or symptoms suggesting the
presence of a functional adrenal mass. A history of hypertension,
obesity and glucose intolerance may be suggestive of sub-clinical
or clinical Cushings syndrome or adrenocortical carcinoma. Symp-
toms, including the constellation of headaches, palpations, flushing
and diaphoresis, raise concern for the presence of a pheochromocy-
toma.
6
Significant hypertension with end organ complications and a
history of hypokalemia gives rise to the possibility of an aldosterone
producing adenoma. A thorough review of patient medications is
prudent, as those taking multiple classes of antihypertensives may
have an etiology other than essential hypertension as a cause of
the difficult to manage blood pressure.
Patients must be carefully questioned regarding a history of malig-
nancies, as this would place the diagnosis of a metastatic disease
ABBREVIATIONS: AI (adrenal incidentaloma), APA (aldosterone producing adrenal adenoma), ARR (aldosterone-to-renin ratio), CT
(computerized tomography), MRI (magnetic resonance imaging), PRA (plasma renin activity), UFC (urinary free cortisol)
34
process much higher in the differential. Additionally, a history of
familial conditions such as multiple endocrine neoplasia type 2,
von Hippel-Lindau syndrome and neurofibromatosis type 1 is im-
portant to elicit, as all of these conditions are known to be associated
with pheochromocytoma.
7
Finally, a history of hirsuitism, acne,
rapidly progressive Cushing syndrome and reproductive dysfunc-
tion should raise concern for primary adrenocortical carcinoma.
4, 8
Physical examination should begin with careful measurement
of blood pressure and heart rate. Attention should then be turned
to evaluating for stigmata associated with the various syndromes
that could potentially be related to hormonally active adrenal le-
sions. The signs and symptoms associated with these syndromes
are reviewed in the Appendix.
1-8
After a thorough history and
physical examination are completed, a biochemical analysis should
be performed.
BIOCHEMICAL/HORMONAL EVALUATION
Cushing syndrome. Autonomous secretion of cortisol can be
found in approximately 5.3% of patients with AIs.
9
Several
screening tests are available for patients with signs and symptoms
suggestive of subclinical Cushing syndrome. Before obtaining these
tests, exogenous steroid use must be ruled out. The most commonly
used tests are 24-hour urinary free cortisol measurement and over-
night cortisol suppression test.
10
Patients are required to collect
several 24-hour urine samples to determine the average UFC. Gen-
erally, a UFC less than 80 g/24 hours excludes the diagnosis of
Cushing syndrome. Cortisol suppression testing is generally be-
lieved to be a more accurate means of diagnosing or excluding
Cushing syndrome. This test consists of oral administration of 1
mg dexamethasone at 23:00 hours followed by measurement of
serum cortisol at 08:00 hours the next morning. A morning serum
cortisol greater than 5 g/dl is considered diagnostic of Cushing
syndrome. The specificity of this study is reported to be 97%.
3, 10
Pheochromocytoma. Pheochromocytoma will be diagnosed in
approximately 4% to 5% of patients with AIs, including those
who are normotensive.
7, 11
Traditional screening for pheochromo-
cytoma has included measurement of plasma catecholamines. More
recently, measurement of plasma or urinary fractionated meta-
nephrines (metabolites of catecholamines) has been used, as
available data demonstrate its improved diagnostic sensitivity
in detecting silent pheochromocytoma. Metanephrine measure-
ment is believed to be a more sensitive assay because pheochromo-
cytoma catecholamine release is episodic while its metabolism is
continuous and, therefore, metanephrines should remain persistently
high in the serum and urine.
3
Pheochromocytoma should be sus-
pected in any patient with increased levels of catecholamines or
their metabolites in the urine or blood. However, one must carefully
review patient medications before interpreting these studies, as
many of them, including levodopa, monoamine oxidase inhibitors,
benzodiazepines and tetracycline, are known to falsely increase
catecholamine and metanephrine levels. Additionally, rapid with-
drawal from clonidine can result in elevated levels of catechola-
mines. If possible, patients should discontinue these medications
before screening. The upper limit of normal values for 24-hour
urinary catecholamines and metanephrines is shown in the table.
11
Upper limit of normal for 24-hour urinary catecholamines and
metanephrines
Mg/24 Hrs
Catecholamines:
Epinephrine 0.02
Norepinephrine 0.08
Total 0.1
Metanephrines:
Metanephrine 0.4
Normetanephrine 0.9
Av 1.3
Each reference laboratory will determine its own cutoff values.
