Cushing's Syndrome

 Cushing’s syndrome (also called hypercortisolism) is a hormonal

disorder caused by prolonged exposure of the body’s tissues to
high levels of cortisol.
 Most commonly affects adults aged 20 to 50, obese, type 2
diabetes, along with poorly controlled blood glucose and high
blood pressure, have an increased risk of developing the
disorder.
 Normally, the production of cortisol follows a chain of events.
First, the hypothalamus, sends corticotropin-releasing
hormone (CRH) to the pituitary gland. CRH causes the
pituitary to secrete adrenocorticotropin hormone (ACTH),
which stimulates the adrenal glands. When the adrenals,
receive the ACTH, they respond by releasing cortisol into the
bloodstream.
 Cortisol performs vital tasks in the body including
i. Helping maintain blood pressure and cardiovascular
function.
ii. Reducing the immune system’s inflammatory response.
iii. Balancing the effects of insulin, which breaks down glucose
for energy.
iv. Regulating the metabolism of proteins, carbohydrates and
fats.
Signs and symptoms of Cushing’s syndrome vary.
i. Most people with the disorder have upper body obesity, a
rounded face, increased fat around the neck and relatively
slender arms and legs.
ii. Children tend to be obese with slowed growth rates.
iii. Skin becomes fragile and thin, bruises easily and heals poorly.
iv. Purple or pink stretch marks may appear on the abdomen,
thighs, buttocks, arms and breasts.
v. The bones are weakened and routine activities such as
bending, lifting or rising from a chair may lead to backaches
and rib or spinal column fractures.
vi. Women with Cushing’s syndrome usually have excess hair
growth on their face, neck, chest, abdomen and thighs.
vii. Menstrual periods may become irregular or stop. Men may
have decreased fertility with diminished or absent desire for
sex and sometimes, erectile dysfunction.
Other common signs and symptoms include:
i. Severe fatigue.
ii. Weak muscles.
iii. High blood pressure.
iv. High blood glucose.
v. Increased thirst and urination.
vi. Irritability, anxiety or depression.
vii. A fatty hump between the shoulders.
Causes:
1. Women in their last 3 months of pregnancy and highly trained
athletes normally have high levels of cortsol. People suffering
from depression, alcoholism, malnutrition or panic disorders also
have increased cortisol levels.
2. Pituitary adenomas.
3. Ectopic ACTH syndrome: Some benign or cancerous tumors
that arise outside the pituitary can produce ACTH. This
condition is known as ectopic ACTH syndrome. Lung tumors,
carcinoid tumors, thymomas, pancreatic Islet’s cell tumors and
medullary carcinomas of the thyroid.
4. Adrenal tumors: Adrenocortical carcinomas are also the
common cause. Adrenal tumors are four to five times more
common in women than men.
5. Familial Cushing’s syndrome.
Tests to Diagnose Cushing’s Syndrome
 24-hour urinary free cortisol level: In this test, a person’s
urine is collected several times over a 24-hour period and tested
for cortisol. Levels higher than 50 to 100 micrograms a day for
an adult suggest Cushing’s syndrome.
 Midnight plasma cortisol and late-night salivary
cortisol measurements: Cortisol production is normally
suppressed at night but in Cushing’s syndrome, this
suppression doesn’t occur. If the cortisol level is more than 50
nmol/L, Cushing’s syndrome is suspected. The test generally
requires a 48-hour hospital stay to avoid falsely elevated cortisol
levels due to stress.
 However, a late-night or bedtime saliva sample can be obtained.
Low-dose dexamethasone suppression test (LDDST)
In the LDDST, a person is given a low dose of
dexamethasone, by mouth every 6 hours for 2 days. Urine is
collected before dexamethasone is administered and several
times on each day of the test. (A modified LDDST uses a onetime
overnight dose).
Cortisol and other glucocorticoids signal the pituitary to
release less ACTH, so the normal response after taking
dexamethasone is a drop in blood and urine cortisol levels. If
cortisol levels do not drop, Cushing’s syndrome is suspected.
