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 includingi. 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 testSome 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 SyndromeCRH 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 InsufficiencyAdrenal 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 InsufficiencyThe 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 CrisisSudden, 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 Disease1. 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 glands6. 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 InsufficiencyIn 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 TestIn 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 TestWhen 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 TestsOnce 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:

SurgeryBecause 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.

IllnessDuring 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.

PregnancyWomen 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 CareIn 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.

HyperparathyroidismIf 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 Hyperparathyroidismi. 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.