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Coitisol, also known as the "stiess hoimone", is a steioiu hoimone piouuceu
by the zona fasciculata of the auienal coitex . The ielease of coitisol can be tiiggeieu
by a vaiiety of stiesses. This incluues physical stiess such as infection, ue-hyuiation
oi theimal exposuie but it can also be physiological stiesses such as feai anu
anticipation. Its function is to iegulate metabolism anu the bouy's ieaction to stiess
anu inflammation. This is achieveu by incieasing bloou sugai, suppiessing the
immune system anu aiuing in metabolism.
1

BA !"# C#9=5(4-0, (,& %##&'()* +#)"(,-./ 01 2034-.05
Coitisol secietion is contiolleu by the hypothalamic-pituitaiy-auienal axis
(BPA) (see fig. 1). Coiticotiopin-ieleasing hoimone (CRB), secieteu by the
hypothalamus, is ieleaseu into the hypophyseal poital bloou vessels. CRB then acts
on the anteiioi pituitaiy anu causes the ielease of ACTB (auieno-coiticotiopic
hoimone). Finally, ACTB stimulates the auienal glanu, which piouuces anu secietes
coitisol. Aftei synthesis, coitisol uiffuses into bloou plasma wheie it is absoibeu by
uiffeient tissues anu implements its iegulatoiy functions as a hoimone. Eventually,
the livei metabolizes the coitisol in the bloou plasma.
2

Coitisol, like many of the othei hoimones iegulateu by the hypothalamus,
iegulates its own secietion by negative feeuback inhibition (see fig. 1) Coitisol is
able to uo this by binuing to the ieceptois on the hypothalamus anu the anteiioi
pituitaiy anu inhibiting the secietion of CRB anu ACTB. Since coitisol is piouuceu
by the action of both CRB anu ACTB, a ieuuction in those will inevitably leau to a
ieuuction in coitisol levels. This allows the bouy to iemain in a hoimonal
homeostasis.
S
This is an incieuibly impoitant system in oui bouy anu any
imbalances in the uegiee of hoimone secietion can leau to a vaiiety of uisoiueis.
These uisoiueis can iesult fiom both hypeicoitisolism (hypeisecietion of coitisol)
oi auienal insufficiency, which is the hyposecietion of coitisol. Byposecietion of
coitisol can leau to Auuison's uisease while hypeisecietion of coitisol leaus to
Cushing's synuiome.
2,4

DA 2=."-,9>. .?,&30/#
Cushing's synuiome uevelops as a iesult of high coitisol levels in the bouy foi a
long time. Symptoms have been known to uevelop giauually so the uiagnosis may
not be cleai foi some time. Theie is a wiue iange of symptoms that chaiacteiize a
patient with Cushing's synuiome (see fig. 2). Symptoms incluue obesity,
chaiacteiizeu by fat aiounu the main bouy aiea, facial puffiness, uiabetes, high
bloou piessuie, muscle weakness, tiieuness, aches anu pains, moou swings, lack of
sex uiive, osteopoiosis, excess thiist anu incieaseu susceptibility to infections.
4

Theie aie foui main causes that can leau to the oveipiouuction of coitisol. The
most common enuogenous cause is a pituitaiy auenoma, which occuis about 7u-
8u% of the time. This is a benign oi non-canceious tumoi of the anteiioi pituitaiy,
which iesults in the piouuction of too much ACTB anu leaus to high volumes of
coitisol (see fig. S). This foim of Cushing's synuiome is known as Cushing's uisease
anu is chaiacteiizeu by high ACTB anu coitisol levels.
S

