CUSHING’S SYNDROME

DEFINITION

Cushing’s disease is a condition in which the pituitary gland releases too

much adrenocorticotropic hormone (ATCH). ACTH stimulates the
production and release of cortisol, a stress hormone. Too much ACTH
means too much cortisol. The pituitary gland is an organ of the endocrine
system.

It is the hyperactivity of the adrenal cortex that results in excessive

secretion of glucocorticoids (cortisol), mineralocorticoids (aldosterone) and
androgen (male sex hormone).

Cortisol is normally released during stressful situations. It controls the

body's use of carbohydrates, fats, and proteins and also helps reduce the
immune system's response to swelling (inflammation).

It may be caused by taking too much corticosteroid medications, such as

prednisone and prednisolone. These drugs are used to treat conditions
such as asthma and rheumatoid arthritis.

This pathology was described by Harvey Cushing in 1932. The syndrome is

also called Itsenko-Cushing syndrome, hyperadrenocorticism or
hypercorticism)

Cushing's syndrome is not confined to humans and is also a relatively

common condition in domestic dogs and horses.
Harvey Williams Cushing, M.D.

(April 8, 1869 - October 7, 1939) was an American neurosurgeon and a

pioneer of brain surgery, and the first to describeCushing's syndrome. He is
often called the "father of modern neurosurgery".

Cushing's Syndrome was also the first autoimmune disease identified in

humans

The incidence of pituitary tumors may be relatively high, as much as one in

five people.

CAUSE
Exogenous vs. endogenous

Hormones that come from outside the body are called exogenous;
hormones that come from within the body are called endogenous.

The most common cause of Cushing's syndrome

is exogenous administration of glucocorticoids prescribed by a health care
practitioner to treat other diseases (called iatrogenic Cushing's syndrome).

This can be an effect of steroid treatment of a variety of disorders such

as asthma and rheumatoid arthritis, or in immunosuppression after an
organ transplant. Administration of synthetic ACTH is also possible, but
ACTH is less often prescribed due to cost and lesser utility.

Although rare, Cushing's syndrome can also be due to the use of

medroxyprogesterone.

Endogenous Cushing's syndrome results from some derangement of the

body's own system of secreting cortisol. Normally, ACTH is released from
the pituitary gland when necessary to stimulate the release of cortisol from
the adrenal glands.

 In pituitary Cushing's, a benign pituitary adenoma secretes ACTH.

This is also known as Cushing's disease and is responsible for 70% of
endogenous Cushing's syndrome.

 In adrenal Cushing's, excess cortisol is produced by adrenal gland

tumors, hyperplastic adrenal glands, or adrenal glands with nodular
adrenal hyperplasia.

 Finally, tumors outside the normal pituitary-adrenal system can

produce ACTH that affects the adrenal glands. This final etiology is
called ectopic or paraneoplastic Cushing's syndrome and is seen in
diseases like small cell lung cancer.

PATHOPHYSIOLOGY

Cortisol excess result in anti-inflammatory effect and excessive catabolism

of protein and peripheral fat to support hepatic glucose production.

The mechanism may be ACTH- dependent, in which elevated plasma

ACTH level stimulate the adrenal cortex to produce excess cortisol, or
ACTH- independent, in which excess cortisol is produced by the adrenal
cortex or exogenously administered. This suppresses the hypothalamic-
pituitary-adrenal axis, also present in ectopic ACTH- secreting tumors.
SIGNS AND SYMPTOMS

 Glucocorticiod

 Mineralocorticoid

• Mood change

• Skinny arms and leg • Fluid volume

• Thin skin • Hypertension

• Muscle weakness • Hypokalemia

• Poor wound healing • Sodium imbalance

• Bruising • Muscle weakness

• Ketonuria

• Buffalo hump  Androgens

• Truncal obesity

• Voice deepening
• Pink/purple stretch mark on
the breast, abdomen, thighs • Hirsutism (female)

• Risk for infection • Menstrual irregularities

• Hyper glycemia • Thinning hair

• Glycosuria • Decreased libido

• Osteoporosis
NURSING DIAGNOSIS

• Risk for injury related to weakness

• Risk for infection related to altered protein metabolism and inflammatory

response

• Self-care deficit related to weakness, fatigue, muscle wasting, and altered

sleep patterns

• Impaired skin integrity related to edema, impaired healing, and thin and
fragile skin

• Disturbed body image related to altered physical appearance, impaired

sexual functioning, and decreased activity level

• Disturbed thought process related to mood swings, irritability, and

depression
NURSING INTERVENTION

• Decreasing Risk of injury

-establishing a protective environment
-Foods high in protein, calcium and vitamin D are
recommended

• Decreasing Risk of Infection

-patient should avoid unnecessary exposure to others w/
infection

• Preparing the Patient for Surgery

-patient is prepared for adrenalectomy,if indicated, and the
postoperative course

-transspenoidal hypophysectomy
• Encouraging Rest and Activity
-Encourage moderate activity
-help patient to plan or make schedule for his/her rest
periods throughout the day

• Promoting Skin Integrity

-Meticulous skin care
-use of adhesive tapes is avoided
-encourage and assists patient to change position frequently
• Improving Body Image
-provide discussion of the effect the changes that had on
his/her self-concept and relationship with others.

• Improving Thought Processes

-Explanations to the patient and family members about the
cause of emotional instability are important
-Psychotic behavior may occur in few patients and should be
reported.
MEDICAL MANAGEMENT

• Agents that inhibit steroidogenesis, such as mitotane, ketoconazole,

metyrapone, aminoglutethimide, trilostane, and etomidate, have been
used to cause medical adrenalectomy. These medications are used
rarely and often are toxic at the doses required to reduce cortisol
secretion. Thus, medical treatment should be initiated cautiously and,
ideally, in conjunction with a specialist. 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. Patients should be
counseled on the signs and symptoms of adrenal insufficiency when
starting these drugs.

