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352
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M. Ciaccio et al.
Salivary Assays
Hormones are present in saliva in a free form and their concentrations correlate signicantly with their free plasma
fraction.
Saliva is usually collected by inserting a swab into the
patient’s mouth and waiting a few minutes until it is completely soaked in saliva; usually, two samples are collected.
Cortisol
Salivary cortisol represents a surrogate marker of free cortisol, in equilibrium with free serum cortisol. Furthermore, it
is not affected by saliva production rate or transport proteins.
The assay is performed by immunometric techniques or by
mass spectrometry.
The determination of cortisol on a saliva sample collected
around midnight (nocturnal salivary cortisol [NSC]) represents an important screening test for Cushing’s syndrome,
characterized by increased salivary and plasma cortisol levels at night. Salivary cortisol has the advantage that it can be
collected at home by self-sampling and, being stable at room
temperature, taken the following morning to a laboratory for
analysis. However, it must be taken into account that the
immunological assay could lead to false positives due to
cross-reactivity with cortisone that salivary glands convert
from cortisol by the enzyme 11-β-hydroxysteroid dehydrogenase type 2.
One of the main advantages of salivary cortisol is that levels tend to be altered when urinary-free cortisol is normal or
only modestly increased in patients with Cushing’s
syndrome.
Salivary cortisol determination performed in the morning
is a helpful screening test for adrenal insufciency; values
<1.5μg/L is strongly indicative of the disease, while values
>6.2μg/L exclude adrenal insufciency.
Dynamic Investigations
Dynamic laboratory investigations are aimed at assessing the
integrity and function of the hypothalamic pituitary adrenal
(HPA) axis; a distinction is made between stimulation tests,
which are useful in diagnosing conditions of hormone deciency, and suppression tests, which are useful in documenting hypersecretion of adrenal hormones (Tables 25.18,
25.19, 25.20, 25.21, 25.22, and 25.23).
Diagnosis andTherapy
Adrenal Insuciency
In the presence of a patient with suspected adrenal insufciency, with characteristic signs and symptoms of the disease
(weakness, hypotension, weight loss, and hyperpigmentation), the morning baseline total serum cortisol or morning
salivary cortisol or free cortisol index is determined, associ-
Table 25.18
Aim Assess the functional reserve of the adrenal gland for
Indications Hypoadrenalism
Principle ACTH directly stimulates the adrenal secretion of
Method Endovenous administration of 0.25mg of a synthetic
Interpretation
ACTH adrenocorticotropic hormone
Table 25.19 Stimulus test with CRH
Aim Assess the function of pituitary corticotropic cells
Indications Differential diagnosis between Cushing’s disease
Principle CRH stimulates the pituitary production of ACTH
Method
Interpretation Normal response: an increase in ACTH of 20–50pg/
ACTH adrenocorticotropic hormone, CRH corticotropin releasing
hormone
Rapid stimulation test with ACTH
cortisol production
Differential diagnosis between primary and
secondary hypoadrenalism
cortisol
analogue of ACTH (cosynthropin)
Dosage of basal plasma cortisol and aldosterone
levels, 30 and 60minutes after administration
The test can be performed at any time of day
Healthy subject: cortisol peak >18–20μg/dL
Subject with hypoadrenalism: cortisol peak <18–
20μg/dL.Aldosterone levels allow for a differential
diagnosis; in the secondary forms, but not in the
primitive ones, there is an increase in aldosterone
levels, at least up to 5ng/dL
(ACTH-dependent pituitary adenoma) and ectopic
forms (hypercortisolism due to ectopic ACTH
secretion)
Differential diagnosis of hypoadrenalism
Endovenous administration of ovine CRH 1μg/kg
Basal and 15, 30, 45, 60, and 90minutes ACTH and
cortisolemia dosage after administration
It is best to test in the afternoon or evening when
baseline cortisol is at its lowest levels for the day
mL compared to baseline 15minutes after
administration, and an increase in cortisolemia
>18μg/dL after 30–60minutes
The ACTH peak conrms ACTH-dependence; in
90% of patients with Cushing’s disease the response
of ACTH and cortisol to the stimulus with CRH is
normal or even higher than normal. In the ectopic
forms, however, no variations are observed
In secondary hypoadrenalism, the ACTH response to
CRH is absent, while in the primary one the basal
ACTH levels are elevated and further increase after
CRH stimulation
ated with the evaluation of ACTH levels; a serum total cortisol <5μg/dL or free cortisol index <12 or salivary cortisol
<1.5μg/L, associated with an ACTH two times higher than
the upper referencelimit, is strongly suggestive of primary
adrenal insufciency. Elevated ACTH levels indicate primary adrenal insufciency because the negative feedback of
cortisol on hypothalamic-pituitary function is eliminated; in
secondary forms, however, ACTH levels are low or “inappropriately” normal. Diagnostic conrmation should be per-
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Table 25.20
Aim Evaluate the integrity of the function of the
Indications Complementary test in the diagnosis of secondary
Principle Insulin-induced hypoglycemia is a stressful condition
Method Endovenous administration, fasting, 0.05–0.1 IU/kg
Interpretation
ACTH adrenocorticotropic hormone, CRH corticotropin releasing
hormone
Table 25.21
Aim Evaluate the function integrity of the hypothalamus-
Indications Diagnosis of Cushing’s disease and secondary
Principle Metyrapone induces hypocortisolemia by inhibiting
Method Oral administration of 30mg/kg of metyrapone at
Interpretation
ACTH adrenocorticotropic hormone
Insulin tolerance test (ITT)
hypothalamus-pituitary-adrenal axis
hypoadrenalism
that stimulates the hypothalamus to secrete CRH and
the pituitary gland to secrete ACTH, thus leading to
an increase in cortisolemia
of rapid insulin
Basal and 15, 30, 45, 60, 90, and 120minutes
glycemia and cortisol dosage after administration
For the successful of the test, it is important that an
adequate state of hypoglycemia is reached (glycemia
<40mg/dL)
Healthy subject: cortisol peak >18–20μg/dL
Subject with hypoadrenalism: cortisol peak <18–
20μg/dL
Metyrapone test
pituitary- adrenal axis
hypoadrenalism
the adrenal enzyme 11β-hydroxylase which mediates
the conversion of 11-deoxycortisol to cortisol.