The LDDST may not show a drop in cortisol levels in people
with depression, alcoholism, high estrogen levels, acute
illness or stress, that falsely indicating Cushing’s syndrome.
On the other hand, drugs such as phenytoin and
phenobarbital may cause cortisol levels to drop.
 Dexamethasone-CRH test
Some people have high cortisol levels but do not develop the
progressive effects of Cushing’s syndrome and may have
pseudo-Cushing’s syndrome. (A condition sometimes found in
people who have depression or anxiety disorders, drink excess
alcohol, have poorly controlled diabetes or are severely obese.)
Pseudo-Cushing’s does not have the same long-term effects
on health as Cushing’s syndrome and does not require
treatment directed at the endocrine glands.
The dexamethasone-CRH test rapidly distinguishes pseudo-
Cushing’s from mild cases of Cushing’s. This test combines
the LDDST and a CRH stimulation test.
Tests to Find the Cause of Cushing’s Syndrome
 CRH stimulation test: In the CRH stimulation test, an
injection of CRH causes the pituitary to secrete ACTH. Huge
elevations of cortisol during this test suggest Cushing’s
syndrome. The CRH test, without pretreatment with
dexamethasone, helps separate people with pituitary adenomas
from those with ectopic ACTH syndrome or adrenal tumors. As
a result of the CRH injection, people with pituitary adenomas
usually experience a rise in blood levels of ACTH and cortisol
because CRH acts directly on the pituitary. This response is
rarely seen in people with ectopic ACTH syndrome and
practically never in those with adrenal tumors.
 High-dose dexamethasone suppression test (HDDST).
 Petrosal sinus sampling.
 Radiologic imaging: Most common are the CT scan and MRI.
Treatment
Treatment depends on the specific reason for excess cortisol and
may include surgery, radiation, chemotherapy or the use of
cortisol-inhibiting drugs.
If the cause is long-term use of glucocorticoids to treat another
disorder, gradually reduce the dosage to the lowest dose adequate
for control of that disorder. Once control is established for the
cause, the daily dose of glucocorticoid hormones may be doubled
and given on alternate days to lessen side effects. In some cases,
noncorticosteroid drugs can be prescribed.
Agents that inhibit steroidogenesis, such as mitotane, ketoconazole,
metyrapone, aminoglutethimide, trilostane and etomidate, have
been used to cause medical adrenalectomy. Thus, medical
treatment should be initiated cautiously. Efficacy of these medical
interventions can be assessed with serial measurements of 24-hour
urinary free cortisol. Patients receiving these medications may
require glucocorticoid replacement to avoid adrenal insufficiency.
 Radiotherapy to the pituitary gland can destroy the pituitary
adenoma.
 Surgery to remove both adrenal glands is an option. This stops
producing any cortisol (and other hormones) from adrenal
glands, so it will need lifelong replacement therapy of
hormones.
Adrenal Insufficiency
Adrenal insufficiency is an endocrine disorder that occurs
when the adrenal glands do not produce enough of
hormones. Adrenal insufficiency can be primary or
secondary.
Primary adrenal insufficiency, also called Addison’s disease,
occurs when the adrenal glands are damaged and cannot
produce enough hormones, esp. cortisol and aldosterone.
Secondary adrenal insufficiency occurs when the pituitary
gland fails to produce enough adrenocorticotropin (ACTH). If
ACTH output is too low, cortisol production drops.
Eventually, the adrenal glands can shrink due to lack of
ACTH stimulation. Secondary adrenal insufficiency is much
more common than Addison’s disease.
Symptoms of Adrenal Insufficiency
The symptoms of adrenal insufficiency usually begin gradually.
i. Chronic, worsening fatigue.
ii. Muscle weakness.
iii. Loss of appetite, weight loss.
iv. Nausea, vomiting, diarrhea.
v. Low blood pressure (usually orthostatic), causing dizziness or
fainting.
vi. Irritability, depression, headache, sweating.
vii. A craving for salty foods due to salt loss.
viii. Hypoglycemia.
ix. In women, irregular or absent menstrual periods.
x. Hyperpigmentation can occur in Addison’s disease but not in
secondary adrenal insufficiency. This darkening is most
visible on skin folds, pressure points such as the elbows,
knees, knuckle, and toes; lips and mucous membranes.