Primary hyperaldosteronism. Primary hyperaldosteronism was
first described as a syndrome of hypertension, hypokalemia,
hyponatremia and alkalosis associated with an aldosterone pro-
ducing adrenal adenoma.
11, 12
However, primary hyperaldosteron-
ism may also be associated with other conditions such as bilateral
adrenal hyperplasia. It is imperative to differentiate between these
entities to separate out those patients who have surgically correcta-
ble hypertension. While approximately 10% of hypertensive pa-
tients have some form of hyperaldosteronism, only 1% to 3% of
AIs will be APAs.
2, 4, 11, 12
Many patients with primary hyperaldosteronism will have evi-
dence of hypokalemia secondary to potassium wasting. However,
upwards of 40% of patients with this condition will be
normokalemic.
2, 13
Therefore, while measurement of serum po-
tassium is important for all patients with adrenal adenomas, it
is not a reliable screening test for hyperaldosteronism. The
aldosterone-to-renin ratio is now a widely accepted screening
test for this condition. To calculate the ARR, plasma renin activity
must first be assessed. The PRA can be assessed by direct renin
assay or via a kinetic assay that determines the amount of angioten-
sin I generated during plasma incubation.
2, 14
In general, the majority
of patients with primary hyperaldosteronism will have a suppressed
PRA, although up to 30% with essential hypertension can be ex-
pected to have a low PRA as well. The ARR is defined by the
ratio of plasma aldosterone-to-PRA. To accurately determine
the ARR, patients must discontinue beta-blockers, clonidine
and diuretics. Beta-blockers and clonidine suppress PRA, there-
fore generating false-positive results, while diuretics stimulate
renin secretion and may yield false-negative results.
12, 15, 16
Early studies demonstrated successful identification of pa-
tients with primary hyperaldosteronism when the ARR was 40
(aldosterone ng/dl to PRA ng/ml per hour) or greater.
15
An
elevated ARR and high normal or high plasma aldosterone are
consistent with primary hyperaldosteronism, although the cutoff
values of ARR used to identify this condition vary widely (15 to
40). Additionally, when PRA values are low (<1 ng/ml per hour),
the ARR will be disproportionately high, even with slight changes
in PRA. Therefore, in any patient with an AI and an increased
ARR confirmatory testing with sodium loading is indicated.
2
Elevated aldosterone levels after sodium loading confirms the
presence of hyperaldosteronism. While increased serum aldos-
terone and ARR values in patients with AIs raise suspicion for
an APA, they do not confirm a unilateral source of aldosterone
production. Therefore, lateralizing studies such as adrenal ve-
35
nous sampling are often performed before contemplating surgi-
cal intervention for hypertension management.
2, 12
Adrenocortical carcinoma. Adrenocortical carcinoma will be
found in 4% to 5% of patients with AIs. Careful assessment for
signs and symptoms of excessive hormone secretion is mandatory,
as 62% to 79% of adrenocortical carcinomas will secrete
hormones.
17, 18
These tumors most commonly secrete cortisol with
resultant Cushing syndrome. There tends to be a higher degree
of virilization in these patients secondary to associated hyperse-
cretion of 17-ketosteroids and di-hydroepiandosterone. Serum
dihydroepiandosterone should be measured in all patients with
signs of excessive hormone secretion. Serum testosterone levels
should be assessed in women with excessive virilization and
serum 17-estradiol levels should be determined in men with
evidence of feminization (ie gynecomastia or testicular at-
rophy).
8
IMAGING CHARACTERISTICS
Benign adrenal adenomas identified on cross-sectional imaging
are often smaller than 3 cm and homogeneous in appearance. When
identified on traditional CT of the abdomen, these lesions typi-
cally have a density of <10 HU and demonstrate >50% washout
of contrast at 10 minutes.
2, 19
On MRI benign adrenal adenomas
similarly display rapid washout of gadolinium and frequently
demonstrate high lipid content.
5
The majority of these lesions
are iso-intense with regard to the liver on T2-weighted imaging.
On the other hand, adrenocortical carcinomas are typically
larger than 4 cm and appear heterogeneous on CT. HU mea-
surements are frequently >25 and <50% washout of contrast
is identified at 10 minutes. Calcifications and necrosis are fre-
quently present in these lesions.
4, 5
Adrenal metastasis may have
an appearance similar to adrenocortical carcinomas and, therefore,
knowledge of medical history is important when interpreting im-
aging studies.
Pheochromocytomas are variable in size, heterogeneous and well
circumscribed, and often contain necrotic or cystic elements.