24hours
Dosage of 11-deoxycortisol, cortisol and ACTH at
8am the following day
Healthy subject: 11-deoxycortisol >7μg/dL and
ACTH >75pg/mL
Pathological subject: 11-deoxycortisol <7μg/dL and
cortisolemia <5μg/dL
formed by stimulation tests. The best screening test is rapid
stimulation by ACTH.In subjects who respond to the test
within normal limits, for example in subjects with chronic
secondary insufciencyhaving reduced ACTH reserve, it is
necessary to perform another stimulation test, such as CRH
or metyraponetests.
The etiological diagnosis is based on the determination of
anti-adrenal antibodies and imaging. Therapy of adrenal
insufciency is gluco- and mineral-corticoid replacement.
Cushing’s Syndrome
To conrm clinical suspicion of Cushing’s syndrome, at least
two of the following laboratory investigations must be
performed:
• Measurement of free cortisol in 24h urine
• Measurement of night-time salivary cortisol, performed
by self-sampling at 24h
Table 25.22
Aim Evaluate the function integrity of the hypothalamus-
Indications Endogenous hypercortisolism diagnosis
Principle Dexamethasone is a potent glucocorticoid whose
Method Night test
Interpretation Night test
Low-dose dexamethasone test
pituitary- adrenal axis
administration results in the suppression of the HPA
axis in healthy individuals and a reduction in urinary
and plasma cortisol. The test can be performed by
one administration at night or serial administration
over 2days
- Oral administration of 1mg of dexamethasone
between 11pm and midnight
- Baseline cortisolemic dosage and at 8am the
next day
Test in 2days
- Oral administration of 0.5mg dexamethasone
every 6hours for 2 consecutive days
- Dosage of creatinine and free cortisol in the urine
of 24hours collected before and during the test
or determination of basal cortisolemia, at 24
a
48
time of the test
- Healthy subject: cortisolemia <1.8μg/dL at
8a.m.
- Hypercortisolism: cortisolemia> 1.8μg/dL
indicateshypercortisolism, regardless of the
cause
Test in 2days
- Healthy subject: cortisolemia <1.8μg/dL and, on
the second day of administration, a reduction in
cortisoluria is observed >50% of baseline
-Hypercortisolism: cortisolemia >1.8μg/dL
a
and
• Dexamethasone suppression test (overnight or over two
days)
In addition, they need to be repeated at different times
because, to date, none of the available surveys have sufciently high sensitivity and specicity.
If all the investigations performed are negative, Cushing’s
syndrome can be ruled out; if two or more tests are positive,
they are indicative of the disease.
Once the diagnosis of Cushing’s syndrome has been
made, it is crucial to identify the cause to determine the specic treatment (Fig.25.21). The rst step in the differential
diagnosis is the plasma measurement of ACTH levels.
Plasma ACTH levels <10 pg/mL (or <2.2 pmol/L) in a
patient with manifest endogenous hypercortisolism suggests
an adrenal or otherwise ACTH-independent cause. CT or
MRI of the adrenal glands can identify the etiology; typically, adenomas are <6 cm in size and homogeneous in
appearance, whereas carcinomas are larger in diameter and
irregular in appearance. The differential diagnosis between
adenomas and carcinomas is also based on the plasma determination of DHEA-S, which is increased in carcinoma and
reduced in adenoma.
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M. Ciaccio et al.
Table 25.23
Aim Evaluate the function integrity of the hypothalamus- pituitary- adrenal axis
Indications Differential diagnosis of Cushing’s disease (pituitary hypophyseal hypersecretion of ACTH) from ectopic ACTH syndrome
Principle In Cushing’s disease, the hypothalamic-pituitary axis is suppressible with high doses of glucocorticoids (dexamethasone),
Method Night test
Interpretation Night test
ACTH adrenocorticotropic hormone
Fig. 25.21 Algorithm for the
differential diagnosis of
Cushing’s syndrome.
(Copyright EDISES 2021.
Reproduced with permission)
High-dose dexamethasone test
and adrenal tumors. In Cushing’s disease, the hypothalamic-pituitary axis is suppressible with supraphysiological doses of
glucocorticoids, while in the case of adrenal tumors or ectopic ACTH syndrome, the secretion of cortisol is autonomous and,
therefore, cannot be suppressed
while in the case of adrenal tumors or ectopic ACTH syndrome, the secretion of cortisol is autonomous and, therefore, cannot
be suppressed
-Oral administration of 8mg of dexamethasone between 11pm and midnight
-Baseline cortisolemic dosage and at 8am the next day
Test in 2days
-Oral administration of dexamethasone 2mg every 6hours for 2 consecutive days
- Measurement of creatinine and free cortisol in the urine of 24hours collected before and during the test or determination
of basal cortisolemia, at 24a and 48a time of the test
-Cushing’s disease: suppression of cortisolemia> 50% of baseline
- Subjects with adrenal tumors or ectopic ACTH syndrome show no change in cortisolemia following administration of
dexamethasone
Test in 2days
-Cushing’s syndrome: suppression of cortisoluria> 50% of baseline
- Subjects with adrenal tumors or ectopic ACTH syndrome show no change in cortisolemia following administration of
dexamethasone
Confirmed Cushing's Syndrome
Plasma ACTH
mL)are doubtful, and a CRH stimulation test may be helpful. Specically, in cases of ACTH-secreting pituitary adenoma, testing with CRH will result in increased ACTH
(positive test), whereas in the presence of an adrenal cause
and ectopic ACTH, the test will be negative.