Addisonian Crisis
 Sudden, severe worsening of symptoms is called an
Addisonian crisis or acute adrenal insufficiency. In most
cases, symptoms of adrenal insufficiency become serious
enough that people seek medical treatment before a crisis
occurs. However, sometimes symptoms first appear during an
Addisonian crisis.
 Symptoms include:
i. Sudden, penetrating pain in the lower back, abdomen or
legs.
ii. Severe vomiting and diarrhea.
iii. Dehydration.
iv. Low blood pressure.
v. Loss of consciousness.
vi. If not treated, an Addisonian crisis can be fatal.
Causes of Addison’s Disease
1. Autoimmune disorders.
2. Genetic defects including abnormal adrenal gland
development.
3. Tuberculosis: Tuberculosis can destroy the adrenal glands,
accounts for less than 20%.
4. Chronic infection, mainly fungal infections.
5. Cancer cells spreading from other parts of the body to the
adrenal glands
6. Amyloidosis, (causes abnormal protein buildup in, and damage to,
various organs).
7. Surgical removal of the adrenal glands.
8. AIDS-associated infections.
9. Bleeding into the adrenal glands.
Causes of Secondary Adrenal Insufficiency
1. It occurs because of lack of ACTH. Without ACTH,
production of cortisol drops. Aldosterone production is not
usually affected.
2. Taking glucocorticoid hormone for a long time and stops
taking the medication abruptly.
3. Surgical removal.
4. Less commonly, adrenal insufficiency occurs when the
pituitary gland either decreases in size or stops producing
ACTH. Causes are—
i. Tumors or infections of the area.
ii. Loss of blood flow to the pituitary.
iii. Radiation for the treatment of pituitary tumors.
iv. Surgical removal of parts of the hypothalamus or pituitary
gland.
Diagnosis of Adrenal Insufficiency
In its early stages, adrenal insufficiency can be difficult to
diagnose. A review of a patient’s medical history and symptoms
may lead to suspect Addison’s disease.
A diagnosis of adrenal insufficiency is confirmed through
laboratory tests. Radiologic exams of the adrenal and pituitary
glands also are useful in helping to establish the cause.

ACTH Stimulation Test

In this test, blood cortisol, urine cortisol or both are measured
before and after a synthetic form of ACTH is given by injection.
The normal response after an ACTH injection is a rise in blood
and urine cortisol levels. People with Addison’s disease or long-
standing secondary adrenal insufficiency have little or no
increase in cortisol levels.
CRH Stimulation Test
When the response to the ACTH test is abnormal, a CRH
stimulation test can help determine the cause of adrenal
insufficiency. In this test, synthetic CRH is injected
intravenously and blood cortisol is measured before and 30,
60, 90 and 120 minutes after the injection.
People with Addison’s disease respond by producing high
levels of ACTH but no cortisol. People with secondary
adrenal insufficiency have absent or delayed ACTH
responses.
CRH will not stimulate ACTH secretion if the pituitary is
damaged, so an absent ACTH response points to the pituitary
as the cause. A delayed ACTH response points to the
hypothalamus as the cause.
Other Tests
Once a diagnosis of Addison’s disease is made, radiologic
studies such as an X-ray or an ultrasound of the abdomen
may be taken to see if the adrenals have any signs of calcium
deposits. Calcium deposits may indicate bleeding in the
adrenal gland or TB for which a tuberculin skin test also may
be used.
Blood tests can detect antibodies associated with
autoimmune Addison’s disease.
If secondary adrenal insufficiency is diagnosed, CT & MRI
can be done.
Treatment of Adrenal Insufficiency
 Cortisol is replaced with a synthetic glucocorticoid such as
hydrocortisone, prednisone or dexamethasone, taken orally
once to three times each day. If Aldosterone is also deficient, it
is replaced with oral doses of a mineralocorticoid, called
fludrocortisone acetate, taken once or twice a day.