Anothei tumoi that can leau to the oveipiouuction of coitisol is a tumoi in the
auienal glanu, which occuis about 1u-2u% of the time. This tumoi can eithei be
benign, such as auienal auenoma oi micionouulai hypeiplasia, oi malignant, such
as auienal caicinoma. When this is the cause of Cushing's synuiome, incieaseu
negative feeuback inhibition has the effect of uecieasing the secietion of tiopic
hoimones. Bowevei, coitisol will iemain high as negative feeuback inhibition will
not have an effect on the auienal glanu.
6
Anothei cause of Cushing's synuiome can be ectopic oi paianeoplastic Cushing's
synuiome. This iefeis to tumois that aie piesent outsiue the noimal pituitaiy-
auienal system anu piouuce ACTB. Small cell lung caicinoma is an example of such
a tumoi.
7
Finally, the most common type of Cushing's synuiome is iatiogenic
Cushing's synuiome, which usually stems fiom tieatment with coiticosteioius foi a
long time.
2
DA 8)3##,-,9 !#.4 103 2=."-,9>. .?,&30/#
Theie aie vaiious ieasons why the bouy can piouuce too much coitisol anu
theie aie complex tests that have been geneiateu to finu the ioot cause of the excess
coitisol. Bue to the fact that the level of coitisol vaiies uepenuing on the time of the
uay, a simple bloou test is not enough to uiagnose Cushing's synuiome.
8

The fiist thing to uo is to ueteimine whethei theie is an excess of coitisol in
the patient's bouy (see fig. 4). The fiist test that is geneially auministeieu is the 24-
houi uiine fiee coitisol level test, which is a test to measuie the amount of coitisol
that is passeu in uiine. The way this test woiks is that the patient neeus to collect all
the uiine that is passeu ovei 24 houis into a plastic containei. The uiine is then sent
to a laboiatoiy to measuie the coitisol levels. Since the secietion of coitisol
noimally follows a ciicauian ihythm, patients with abnoimal patteins of secietion
can be iuentifieu anu uiagnoseu with Cushing's synuiome.
9

In auuition, an alteinative test that can be auministeieu is a bloou oi uiine
test that can be aiiangeu aftei the patient takes a uiug calleu uexamethasone. This
uiug suppiesses the amount of coitisol the bouy is supposeu to make as
uexamethasone is a human maue steioiu that is similai to coitisol. Noimally, it
shoulu ieuuce the level of ACTB anu subsequently coitisol. Thus, if the amount of
coitisol in the bloou is still high aftei taking this uiug then a uiagnosis of Cushing's
synuiome can be confiimeu. Theie aie two uiffeient kinus of uexamethasone
scieening tests that aie auministeieu to patients suspecteu of Cushing's synuiome.
Both of these uexamethasone suppiession tests can be uone eithei oveinight oi a
stanuaiu (S-uay) way.
1u

The fiist is a low-uose uexamethasone suppiession test. Foi the oveinight
low-uose methou, 1mg of uexamethasone is auministeieu at 11 pm. The next uay,
the patient's bloou coitisol level is measuieu at 8 am. The stanuaiu low-uose
methou is uiffeient in that the coitisol level is measuieu in uiine which is collecteu
ovei S uays. The uiine is stoieu in 24-houi collection containeis. 0n the fiist uay, a
uiine sample is taken anu then staiting the seconu uay, u.Smg of uexamethasone is
auministeieu eveiy 6 houis foi 48 houis with uiine collecteu eveiy uay. The seconu
test is a high-uose uexamethasone suppiession test. The oveinight high-uose
methou involves measuiing the baseline coitisol level on uay 1 in the moining.
Then, 8mg uexamethasone is auministeieu at 11pm the same uay. The bloou
coitisol is then measuieu at aiounu 8am the next uay. Foi the stanuaiu high-uose
test, uiine is collecteu foi thiee uays eveiy 24 houis. 0n uay 2, 2mg of
uexamethasone is auministeieu eveiy 6 houis foi 48 houis, similai to the low-uose
stanuaiu uexamethasone suppiession. The low-uose test is auministeieu to help
ueteimine whethei the bouy is piouucing too much coitisol, thus helping uiagnose
Cushing's synuiome. 0n the othei hanu, the high-uose test can be auministeieu in
oiuei to ueteimine the ioot of the pioblem, such as if the patient has Cushing's
uisease.
1u
Theie is anothei set of tests ielating to Cushing's synuiome that can help us
uistinguish between the uiffeient types of Cushing's synuiome patients may have.
Biffeient iesults fiom the uexamethasone suppiession test combineu with a bloou
ACTB test can help ueteimine wheie Cushing's synuiome in a patient stems fiom
(see table 1). If theie is no change in the coitisol level aftei the auministiation of the
low-uose test anu if the ACTB level is low, then that is inuicative of Cushing's
synuiome causeu by an auienal tumoi. If theie is no change in coitisol levels aftei
both a low anu a high-uose test anu the ACTB levels aie high then the Cushing's
synuiome is a iesult of an ectopic ACTB-piouucing tumoi. Finally, if theie is no
change in coitisol levels thiough a low-uose test but noimal suppiession thiough a
high-uose test, then it is most likely Cushing's synuiome causeu by a pituitaiy
tumoi.
11
In oiuei to uistinguish between ectopic Cushing's synuiome anu Cushing's
uisease, a CRB stimulation test can also be peifoimeu. Patients with Cushing's
uisease will iesponu to the CRB stimulation with an inciease in ACTB anu coitisol
but patients with ectopic Cushing's synuiome won't iesponu. In auuition, the
uexamethasone suppiession test can be combineu with the CRB stimulation test to
uiffeientiate patients with Cushing's synuiome fiom patient's with pseuuo-
Cushing's synuiome oi noimal patients. Patients with pseuuo-Cushing's synuiome
have noimal coitisol levels aftei auministiation of the test while abnoimal iesults
point to Cushing's synuiome. Finally, NRI of the pituitaiy anu a CT scan of auienals,
chest anu abuomen can also help pinpoint the souice of coitisol oveipiouuction.
12