<10 pg/mL (<2.2 pmol/L)
ACTH-independent
, DHEA-S
Differential diagnosis
between adenoma and
unilateral cancer or
bilateral hyperplasia
organs (neck, abdomen, chest, and pelvis)
Follow-up
MRI or CT scan of other
Negative
ACTH values between 2.2 and 4.4 pmol/L (1020 pg/
10-20 pg/mL (<2.2–4.4 pmol/L)
CRH test
Negative
Positive
Positive
Selective pituitary
venous catheterization
Negative
Ectopic ACTH-secreting
>20 pg/mL (<4.4 pmol/L)
ACTH-dependent
• High dose dexamethasone
suppression test
• CRH test
• MR
Adenoma <6 cm
Discordant tests
Positive
cancer
Adenoma >6 cm
Concordant tests
Confirmed
Cushing’s disease
High ACTH values (>20pg/mL or >4.4pmol/L) indicate
ACTH-dependent Cushing’s syndrome. Although plasma
ACTH levels are >40pmol/L (200pg/mL) in ectopic secretory forms and range between 6 and 30pmol/L (30–150pg/
mL), in forms due to pituitary adenoma or hypothalamicpituitary dysfunction, it is helpful to determine cortisol
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secretion in response to high-dose dexamethasone administration, perform CRH testing, and an MRI of the adrenals to
differentiate between ectopic and pituitary ACTH production. Patients with pituitary adenoma (Cushing’s disease)
show a normal or increased response to CRH testing and
cortisol suppression >50% of baseline values in response to
testing with high doses of dexamethasone; positivity of both
tests has high diagnostic accuracy (>95%). MRI with contrast medium can detect pituitary adenomas in only half of
Cushing’s disease patients. In addition, in some subjects
(10–20%) without pituitary pathology, an occasional lesion
≤6cm may be found on MRI.In subjects with questionable
MRI and discordant laboratory tests, selective venous catheterization of the petrous sinuses (pituitary outow venous
pathways) can be performed by ACTH assay. If there is an
ACTH-secreting pituitary tumor, ACTH levels measured in
that area will be very high; if it is a tumor with ectopic ACTH
production, the levels in this area will be the same as in the
venous sampling. Selective venous catheterization of the
petrous sinuses is the gold standard to discriminate between
the ectopic or pituitary origin of increased ACTH secretion,
with high sensitivity and specicity, although it is a very
invasive technique.
Treatment of Cushing’s syndrome can be surgical, medical, or radiation; in most cases, the surgical approach is
preferred.
Primary Hyperaldosteronism
Diagnosis of primary hyperaldosteronism begins with a
screening test, which includes the relationship between
plasma aldosterone and PRA values, followed by a conrmatory test and, nally, investigations to assess the cause of
hyperaldosteronism.
The screening test is recommended in patients with:
• Sustained blood pressure >150/100mmHg, measured on
three different days
• Hypertension (blood pressure >140/90mmHg), resistant
to three antihypertensive medications (including a
diuretic)
• Blood pressure (<140/90mmHg) controlled with four or
more antihypertensive medications
• Hypertension and spontaneous or diuretic-induced
hypokalemia
• Hypertension and adrenal incidentaloma
• Hypertension and sleep apnea
• Hypertension and family history of early-onset hyper-
tension or cerebrovascular event at a young age
(<40years)
• Hypertension in subjects with at least one rst-degree
relative with primary hyperaldosteronism
Assessment of the aldosterone/PRA ratio (ARR) reduces
the intra-individual variability in plasma aldosterone and
renin levels due to changes in sodium intake, serum potassium levels, position (supine or standing), and age.
Determination of MRA must be preceded by discontinuation of antihypertensive medications for at least 6 weeks
(varies by drug type). Currently, there is no uniformity in
assay methods; therefore, there is wide variability in the cutoffs used for ARR.However, when sampling is performed in
the morning in a seated patient, the most commonly used
cutoff values are in the range 20–40ng/dL aldosterone per
ng/mL/h PRA; levels ≥40ng/dL plasma aldosterone per ng/
mL/h PRA, in addition to plasma aldosterone concentrations
≥15ng/dL, are indicative of hyperaldosteronism. The MRA
is a very sensitive but non-specic test; therefore, the diagnosis must be conrmed or excluded by a dynamic suppression
test with a positive MRA.The most commonly used conrmatory tests are the oral sodium loading test, saline infusion
test, udrocortisone suppression test, captopril test, and
losartan test.
Oral Sodium Load Test
It involves increasing dietary sodium intake (>200mmol–
about 6g per day) for 3days and the concomitant potassium
chloride intake to keep potassium within normal limits. The
24-hour urinary aldosterone concentration (morning of day 3
to the morning of day 4) is then determined. In the absence
of renal disease, aldosteronuria >12 μg/day (>33.3 mmol/
day)supportsthe diagnosis of primary hyperaldosteronism.