4, 5
These lesions generally enhance on contrast studies and demonstrate
high signal intensity on T2-weighted imaging. The light bulb
signal on T2-weighted MRI has classically been used to identify
pheochromocytoma, although more recent studies demonstrate
that this signal may be less sensitive and specific than previously
thought. Currently available imaging techniques cannot defini-
tively differentiate between benign and malignant pheochromocyto-
mas. Metaiodobenzylguanidine scanning may be considered to as-
sess for extra-adrenal location. While certain radiological features
may be suggestive of a particular type of adrenal mass, it must be
noted that there is significant variation among different lesions.
Therefore, treatment decisions for AIs are rarely based solely
on radiographic findings.
20
ROLE OF BIOPSY
The role of adrenal biopsy is generally reserved for differenti-
ating between benign adrenal tissue and metastatic disease.
Biopsy is most commonly used in cases of known extra-adrenal
malignancies which are subsequently found to have an adrenal
lesion.
2, 21, 22
While CT guided adrenal biopsy is associated with
few complications, little data exist to support its routine use in
patients presenting with AIs.
23
A recent study demonstrated a
70.6% probability of detecting malignancy on adrenal biopsy in
patients with a history of malignant disease. That same study dem-
onstrated only a 16.7% probability of detecting malignancy in
patients presenting with an AI. In the patients with AIs the sensitiv-
ity of detecting an adrenal carcinoma based on biopsy was only
50%.
22
In most series the size of the adrenal lesion is the strongest
predictor of malignancy and management of these lesions is not
affected by biopsy results.
22, 24
Adrenal biopsy should be used
selectively and it is imperative that a biochemical assessment
be performed before this procedure to avoid a potential hyper-
tensive crisis.
1, 2, 4, 22, 24
MANAGEMENT
Management options, which include observation, resection or
medical therapy, for AIs depend on several factors including lesion
size, functionality and malignant potential as well as the overall
health status of the patient and candidacy for surgery.
Lesion size. More than 60% of AIs smaller than 4 cm are benign
adenomas and fewer than 2% of these masses will be primary
adrenocortical carcinomas. Adrenocortical carcinoma will account
for only 6% of AIs between 4.1 and 6 cm. For lesions larger than
6 cm, the incidence of primary adrenal malignancy dramatically
increases to 25%. For this reason, all lesions larger than 6
cm must be considered malignant until proven otherwise and,
therefore, should be surgically resected.
1, 11
More difficult decisions are involved when non-functional 4 to
6 cm lesions are identified. In these cases imaging characteristics
such as necrosis, hemorrhage, calcifications and delayed washout
may aid in decision making regarding the need for surgery. For
patients whose mass is between 4 and 6 cm, patient age and need
for continued surveillance along with comorbidities will be factors
in the decision making process. It is important to note that CT
may underestimate the size of AIs in upwards of 20% to 47%
of cases.
25
Therefore, some suggest that exploration and resec-
tion be performed for all lesions 5 cm or larger based on cross-
sectional imaging.
2, 11
The importance of surgical resection of
adrenal lesions larger than 5 to 6 cm should not be underestimated,
as early detection and resection of adrenocortical carcinomas can
portend increased survival for patients with this rare malignancy.
Given the decreased surgical morbidity associated with laparoscopic
adrenalectomy, it is reasonable to offer surgery to patients with
masses 5 cm or larger.
Functionality of lesion. Most non-functional, small (<5 cm) AIs
without adverse imaging features can be observed with serial im-
aging studies. However, the majority of functional AIs should be
resected to prevent long-term adverse effects that may be associated
with hypersecretion of glucocorticoids, catecholamines or aldos-
terone.
Excessive glucocorticoid production can result in significant mor-
bidity related to obesity, hypertension and the development of
diabetes mellitus. Patients with hypersecretion of cortisol from an
AI should undergo resection provided they are appropriate candi-
dates for surgery. For non-operative candidates, medical treat-
ment to control secretion of functional steroids should be initi-
ated. Agents such as aminoglutethimide, metyrapone and
ketoconazole (all of which interfere with various steps of steroid
synthesis) have been used with some success.
11
These patients
36
should be carefully monitored for evidence of adrenal insuffi-
ciency.
Pheochromocytoma may be associated with life threatening com-
plications such as congestive heart failure, cerebrovascular accident
or myocardial infarction. Catecholamine induced cardiomyopa-
thy with resultant myocardial necrosis and reduced ejection
fraction is an additional complication that can often be reversed
with appropriate treatment.