Lastly, a night-time bloou test oi saliva test can be auministeieu to measuie
the level of coitisol. Since the secietion of coitisol follows a ciicauian ihythm,
coitisol peaks in the moining anu ieaches its low at night time. Patients with
Cushing's synuiome uo not show a change in coitisol levels thioughout the uay anu
thus, auministeiing a bloou oi saliva test at night time can help confiim the
uiagnosis of Cushing's synuiome.
8,1S
EA 20,)5=.-0,
The uelicate balance in homeostasis that is iegulateu by feeuback inhibition
can leau to uetiimental consequences if it goes askew. Coitisol pioviues negative
feeuback inhibition to both the anteiioi pituitaiy anu auienal glanu, which allows a
ueciease in the piouuction of coitisol. When this system is alteieu, foi example, uue
to the piesence of a tumoi in the anteiioi pituitaiy oi auienal glanu, then that can
leau to Cushing's synuiome. Scieening tests such as the 24-houi uiine fiee coitisol
test oi uexamethasone suppiession tests can not only help confiim a uiagnosis of
Cushing's synuiome but also figuie out wheie the pathology of the uisease lies.














%-9=3#. (,& !('5#.

%-9=3# @A The components of the hypothalamic axis incluue the hypothalamus, the
anteiioi pituitaiy anu the auienal glanu. When the bouy encounteis stiess, it causes
the hypothalamus to seciete CRB, which acts on the anteiioi pituitaiy to piouuce
ACTB. ACTB then acts on the auienal glanu to piouuce coitisol, which battles the
vaiious stiesses that aie enuuieu by the human bouy. Coitisol iegulates its own
secietion by pioviuing negative feeuback to both the anteiioi pituitaiy anu the
hypothalamus. By acting on the fiist two components of the hypothalamic axis, the
secietion of CRB anu ACTB gets uecieaseu. Eventually, these changes cause the
coitisol level in the human bouy to also ueciease. + iepiesents secietion of the
associateu hoimone anu - iepiesents a uiminishment in secietion of the associateu
hoimone.
14



%-9=3# BA This figuie outlines the vaiious uiffeient symptoms that can be associateu
with Cushing's synuiome. The iange anu geneiality of many of these symptoms
make it haiu to uiagnose Cushing's synuiome.
1S

%-9=3# DA The piesence of a tumoi in the anteiioi pituitaiy, also known as a
pituitaiy auenoma, make up foi 7u-8u% of enuogenous Cushing's synuiome.
6

Results of Low-
Bose Test
Results of Bigh-
Bose Test
ACTB Level Likely Cause of
Cushing's
Synuiome
No suppiession -- Low Causeu by Auienal
Tumoi
No Suppiession No Suppiession Bigh Relateu to Ectopic
Tumoi
No suppiession Noimal
suppiession
-- Causeu by a
Pituitaiy Tumoi