Saline Infusion Test
It involves the infusion, in the patient supine for at least
1hour, of 2liters of 0.9% saline over 4hours (500mL/h).
Blood samples for plasma aldosterone measurementare collected at time zero and, after 4hours, at the end of the saline
infusion. The test is positive if, after the infusion, plasma
aldosterone is >10ng/dL, and negative if plasma aldosterone
is <5ng/dL.Plasma aldosterone values between 5 and 10ng/
dL are questionable, and further testing is recommended.
Fludrocortisone Suppression Test
It is based on the administration of udrocortisone acetate,
0.1mg per os every 6hours for 4days, in combination with
slow-release potassium chloride supplements (also every
6hours and at doses sufcient to maintain serum potassium
around 4,0 mEq/L), slow-release sodium chloride supplements with meals (30 mmol 3 times/day), and sufcient
dietary sodium intake to maintain daily urinary sodium
excretion of at least 3mmol/kg body weight.
On the fourth day, at 8a.m., a plasma cortisol sampling is
performed; at 10a.m., in the seated patient, plasma aldoste-
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rone and PRA sampling is performed, and the plasma cortisol sampling is repeated. The test is positive if plasma
aldosterone is ≥6 ng/dL and PRA values <1 ng/mL/hour,
serum potassium in the normal range, and plasma cortisol is
lower than at eighto’clock.
Captopril Test
It involves administering captopril, 25–50 mg per os, to a
patient seated for at least 1hour. At time zero and after the
patient has been sitting for 1–2hours, blood samples are collected to determine PRA and plasma aldosterone. The test is
positive if PRA remains suppressed while plasma aldosterone is not suppressed and, thus, remains elevated. In other
forms of hypertension, however, there is a reduction in aldosterone levels and an increase in PRA.
Losartan Test
It is based on the administration of 50 mg of losartan. In
cases of primary hyperaldosteronism, after 2hours the ARR
is >35ng/dL ofaldosterone/ng/mL/h PRA and plasma aldosterone concentration is >10ng/dL.
Once the diagnosis of primary hyperaldosteronism has
been conrmed, the cause must be identied. CT scanning is
the most commonly used test for this purpose.
All patients with primary hyperaldosteronism whohaveto
undergo surgical treatment (unilateral adrenalectomy) should
perform adrenal venous sampling (AVS) to distinguish
between unilateral and bilateral adrenal disease. This distinction is fundamental because adrenalectomy is indicated only
in unilateral forms, while bilateral forms must be treated
with medical therapy. AVS involves the determination of
aldosterone and cortisol plasma concentrations in the two
adrenal veins and in the inferior vena cava or in another
peripheral vein; there are three different protocols:
• Unstimulated sequential or simultaneous sampling of the
two adrenal veins
• Basal, unstimulated, sequential, or simultaneous sam-
pling of the two adrenal veins, followed by another simi-
lar sampling stimulated by intravenous injection of a
bolus of ACTH (or tetracosactide)
• Continuous ACTH infusion with sequential bilateral adre-
nal venous sampling
The ratio of plasma aldosterone concentration to plasma
cortisol concentration in blood collected from the adrenal
vein is termed the aldosterone corrected for cortisol ratio
(A/C ratio).
When AVS is performed without ACTH stimulation, an
A/C ratio of the adrenal veins of the two sides >2:1 indicates
an unilateral form. Similarly, a diagnosis of lateralization
can be made if the ratio of the A/C ratio of one side to the
simultaneous A/C ratio of a peripheral vein is >2:1 and if, at
the same time, the contralateral A/C ratio is less than or
equal to the A/C ratio of a peripheral vein or inferior vena
cava.
With the continuous infusion of ACTH, an A/C ratio of
the two adrenal veins >4:1, indicates unilateral disease; a
ratio <3:1 is suggestive of bilateral excess secretion of aldosterone and, therefore, the absence of lateralization; nally, a
ratio between 3:1 and 4:1 may indicate either monolaterality
or bilaterality of excessaldosterone production.
On the other hand, bolus infusion involves AVS being performed before and after intravenous injection of a 250μg
bolus of ACTH. However, this technique has shown poor
diagnostic accuracy.
Finally, genetic testing for familial forms is recommended
in subjects with primary hyperaldosteronism <20 years or
with a family history of primary hyperaldosteronism or a
cerebrovascular event occurring at <40years. The diagnosis
of familial hyperaldosteronism type I is based on detecting
the chimeric gene CYP11B1/CYP11B2 by Southern blotting
or PCR (Polymerase Chain Reaction). In the case of familial
type II hyperaldosteronism, the diagnosis is based on conrmation of primary hyperaldosteronism in at least two family
members and theexclusion of type I in hypertensive family
members. Finally, tests for mutations in the KCNJ5 gene are
not yet commercially available for familial type III.
Secondary Hyperaldosteronism
Elevated plasma aldosterone, PRA, and hypokalemia are suggestive of secondary hyperaldosteronism. In particular, elevated PRA levels allow for differentiating primary
hyperaldosteronism from secondary hyperaldosteronism.
However, since the determination of baseline values has low
specicity and sensitivity, PRA should be determined after the
captopril test (25mg per os with samples taken after 60 and
90minutes), which shows sensitivity and specicity >95%.
Renal scintigraphy associated with captopril administration allows the diagnosis of nephrovascular hypertension,
while CT and MRI are essential for diagnosing reninsecreting tumors. Identifying the underlying pathology in
other forms of secondary hyperaldosteronism allows for
detecting the endocrine disturbance’s cause.