 During an Addisonian crisis, low blood pressure, low blood
glucose and high levels of potassium can be life threatening.
Standard therapy involves intravenous injections of
glucocorticoids and large volumes of intravenous saline
solution with dextrose. This treatment usually brings rapid
improvement.
Special problems with adrenal insufficiency:
Surgery
Because cortisol is a stress hormone, people with chronic
adrenal insufficiency who need any type of surgery requiring
general anesthesia must be treated with intravenous
glucocorticoids and saline. Intravenous treatment begins
before surgery and continues until the patient is fully awake
after surgery and able to take medication by mouth.
In addition, people who are not currently taking
glucocorticoids but who have taken long-term glucocorticoids
in the past year, they may have sufficient ACTH for normal
events, but they need intravenous treatment for the stress of
surgery.
Illness
During illness, oral dosing of glucocorticoid may be adjusted to
increase the normal response. Significant fever or injury may
require triple oral dosing. Once recovery from the stress event is
achieved, dosing is then returned to maintenance levels.
Immediate medical attention is needed if severe infections,
vomiting or diarrhea occur. These conditions can precipitate an
Addisonian crisis.
Pregnancy
Women with adrenal insufficiency who become pregnant are
treated with standard replacement therapy. If nausea and
vomiting in early pregnancy interfere with taking medication by
mouth, injections of the hormone may be necessary. During
delivery, treatment is similar to that of people needing surgery.
Following delivery, the dose is gradually tapered and the usual
maintenance doses of oral hydrocortisone and fludrocortisone
acetate are reached about 10 days after childbirth.
Medical Care
In patients in acute adrenal crisis, IV access should be
established urgently and an infusion of isotonic sodium
chloride solution should be begun to restore volume deficit
and correct hypotension.
Some patients may require glucose supplementation.
The precipitating cause should be sought and corrected
where possible.
In stress situations, the normal adrenal gland output of
cortisol is approximately 250—300 mg in 24 hours. This
amount of hydrocortisone in soluble form (hydrocortisone
sodium succinate or phosphate) should be given, preferably by
continuous infusion.
 Administer 100 mg of hydrocortisone in 100 cc of isotonic
sodium chloride solution by continuous IV infusion at a rate of
10—12 cc/hours. Infusion may be initiated with 100 mg of
hydrocortisone as an IV bolus.
 An alternative method of hydrocortisone administration is 100
mg as an IV bolus every 6—8 hours.
 Clinical improvement, especially blood pressure response,
should be evident within 4—6 hours of hydrocortisone infusion.
Otherwise, the diagnosis of adrenal insufficiency would be
questionable. After 2—3 days, the stress hydrocortisone dose
should be reduced to 100—150 mg, infused over a 24-hour
period, irrespective of the patient's clinical status.
Hyperparathyroidism
If the parathyroid glands secrete too much hormone, as happens
in primary hyperparathyroidism, the balance is disrupted, blood
calcium rises.
Causes includes adenoma, hyperplasia and very rarely cancer of
a parathyroid gland.
This excess PTH triggers the release of too much calcium into
the bloodstream. The bones may lose calcium and too much
calcium may be absorbed from food. The levels of calcium may
increase in the urine, causing kidney stones. PTH also lowers
blood phosphorus levels by increasing excretion of phosphorus
in the urine.
Symptoms of Hyperparathyroidism
i. Often people with primary hyperparathyroidism either have no
symptoms or only have mild symptoms.
ii. Tiredness, weak muscles, depression.
iii. Nausea, vomiting, constipation.
iv. Abdominal pain.
v. Feeling very thirsty and passing urine frequently.
vi. High blood pressure.
vii. In extreme cases, if left untreated, a high calcium level can lead
to confusion, loss of consciousness, heart rhythm disturbances.
viii. If secondary hyperparathyroidism, calcium level is not high but
low, so may not develop all of the symptoms described above.
However, can develop bone complications and the symptoms.