Iqra Mumal

14/04/14

Discuss the feedback mechanisms controlling the secretion of cortisol. What laboratory
tests are used in the evaluation of suspected Cushings syndrome?

1. Introduction
1. a. Cortisol and Its Regulation
Cortisol, also known as the stress hormone is a steroid hormone produced by the
zona fasciculata of the adrenal cortex . The release of cortisol can be triggered by a variety
of stresses. This includes physical stress such as infection, de-hydration or thermal
exposure but it can also be physiological stresses such as fear and anticipation. Its function
is to regulate metabolism and the bodys reaction to stress and inflammation, this is
achieved by increasing blood sugar, suppressing the immune system and aiding in
metabolism.
Cortisol secretion is controlled by the hypothalamic pituitary adrenal axis (HPA)
(see fig. 1). Corticotropin releasing hormone (CRH), secreted by the hypothalamus, is
released into the hypophyseal portal blood vessels. CRH then acts on the anterior pituitary
and causes the release of ACTH (adreno-corticotropic hormone). ACTH then stimulates the
adrenal gland, which produces and secretes cortisol. After synthesis, cortisol diffuses into
blood plasma where it is absorbed by different tissues and implements its regulatory
functions as a hormone. Eventually, the liver clears away the cortisol in the blood plasma.
1.b. Feedback Mechanism of Cortisol
Cortisol, like many of the other hormones regulated by the hypothalamus, regulates
its own secretion by negative feedback inhibition. Cortisol is able to do this by binding to
the receptor on cells in the hypothalamus and anterior pituitary and is thus able to inhibit
the secretion of the tropic hormones, CRH and ACTH. Since cortisol is produced by the
action of both CRH and ACTH, a reduction in those will inevitable lead to a reduction in
cortisol levels. This allows the body to remain in a hormonal homeostasis. This is an
incredibly important system in our body and any imbalances in the degree of hormone
secretion can lead to a variety of disorders. These disorders can results from both
hypercortisolism (hypersecretion of cortisol) or adrenal insufficiency, which is
hyposecretion of cortisol. Hyposecretion of cortisol can lead to Addisons disease while
hypersecretion of cortisol leads to cushings syndrome.
2. Cushings syndrome and Causes
Cushings syndrome develops as a result of high cortisol levels in the body for a long
time. Symptoms have been known to develop gradually so the diagnosis may not be clear
for some time. There is a wide range of symptoms that characterize a patient with cushings
syndrome and because of some of them are very general, it can be hard to diagnose
cushings syndrome (see fig. 2). Symptoms include obesity, characterized by fat around the
main body area, facial puffiness, diabetes, high blood pressure, muscle weakness, tiredness,
aches and pains, mood swings, lack of sex drive, osteoporosis, excess thirst and increased
susceptibility to infections.
There are four main causes which can lead to the overproduction of cortisol. The most
common cause is a pituitary adenoma, which occurs about 70-80% of the time. This is a
benign or non-cancerous tumor of the anterior pituitary, which result in too much ACTH
and leads to the production of high volumes of cortisol (see fig. 3). This form of cushings
syndrome is known as cushings disease and is characterized by both ACTH and cortisol
levels being too high.
Another tumor that can lead to the overproduction of cortisol is a tumor in the adrenal
gland, which occurs about 10-20% of the time. This tumor can be either benign, such as
adrenal adenoma or micronodular hyperplasia, or malignant, such as adrenal carcinoma.
When this is the cause of cushings syndrome, increased negative feedback inhibition has
the effect of decreasing the secretion of tropic hormone. However, cortisol will remain high
as negative feedback inhibition will not have an effect on an adrenal gland tumor.
Another cause of cushings syndrome can be ectopic or paraneoplastic cushings
syndrome. This refers to tumors that are present outside the normal pituitary-adrenal
system that produce ACTH, for example, small cell lung carcinoma. Finally, the most
common type is iatrogenic cushings syndrome, which usually stems from treatment with
corticosteroid for a long time.
3. Screening Test for Cushings syndrome
There are various reasons why the body can produce too much cortisol and there
are complex tests that have been generated to find the root cause of excess cortisol. Due to
the fact that the level of cortisol varies depending on the time of the day, a simple blood test
is not enough to diagnose Cushings syndrome.
The first thing is to determine whether there is an excess of cortisol in the patients