Adrenal Medullary Hormones
The chromafn cells of the adrenal medullary synthesize,
accumulate, and release the catecholamine hormones: dopamine, norepinephrine, and adrenaline (epinephrine)
(Fig. 25.22); of these, adrenaline represents the primary
product of the adrenal medullary (80%) and the only one
synthesized exclusively in the adrenal.
Adrenaline circulates bound to albumin or another lowafnity protein.
ylethanolamine-
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Ty rosine
Tyrosine
hydroxylase
L-dopa
Dopadecarboxylase
Dopamine
Noradrenaline
Phen
N-methyltransferase
Adrenaline
Fig. 25.22 Synthesis of catecholamines. (Copyright EDISES 2021.
Reproduced with permission)
Catecholamines are released into the circulation in
response to physical or emotional stress and mediate their
biological action through interaction with α (α1, α2) and β
(β1, β2, β3) adrenergic receptors; biological effects vary
based on the receptor bound.
Endogenous catecholamines are involved in regulatingcardiovascular function and circulatory hemodynamics.
In particular, they mediate nervous control of vasomotor
tone, inuencing peripheral resistance; moreover, they have
inotropic (increase in contractile force of cardiac muscle)
and positive chronotropic (increase in heart rate) effects.
Other effects of catecholamines unrelated to hemodynamics
includestimulation of hepatic glycogenolysis and peripheral
lipolysis, mydriasis, slowing of intestinal motility, uterine
contractions and relaxation, and bronchodilation. The combined action on the cardiovascular function and the energetic
substrates is related to the possibility of reacting in emergencies. Adrenaline is, by denition, the hormone of stress and
fear (β-adrenergic effects).
Catabolism of catecholamines begins with degradation by
the enzymes catechol-O-methyltransferase (COMT) and
monoamine oxidase (MAO), which form inactive
O-methylated and deaminated metabolites that are further
modied by conjugation with glucuronic or sulfuric acid
before being excreted renally. The primary catecholamine
metabolites are metanephrine (derived from adrenaline),
normetanephrine (derived from norepinephrine), and vanillyl mandelic acid (derived from norepinephrine and adrenaline). A minimal amount of adrenaline and noradrenaline
(<5%) is excreted directly in the urine.
Pheochromocytoma andParaganglioma
Pheochromocytoma and paraganglioma are rare neuroendocrine tumors arising from chromafn cells. These cells origi-
nate from the neural crest and, upon migration, localize in
the adrenal medulla and in the ganglia of the sympathetic
chains of the thorax and abdomen, where they may give rise
to tumors. In 85% of cases, the tumor originates in the adrenal medulla, where most of the chromafn cells of our organism are located, and it is called pheochromocytoma; in the
remaining 15% of cases, it can be found extra-adrenal, in the
sympathetic paraganglia (mainly located in the retroperitoneum and the thorax), where it is called paraganglioma.
Paraganglioma also refers to other parasympathetic tumors
in the head, neck, and anterior thorax regions. However,
unlike sympathetic paragangliomas and pheochromocytomas, they generally do not secrete catecholamines and are
evident only by a compressive effect on surrounding vascular
and nervous structures.
Pheochromocytomas and paragangliomas can occur as
sporadic or as components of a genetically transmitted syndrome. Pheochromocytomas can occur at any age but are
most common between the fourth and fth decades of life
and rare in infancy. 10% of cases are bilateral, 25% hereditary, and most are benign. Mainly catecholamine-secreting
tumors produce noradrenaline, some noradrenaline and
adrenaline, a few only adrenaline, and minimal part dopamine; the latter is more frequently associated with a malignant phenotype. These tumors are characterized by extreme
variability in the clinical presentation, which includes signs
and symptoms related to the production of catecholamines
and their metabolites; among these, the most common are
headache, sweating, and palpitations, which constitute a
classical triad. The most relevant clinical feature is hypertension, which can be persistent (50%) or paroxysmal (45%).
The classic triad and hypertension raises a strong diagnostic
suspicion of pheochromocytoma. However, it may remain
asymptomatic for years and, in some cases, grow to a considerable size before symptoms appear.
Laboratory Investigations
Laboratory investigations, both basal and dynamic, include
assays of free catecholamines and their metabolites in plasma
and 24-hour urine.
Basal Measurements
Plasma and urinary catecholamines, metanephrines, and
vanillyl mandelic acid
Catecholamines have a short half-life; therefore, their
determination, both plasma, and urinary, makes it difcult to
discriminate between a pathologic overproduction and a
peak secretion during sampling. Furthermore, their secretion
is intermittent and independent of tumor size.
Metanephrines (metanephrine and normetanephrine)
within the tumor are consistently produced through a process
independent of catecholamine release. Furthermore, they
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have a longer half-life in circulation than catecholamines.
Therefore, the metanephrine assay has a higher sensitivity
and specicity than the catecholamine assay. Plasma and urinary concentrations of metanephrines correlate with tumor
size and activity. Since some tumors produce only one type
of catecholamine, it is preferable to measure metanephrines
and normetanephrine separately; in this case, we speak of
fractionated metanephrines. Finally, increased adrenaline or
metanephrine indicates the adrenal gland origin, being the
exclusive site of adrenaline production and contributing 90%
to circulating metanephrine and only 35% to circulating
normetanephrine.