!('5# @A The iesults of low-uose anu high-uose uexamethasone suppiession tests
can be combineu with the iesults of an ACTB level test in oiuei to ueteimine the
likely cause of Cushing's synuiome in a patient.
11

%-9=3# EA When a patient is suspecteu of Cushing's synuiome, the fiist test
auministeieu is the 24-houi uiine fiee coitisol test. Bepenuing on how much the
coitisol level is elevateu, a uiagnosis of Cushing's uisease can be maue oi if it is
miluly elevateu then fuithei tests can be uone to ueteimine if a uiagnosis of
Cushing's synuiome can be maue. In oiuei to ueteimine wheie the Cushing's
synuiome stems fiom, many othei tests can be auministeieu, such as
uexamethasone suppiession test, test to ueteimine ACTB levels, CRB-stimulation
test anu many otheis. These tests can not only uiagnose Cushing's synuiome but
also ueteimine wheie the pathology lies.
16

C#1#3#,)#.
@A Bickeison, Sally S., anu Naigaiet E. Kemeny. "Acute stiessois anu coitisol
iesponses: a theoietical integiation anu synthesis of laboiatoiy ieseaich."
!"#$%&'&()$*' ,-''./)0 1Su.S (2uu4): SSS.
BA Binan, Timothy u., anu Lucinua v. Scott. "Anatomy of melancholia: focus on
hypothalamic-pituitaiy-auienal axis oveiactivity anu the iole of
vasopiessin." 1&-20*' &3 *0*/&4# 2u7.S (2uuS): 2S9-264.
DA Yehuua, Rachel, ./ *'5 "Alteiations in coitisol negative feeuback inhibition as
examineu using the ACTB iesponse to coitisol auministiation in PTSB."
!"#$%&0.-2&.06&$2)0&'&(# S1.4 (2uu6): 447-4S1.
EA Reincke, Naitin. "Subclinical Cushing's synuiome." 706&$2)0&'&(# *06
4./*,&')"4 $')0)$" &3 8&2/% 94.2)$* 29.1 (2uuu): 4S-S6.
FA Lageiquist, Lynn u., ./ *'5 "Cushing's uisease with cuie by iesection of a
pituitaiy auenoma: Eviuence against a piimaiy hypothalamic uefect." :%.
94.2)$*0 ;&-20*' &3 4.6)$)0. S7.S (1974): 826-8Su.
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pathological featuies suggesting auienocoitical tumoi." :%. 1&-20*' &3
<')0)$*' 706&$2)0&'&(# = >./*,&')"4 24.1u (1964): 947-9SS.
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auveise piognostic factoi in patients who uie eaily with small cell lung
cancei." <*0$.2 69.1 (1992): 66-71.
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excietion anu salivaiy coitisol levels sampleu fiom awakening to beutime in
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(1984): SuS-S1S.
@@A Fang, victoi S., ./ *'5 "Plasma ACTB anu coitisol levels in uepiesseu patients:
ielation to uexamethasone suppiession test." A)3. B$).0$." 29.9 (1981): 9S1-
9S8.
@BA Nieman, L. K., ./ *'5 "The ovine coiticotiopin-ieleasing hoimone (CRB)
stimulation test is supeiioi to the human CRB stimulation test foi the
uiagnosis of Cushing's uisease." :%. 1&-20*' &3 <')0)$*' 706&$2)0&'&(# =
>./*,&')"4 69.1 (1989): 16S-169.
@DA Yaneva, Naiia, ./ *'5 "Niunight salivaiy coitisol foi the initial uiagnosis of
Cushing's synuiome of vaiious causes." 1&-20*' &3 <')0)$*' 706&$2)0&'&(# =
>./*,&')"4 89.7 (2uu4): SS4S-SSS1.
@EA Tsigos, Constantine, anu ueoige P. Chiousos. "Bypothalamic-pituitaiy-
auienal axis, neuioenuociine factois anu stiess." 1&-20*' &3 @"#$%&"&4*/)$
2.".*2$% SS.4 (2uu2): 86S-871.
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