body (see fig. 4). The first test that is generally administered is the 24-hour urine free
cortisol level test, which is a test to measure the amount of cortisol that is passed in urine.
The way this test works is that the patient needs to collect all the urine that is passed over
24 hours into a plastic container, which is then sent to a laboratory to measure the cortisol
levels. This allows the healthcare professionals to determine if a patients cortisol levels are
abnormal.
In addition, an alternative test that can be administered is a blood test that can be
arranged after the patient takes a medicine called dexamethasone. This drug suppresses the
amount of cortisol the body is supposed to make as dexamethasone is a human made
steroid that is similar to cortisol. Normally, it should reduce the level of ACTH and
subsequently cortisol. Thus, if the amount of cortisol in the blood is still high after taking
this medicine then a diagnosis of cushings syndrome can be confirmed. There are two
different kinds of dexamethasone screening tests that are administered to patients
suspected of cushings syndrome. Both of these dexamethasone suppression tests can be
done either overnight or a standard (3-day) way.
The first is a low dose dexamethasone suppression test. For the overnight low dose
method, 1mg of dexamethasone is administered at 11 pm. The next day, the patients blood
cortisol level is measured at 8 am. The standard low dose method is different in that the
cortisol level is measured in urine which is collected over 3 days. The urine is stored in 24-
hour collection containers. On the first day, a urine sample is taken and then starting the
second day, 0.5 mg of dexamethasone is administered every 6 hours for 48 hours with urine
collected every day. The second test is a high dose dexamethasone suppression test. The
overnight high dose method involves measuring the baseline cortisol level around 7-8 am
on day 1 in the morning. Then, 8mg dexamethasone is administered at 11pm the same day.
Then blood cortisol is measured at around 7-8 am the next day. For the standard high-dose
test, urine is collected for three days every 24 hours. On day 2, 2 mg of dexamethasone is
administered every 6 hours for 48 hours, similar to the low dose standard dexamethasone
suppression. The low-dose test is administered to help determine whether the body is
producing too much cortisol. On the other hand, the high-dose test is administered to
determine if the route of the problem is in the pituitary gland or cushings disease.
There is another set of tests relating to cushings syndrome that can help us
distinguish what type of cushings syndrome different patients have. Different results from
the dexamethasone suppression test combined with a blood ACTH test can help determine
where cushings syndrome stems from. If there is no change in the ACTH level after the
administration of the low-dose test and if the ACTH level is high using the ACTH blood test,
then that is indicative of cushings syndrome caused by an adrenal tumor. If there is no
change in cortisol levels after both a low and a high dose test and the ACTH levels are high
then the cushings syndrome is a result of an ectopic ACTH-producing tumor. Finally, if
there is no change in cortisol levels through a low-dose test but normal suppression
through a high-dose test, then it is most likely cushings syndrome caused by a pituitary
tumor.
In order to distinguish between ectopic cushings syndrome and cushings disease, a
CRH-stimulation test can be performed. Patients with cushings disease will respond to the
CRH stimulation with an increase in ACTH and cortisol but patients with ectopic cushings
syndrome wont respond. The dexamethasone suppression test can be combined with the
CRH stimulation test to differentiate cushings syndrome with pseudo-cushings syndrome.
Lastly, a night-time blood test or saliva test can be administered to measure the
level of cortisol. Since the secretion of cortisol follows a circadian rhythym, cortisol peaks in
the morning and reaches its lowest point at night time. Patients with cushings syndrome do
not a show a change in cortisol levels throughout the day and thus, administering a blood or
saliva test at night time can help confirm the diagnosis of cushings syndrome.
4. Conclusion
The delicate balance in homeostasis that is regulated cortisol can lead to detrminental
consequenses if it goes awry. The negative feedback inhibition that cortisol provides to both
the anterior pituitary and adrenal gland allows a decrease in the production of cortisol and
allows One of the major examples is cushings syndrome, which, if left untreated cane be
fatal.












Figures
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