Since some drugs, psychological stress, intense exercise,
high protein meals, and some foods rich in catecholamines
(banana, coffee, citrus fruits, cocoa, nuts, vanilla, pineapple)
may alter the levels of catecholamines and their metabolites,
blood sampling should be performed in the morning, after
overnight fasting (8–12hours) and in clinostat, to minimize
the effect of the sympathetic nervous system. Similarly, for
the determination of catecholamines and their metabolites in
24-hour urine, certain foods (see above) and drugs that might
interfere should be avoided in the 48hours before and during
sample collection; in addition, emotional and physical
stresses and strenuous exercise should be minimized before
and during collection. Urinary catecholamines are unstable;
therefore, collected urine should be stored in acid and away
from light. On the other hand, urinary metanephrines are
stable at room temperature for up to 3days or longer if stored
at 4 °C, without the need to add acid. Creatinine should
always be assessed for adequacy in the 24-hour urine collection. Both plasma and urinary assays of catecholamines and
metanephrines are performed by high-pressure chromatography (HPLC).
Vanil mandelic acid, the end-product of catecholamine
(adrenaline and noradrenaline) metabolism, similarly to catecholamines, is measured on a 24-hour urine sample, after
diet, abstention from strenuous exercise and stress in the
48hours preceding collection; an acid, such as hydrochloric
or muriatic acid, must be added to the container.
Chromogranin A
Chromogranin A is a glycoprotein secreted by medullary
cells of the adrenal medulla and sympathetic nervous system. The measurement is performed by the immunoradiometric method (IRMA). In the case of pheochromocytoma,
although its levels correlate with the tumor mass, plasma
chromogranin A has a modest sensitivity, and, therefore, its
use in clinical practice is limited. High levels of chromogranin A are also found in medullary thyroid carcinoma,
small cell lung carcinoma, and epithelial carcinomas with
neuroendocrine differentiation (prostate, breast, ovary, pancreas, colon).
Dynamic Investigations
Refer to Table25.24 for the clonidine suppression test.
Diagnosis andTherapy
Patients with clinical signs and symptoms or at high risk of
developing a pheochromocytoma/paraganglioma
(Table 25.25) should undergo laboratory investigations to
demonstrate excessive catecholamine production
(Fig.25.23).
Since catecholamines are metabolized within chromafn
cells to metanephrines (an intratumoral process that occurs
independently of catecholamine release), the measurement
of free plasma metanephrines is the test of choice to conrm
the diagnosis of pheochromocytoma, with the highest sensitivity and specicity (99% and 89% respectively).
Alternatively, fractionated urine metanephrines can be measured, but they have a slightly lower sensitivity and specicity (97% and 67%, respectively). The sensitivity and
specicity of the plasma and urinary catecholamine assay are
84% and 81%, 86%, and 88%, respectively. The urinary
vanyl mandelic acid assay has a very low sensitivity (68%),
although the specicity is high (95%); the low sensitivity of
this test makes it less useful in clinical practice.
Normal values of free plasma metanephrines exclude the
presence of a pheochromocytoma. In contrast, a 4-fold
increase in free plasma metanephrines above the reference
limit indicates an almost 100% probability of tumor. In cases
where plasma/urinary free metanephrines are only slightly
increased (<3–4 times the reference limit), the assay should
be repeated after discontinuing interfering drugs; persistently elevated values suggest the presence of tumor, whereas
Table 25.24 Clonidine suppression test
Aim Inhibition of the sympathetic system
Indications Urinary and plasma metanephrine concentration
Principle
Method Determination of blood pressure and heart rate, 3
Interpretation Normal response: decrease in plasma norepinephrine
values increased, but not diagnostic for
pheochromocytoma
Clonidine, agonist of α2-adrenergic receptors, in the
absence of chromafn tumor, inhibits the release of
catecholamines by the sympathetic system causing a
reduction of circulating catecholamines and
metanephrines
times at 1-minute intervals, and basal plasma levels
of norepinephrine and adrenaline
Administration of 0.3mg of clonidine orally
Evaluation of blood pressure, heart rate and plasma
levels of norepinephrine or normetanephrine at
30-minute intervals for 3hours
>50% from baseline and/or decrease in
normetanephrine >40% from baseline
Pheochromocytoma: reduction in plasma
norepinephrine <50% from baseline and/or reduction
in normetanephrine <40% from baseline
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359
normal values make it less likely. The clonidine suppression
test that does not suppress elevated plasma levels of normetanephrine after 3hours of administration has high sensitivity
and specicity (100 and 96%, respectively) for tumor diagnosis in doubtful cases.
Table 25.25
paraganglioma
Condition/disease
MEN type 2A
MEN type 2B
VHL 10–20%
Neurobromatosis type 1
SDHB mutation 52%
SDHD mutation 29%
First degree relatives affected by the diseases
listed above
Adrenal incidentaloma 4%
Resistant hypertension 0.5%
Unexplained heart failure –
Headache, palpitations, sweating in association
with hypertension
Patients who develop hypertensive crises during
surgery or under general anesthesia
Patients with hypertension triggered by
β-blockers, monoamine oxidase inhibitors
Orthostatic hypotension in a hypertensive patient –
Diabetes onset in a young and thin subject with
hypertension
FCC pheochromocytoma, MEN multiple endocrine neoplasm, PGL
paraganglioma, SDHB succinate dehydrogenase subunit B, SDHD succinate dehydrogenase subunit D, VHL Von Hippel-Lindau disease
Patients to be screened for pheochromocytoma/
Prevalence of
FCC/PGL
≈50%
≈50%
≈2%
–
–
–
–
–
Tumors secreting only dopamine are rare, and, therefore,
plasma dopamine and its metabolite 3-methoxytyramine are
not routinely evaluated in most laboratories when pheochromocytoma/paraganglioma is suspected. However, these tests
may be helpful in some cases, especially in metastatic disease
where the metastatic tissue lacks the enzymes necessary for
catecholamine synthesis. High levels of 3- methoxytyramine
are a very sensitive marker of malignancy.