11
Therefore, surgical resection is
essential in all patients with suspected pheochromocytoma. All
patients require preoperative management with alpha and beta-
adrenergic blockade to help prevent an intraoperative hypertensive
crisis. Phenoxybenzamine, a long-acting alpha-blocker, is gener-
ally initiated before beta-blockade to prevent elevated periph-
eral vascular resistance in the face of unopposed excessive
alpha-adrenergic stimulation. After appropriate alpha-block-
ade has been initiated, a beta-blocker such as propanolol should
be added for protection against dysrhythmias.
2, 11
Various anes-
thetic conditions must be considered at the time of surgery, includ-
ing choice of inhalational agents and muscle relaxants, but this is
beyond the scope of this Update.
Hyperaldosteronism is often associated with severe hypertension,
electrolyte disturbances and end organ damage.
12
Therefore, surgi-
cal resection is recommended in patients with APAs and proven
unilateral hypersecretion of aldosterone. The postoperative cure
rate of hypertension is 33% to 72%. Significant improvements in
blood pressure control will be demonstrated in 40% to 50% of
patients, although they may require continued treatment with antihy-
pertensive medications.
12, 26
For patients who are poor operative
candidates medical management with mineralocorticoid recep-
tor antagonists such as aldactone is indicated.
For patients with adrenocortical carcinomas, the only chance
for cure is en bloc excision of the adrenal gland and any involved
organs (if possible). It is imperative to avoid disruption of the
tumor capsule and prevent spillage to reduce the risk of local
recurrence
8, 17, 27
To prevent inadequate resection and tumor spill-
age, open as opposed to laparoscopic resection is generally used
by surgeons without significant minimally invasive surgical experi-
ence. Patients with stages I to III disease are considered potential
candidates for surgical resection. Those with stage IV disease and
metastases are candidates for medical treatment with mitotane,
a compound that exerts a cytotoxic effect on adrenocortical
cells and has been shown to yield tumor regression in approxi-
mately 25% of patients.
8, 28
Its role in adjuvant therapy after
surgery remains unclear at this time. Mitotane induces adrenal
insufficiency and all patients treated with this compound re-
quire high dose glucocorticoid replacement. Several chemothera-
peutic protocols for the treatment of adrenocortical carcinoma exist,
with response rates in the range of 36% to 49%. Randomized
control trials comparing the various regimens are currently under
way.
29
Survival rates for patients with adrenocortical carcinoma
are inversely related to disease stage at presentation. Reported 5-
year overall survival rates are low (15% to 38%) and median
survival rates for those with metastasis are invariably less than 12
months.
8
Surgical approaches. Laparoscopic adrenalectomy has
emerged as the treatment of choice for the majority of benign,
functional or non-functional adenomas.
30, 31
As experience with
laparoscopic adrenalectomy has increased, the indications for its
use have been expanded. At some specialty centers with experienced
minimally invasive surgeons laparoscopy has been successfully
used for the treatment of malignant lesions of the adrenal gland,
and the results have been comparable to those of open surgery.
32, 33
However, due to the high rates of local and distant recurrences
associated with larger primary adrenal carcinomas and the need
for careful handling of the tumor capsule, open adrenalectomy with
wide margins and en bloc excision of involved structures remains
the procedure of choice for large suspected or proven primary
adrenal cancers. Use of the Da Vinci

robotic system for adrenalec-

tomy has been described in animal models and humans.
34
In 2
studies of only 32 patients the robotic approach was compared
to conventional laparoscopy.
35, 36
Operative time and cost were
increased, and no quantitative significant advantage was noted with
the use of the robotic system in either study. For functional adrenal
masses, no matter which surgical approach is chosen, we find it
prudent to work closely with the endocrine service for preoperative
and postoperative medical management of complex cases.
FOLLOW-UP
For patients undergoing conservative management of non-
functional AIs, follow-up is required to assess for increasing
lesion size, changes in imaging characteristics and development
of functional status.
1, 2, 4
If the size increases by 1 cm or more,
surgery should be considered. Most AIs remain stable in size over
time. With long-termfollow-up only 5% to 25%of AIs will increase
in size by greater than 1 cm. Approximately 2% to 8% of previously
non-functioning lesions can be expected to develop functionality
over time, with hypersecretion of cortisol being the most common
disorder.
Suggested algorithm for evaluation and management of adrenal incidentalomas. FNA, fine needle aspiration. mets, metastases.