Once the diagnosis is made, radiologic evaluation allows
localization of the tumor by anatomic imaging followed by
functional imaging of the tumor tissue to distinguish between
pheochromocytomas, paragangliomas, and other lesions. CT
and MRI are recommended for initial anatomic tumor localization; both have high sensitivity (90–100%) but limited
specicity (70–80%) due to the high prevalence of adrenal
masses not associated with pheochromocytoma in the general population. MRI cannot expose the patient to radiation
and, therefore, can be performed in children and pregnant
women. Adrenal scintigraphy with iodine 123-labeled
metaiodiobenzyl-guanidine (123I-MIBG) allows differential
diagnosis between pheochromocytoma and paraganglioma
because 123I-MIBG is concentrated in the chromafn tumor
tissue. Furthermore, scintigraphy can reveal the possible
presence of multiple tumors and metastases. Scintigraphy
has a high specicity (95–100%), especially in the case of
malignant tumors and familial forms, but a limited sensitivity
(85%), especially in the detection of metastases. Therefore,
other investigations are recommended in cases where metastases are suspected, such as octreoscan with 111in- octreotide,
since some tumors express somatostatin receptors, or posi-
Fig. 25.23 Diagnostic
algorithm for
pheochromocytoma/
paraganglioma. (Copyright
EDISES 2021. Reproduced
with permission)
Clinical suspicion of pheochromocytoma or paraganglioma
Plasma/urinary fractionated
metanephrines
Normal
Highly unlikely
cancer
>4 times the
reference limit
Highly probable
cancer
Cancer characterization by
radiological imaging
(CT, MRI, scintigraphy)
<3–4 times the
reference limit
Stop drugs
to rule out false
positives and repeat test
<3–4 times the
reference limit
Possible cancer
Clonidine
suppression test
Suppression
<40%
suppression
Normal
Highly unlikely
cancer
Total
360
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M. Ciaccio et al.
tron emission tomography with 18F-dihydroxyphenylalanine
(18F-DOPA), which appears to be superior to scintigraphy in
detecting metastatic lesions.
Finally, genetic investigations aimed at identifying the
mutated gene are indispensable for diagnosing hereditary
forms of pheochromocytoma/paraganglioma and should be
performed in all patients with the disease. At least one-third
of patients have germline mutations responsible for the
disease.
Since 1990, 14 different susceptibility genes have been
identied. Among these, the primary are NF1 gene associated with neurobromatosis type 1 (NF-1), RET gene
associated with multiple endocrine neoplasia type 2
(MEN2), VHL gene responsible for von Hippel-Lindau
syndrome (VHL), and the genes encoding the B, C, and D
subunits of mitochondrial succinodehydrogenase (SDH),
associated with pheochromocytoma/paraganglioma syndromes named PGL4, PGL3 and PGL1, respectively;
SHDB mutations lead to the development of metastases in
more than 40% of individuals with pheochromocytoma/
paraganglioma.
In addition to family history, features suggestive of a
hereditary form of the disease are young age, bilateral or
recurrent pheochromocytomas, bilateral or multiple head/
neck paragangliomas, or association between pheochromocytomas/paragangliomas and other malignancies. Since
patients with pheochromocytoma or paraganglioma have a
high prevalence of hereditary syndromes (MEN2, NF-1, and
VHL), it is helpful to search for germline mutations even in
patients without a known family history. Once an inherited
syndrome is identied, genetic screening can be extended to
family members.
The therapy of the rst choice for pheochromocytomas is
surgical excision.
Incidentaloma
Incidentaloma is a clinically silent adrenal mass incidentally
found during imaging procedures (ultrasound, CT scan,
MRI) performed for diseases unrelated to the adrenal gland.
The increasing use of non-invasive imaging techniques has
led to an increased incidence of adrenal incidentaloma diagnosis. Autopsy studies suggest a prevalence of incidentaloma
of approximately 2%, increasing with age; radiologic studies
estimate the frequency to be around 3% in patients <50years,
increasing to 10% in elderly. In childhood, incidentalomas
are extremely rare.
In most cases, the adrenal mass is a non-secreting cortical
adenoma, but sometimes it may represent a primary or metastatic malignant tumor or hide mild hormonal hypersecretion
(Table25.26). These rare forms need to be carefully evaluated and recognized as they require appropriate surgical or
medical treatment.
Table 25.26 Classication and prevalence of adrenal incidentalomas
Incidentaloma
Tumors of the adrenal cortex
-Non-functioning benign adenoma
-Subclinical Cushing’s Syndrome
-Aldosterone-secreting adenoma
-Nodular hyperplasia
-Adrenal carcinoma
Tumors of the adrenal medulla
-Pheochromocytoma
-Ganglioneuroma
-Gangioneuroblastoma, neuroblastoma, carcinoma
Other adrenal tumors
-Myelolipoma
-Lipoma
-Lymphoma, hemangioma, angiomyolipoma
Cysts and pseudocysts 4–22
Hematoma and hemorrhage 0–4
Infections, granulomas <1
Metastases (lung, liver, breast, kidney, melanoma) 2.5
Pseudo-adrenal masses (stomach, pancreas, kidney,
liver, lymph nodes, vascular lesions, technical artifacts)
Prevalence
(%)
70–94
71–84
9
1.6–3.3
7–17
4
1.5–11
0–6
<1
7–15
0–11
<1
0–10
Diagnosis andTherapy
Following the incidental nding of an adrenal mass, the risk
of mortality and morbidity due to hormonal hypersecretion
or the presence of a malignant tumor must always be
considered.
Although adrenal incidentalomas are clinically silent,
they can sometimes present with hypersecretion of glucocorticoids, mineralocorticoids, or catecholamines associated
with endocrine alterations. Therefore, patients should
undergo a careful history and physical examination for signs
and symptoms of hormonal hypersecretion, in association
with laboratory investigations to document any hormonal
alteration. The overnight dexamethasone suppression test is
recommended to assess cortisol secretion. After stimulation,
a cortisol value <1.8μg/dL allows to exclude autonomous
cortisol secretion; cortisol values between 1.9 and 5.0μg/dL
indicates autonomous cortisol secretion, while cortisol levels
>5μg/dL suggests autonomous cortisol secretion. The 5μg/
dL threshold dramatically reduces false positives at the
expense of sensitivity. Therefore, guidelines recommend
lowering the threshold to 1.8μg/dL and possibly conrming
cortisol hypersecretion with more specic tests.
Fractionated plasma or urinary-free metanephrines assay
is recommended to exclude the presence of a pheochromocytoma. Evaluation of the aldosterone/PRA ratio to rule out
primary hyperaldosteronism is recommended only in patients
with concomitant unexplained hypertension or hypokalemia.
Finally, sex hormone and steroid precursor assay is
recommended only in patients with clinical (hirsutism or virilization) or imaging features suggestive of corticosurrenal
carcinoma.
Adrenal Incidentaloma
Benign, non-functioning
follow-up
adrenectomy
25 Endocrine System
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Fig. 25.24 Diagnostic
algorithm of adrenal
incidentaloma. (Copyright
EDISES 2021. Reproduced
with permission)
361
Evaluate simultaneously
To evaluate the nature of the tumor (benign or malignant),
the patient should undergo imaging procedures to assess the
size and appearance of the lesion; the nding of a homogeneous mass, rich in lipids, with regular margins and <4cm in
diameter is indicative of benignity.
Therapy depends on the nature of the incidentaloma. No
therapeutic measures are necessary for benign, nonfunctioning lesion, but periodic follow-up is recommended.
A diagnostic algorithm for adrenal incidentaloma is proposed in Fig.25.24. In the case of malignant tumors, pheochromocytoma and hormone-secreting adenomas,
adrenalectomy is indicated. Autonomous cortisol secretion
should be considered a high-risk condition for the development of overt Cushing’s syndrome. The guidelines recommend that patients with both possible and overt autonomic
cortisol secretion should be screened for hypertension and
type 2 diabetes mellitus, and the possible treatment of these
conditions should be considered. In addition, for patients
with (overt) autonomic cortisol secretion, a personalized
approach should be considered to evaluate the possibility of
surgical intervention, considering the patient’s age, degree of
excess cortisol, general well-being, presence of comorbidities, and patient preferences.
In patients with undeterminated adrenal masses (by imaging) who choose not to undergo adrenalectomy, repeat imaging (CT or MRI) is recommended after 6–12months to rule
out signicant growth; if the lesion shows an increase >20%,
surgical intervention is recommended.
Testis
MarcelloCiaccio, BrunaLoSasso, and LuisaAgnello
Nature of cancer
CT scan or MRI
lesion
(e.g. adenoma, lipoma)
Periodic
Cancer Functionality:
• Clinical evaluation
• Dexamethasone overnight test
• Plasma or urinary methanephrines
• Aldosterone/ARR ratio
• Sex hormones and steroid
precursors
Adrenal adenoma with
autonomous
secretion of cortisol
Evaluate
Clinically relevant
hormone excess or
malignant
cancer (e.g.
pheochromocytoma,
Conn, Cushing's, etc.)
Evaluate
adrenectomy
Indeterminate
mass
Evaluate
adrenectomy
or periodic
checkup
Anatomy
The gonads, male and female, are endocrine glands that,
beyond the rolein gametes, synthesize hormones called sex
steroids, whose primary role is regulating reproductive
function.
In particular, the male reproductive system is involved in
several processes, such as sexual differentiation, hormonal
changes, development of male sexual characteristics, spermatogenesis, and sexual reproduction. It consists of internal
and external organs, the latter represented by the penis and
testes. The internal organs include the vas deferens, seminal
vesicles, ejaculatory ducts, prostate, and urethra. The testicle
is an ovoid organ responsible for spermatogenesis and the
production of male sex hormones. It develops during fetal
life in the abdomen, from where it descends into the scrotum
through the inguinal canal during the third trimester of life.
This event is essential to ensure that the testicle is at a lower
temperature than the body temperature, a necessary condition to perform its functions. Each testicle is located in the
scrotal bursa, suspended at the extremity of the corresponding spermatic funiculus, surmounted by the epididymis, and
lined almost entirely by the visceral leaet of the tunica vaginalis propria in whose cavity it is contained; it is surrounded
by the tunica albuginea consisting of smooth muscle and
collagen. Fibrous septations from the tunica albuginea divide
the testicular parenchyma into pyramidal lobules (Fig.25.25).
The seminiferous tubules are within each lobule. The terminal part of the seminiferous tubules has a rectilinear
course, forming the recti tubules, which converge in a complex canalicular system of ducts, the rete testis, from which
originate a dozen of efferent canaliculi converging in one
only canal, the epididymis. The epididymis distal portion
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