37
No strong data exist regarding timing of follow-up imaging or
biochemical reassessment. The National Institutes of Health
state-of-the-science statement on AIs in 2003 recommended re-
peat cross-sectional imaging at 6 and 12 months following the
initial study on which the lesion was found. For lesions that do
not increase in size, no evidence to support repeated imaging
was identified. Additional recommendations included reassess-
ment for functionality at yearly intervals (or sooner if clinically
indicated) for up to 4 years. For AIs remaining stable in size
on 2 imaging studies at least 6 months apart which do not
demonstrate hormonal hypersecretion, further follow-up may
not be warranted.
1
For patients undergoing resection of adrenocortical carcinoma,
close radiological follow-up after resection is imperative given the
high rate of local recurrence and metastatic spread. Cross-sectional
imaging of the chest, abdomen and pelvis at 3-month intervals is
mandatory for the first 2 years after resection. This interval may
be increased after 2 years but should continue for at least 5 years
or more postoperatively. The role of fluorodeoxyglucose photon
emission tomography for follow-up has not been well-defined and
remains under study.
8
SUMMARY AND ALGORITHM
With widespread use of high resolution cross-sectional imaging,
identification of asymptomatic adrenal lesions has become a rela-
tively common occurrence. As cross-sectional imaging becomes
even more readily available, higher rates of detection may be ex-
pected. The increased detection will continue to generate a large
cohort of patients who will require evaluation of these lesions.
Unfortunately, a large body of data to support a specific algorithm
for the management of these lesions does not exist. Based on the
APPENDIX: SIGNS AND SYMPTOMS ASSOCIATED WITH FUNCTIONAL OR MALIGNANT ADRENAL LESIONS
Syndrome Signs Symptoms
Cushing syndrome Hypertension, hyperglycemia (fasting), Central obesity, buffalo hump, easy bruising, thin skin,
(clinical or subclinical) diabetes, osteopenia/osteoporosis, striae, acne, hirsuitism, muscle weakness, reproductive
dyslipidemia dysfunction
Pheochromocytoma Hypertension (may be paroxysmal), Paroxysms of tremor, headache, diaphoresis, elevated/
orthostatic hypotension, tachycardia, pounding heartbeat (may be precipitated by
tremor positional change), anxiety, increased abdominal
pressure (ie with defecation), trauma, exercise
Primary Hypertension Muscle cramping, nocturia/polyuria (related to
hyperadosteronism hypokalemia)
Adrenocortical carcinoma Hypertension, hyperglycemia (fasting), Cortisol hypersecretion (same as Cushing syndrome),
diabetes, osteopenia/osteoporosis, androgen hypersecretion (acne, hirsutism), estrogen
dyslipidemia hypersecretion (gynecomastia, reproductive
dysfunction)
Metastatic disease Non-specific History of malignant disease
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39
33. Moinzadeh A and Gill IS: Laparoscopic radical adrenalectomy for
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Study Questions Volume 29 Lesson 4
1. According to 1 study the overall sensitivity of adrenal biopsy
to detect malignancy in patients diagnosed with AI is
a. 10%
b. 25%
c. 40%
d. 50%
e. 70%
2. Adrenal masses larger than this size have a greater than 25%
chance of portending primary adrenal cell cancer
a. 4 Cm
b. 5 Cm
c. 6 Cm
d. 7 Cm
e. 8 Cm
3. The most commonly used chemotherapeutic agent for adrenal
cell carcinoma is
a. Mitotane
b. Etoposide
c. Doxorubicin
d. Cisplatin
e. Streptozocin
Take this test online at http://www.auanet.org/eforms/cme/
4. A 42-year-old male with a 3.2 cm non-functioning adrenal
mass with CT characteristics consistent with adenoma
chooses to be followed conservatively. Repeat CT at 6 and
12 months later shows no change in size or CTcharacteristics.
According to the National Institutes of Health statement on
AI from 2003 this patient
a. Does not need any further biochemical evaluation
b. May be considered for biochemical evaluation every 6
months for 4 years
c. Should undergo cross-sectional imaging every 6 months
for 4 years
d. Requires no further cross-sectional imaging as long as
there is no hypersecretion within a 4-year period
e. Should undergo yearly cross-sectional imaging indefi-
nitely
5. The most specific test for the diagnosis of Cushing syn-
drome is
a. 24-Hour urine collection to assess for free cortisol
b. 1 Mg dexamethasone suppression at 23:00 hours fol-
lowed by serum cortisol at 08:00 hours
c. Random serum cortisol assessment
d. Salivary cortisol test
e. Random urinary cortisol