• Metyrapone and trilostane are agents that competitively inhibit a

single steroidogenic enzyme. Ketoconazole and aminoglutethimide
act at several sites. In ACTH-dependent Cushing syndrome, ACTH
secretion continues to stimulate steroidogenesis, which counters the
actions of these medications.

• Ketoconazole is probably the most popular and effective of these

agents for long-term use and usually is the agent of choice. It acts on
 several of the P450 enzymes, including the first step in cortisol
synthesis, cholesterol side-chain cleavage, and conversion of 11-
deoxycortisol to cortisol.

o A daily dose of 600-800 mg often decreases cortisol production.

If this agent is ineffective at controlling hypercortisolism, the
dose may be maintained while another steroid enzyme inhibitor,
typically metyrapone, is initiated.
o Adverse effects of ketoconazole include headache, sedation,
nausea, irregular menses, decreased libido, impotence,
gynecomastia, and elevated liver function tests. The drug is
contraindicated during pregnancy.
o Ketoconazole is less effective in patients on H2 blockers or
proton-pump inhibitors because gastric acidity is required for
metabolism.

• Metyrapone blocks 11-beta-hydroxylase activity, the final step in

cortisol synthesis. Therapy is begun at 1 g/d divided into 4 doses and
increased to a maximum dose of 4.5 g/d. Adverse effects are from
increases in androgen and mineralocorticoid precursors, including
hypertension, acne, and hirsutism.
• Aminoglutethimide is an anticonvulsant agent that blocks cholesterol
side-chain cleavage to pregnenolone. It is a relatively weak adrenal
enzyme inhibitor at doses that patients can tolerate.
Aminoglutethimide is typically initiated at 250 mg twice daily, and
doses of 1-2 g daily are often used.

o Adverse effects of aminoglutethimide include somnolence,

headache, a generalized pruritic rash, hypothyroidism, and
goiter.
o In rare cases, it may cause bone marrow suppression.
o Aminoglutethimide increases the metabolism of
dexamethasone but not cortisol.

• Mitotane is an adrenolytic agent that acts by inhibiting 11-beta

hydroxylase and cholesterol side-chain cleavage enzymes. This drug
also leads to mitochondrial destruction and necrosis of adrenocortical
cells in the zona fasciculata and reticularis. For this reason, it is used
in treatment of adrenal cancer at doses of 2-4 g daily. Its survival
benefit is unclear. It can be used in addition to radiation therapy for
treatment of Cushing disease and in combination with metyrapone or
aminoglutethimide for treatment of ectopic ACTH secretion.
o Unfortunately, mitotane is expensive, and its utility is limited by
adverse gastrointestinal and neurologic effects, including
nausea, diarrhea, dizziness, and ataxia. Other adverse effects
include rash, arthralgias, and leukopenia.
o It is taken up by adipose tissues and persists in the circulation
long after discontinuation.
o It is a potential teratogen and can cause abortion; therefore, it is
relatively contraindicated in women interested in remaining
fertile.
SURGICAL MANAGEMENT

When Cushing's syndrome results from an ACTH-producing tumor of the

pituitary gland (Cushing's disease), treatment may include surgery,
radiation, or medication to lower cortisol levels.

Surgery

Surgical removal of a small, well-defined pituitary adenoma is called

transsphenoidal adenomectomy. The pituitary is located at the base of the
brain. It is possible to access this area through the gums above the upper
front teeth or the nose.

Using special instruments, the surgeon makes an incision in one of these

areas. The incision is extended through the sphenoid sinus, allowing the
surgeon to see and remove the adenoma with an endoscope (a thin,
lighted tube with a camera).

This type of surgery permanently cures Cushing's syndrome in 60 to 70

percent of people.

Sometimes a tumor cannot be identified; in these cases, half of the pituitary

gland may be removed (hemihypophysectomy) or 85 to 90 percent of the
pituitary gland may be removed (subtotal hypophysectomy) to be certain
that the tumor has been removed.

Surgical removal of half or more of the pituitary gland can reduce pituitary
function and interfere with ovulation (in women) and sperm production (in
men). Lifelong hormone replacement is often necessary after surgery.
Radiation

Radiation can be a useful treatment when pituitary tumors cannot be

completely removed by surgery. Radiation of pituitary tumors reduces
cortisol levels in about half of adults and most children with Cushing's
disease.

Because this cortisol-lowering effect takes time (3 to 12 months),

medications that lower adrenal cortisol production may be given while
waiting for the effects of radiation.

These medications include ketoconazole, metyrapone, and

aminoglutethimide.

Adrenalectomy

Surgical removal of the adrenal glands (adrenalectomy) is a final measure

that may be recommended if other treatments are not successful.

Adrenalectomy stops excess cortisol production but requires that you

begin lifelong daily glucocorticoid and mineralocorticoid replacement
therapy.
MEDICATION

Metyrapone (Metopirone)

- blocks cortisol synthesis by inhibiting steroid 11β-hydroxylase.

- Metyrapone 30mg/kg, maximum dose 3000 mg, is administered at

midnight usually with a snack.

- Metyrapone is used to test if your pituitary gland is sending the proper

Ketoconazole(Nizoral)

- probably the most popular and effective of these agents for long-term use
and usually is the agent of choice.

-suppression of glucocorticoid synthesis

- It is usually taken once a day.

- Adverse effects of ketoconazole include headache, sedation, nausea,

irregular menses, decreased libido, impotence, gynecomastia, and
elevated liver function tests. The drug is contraindicated during pregnancy.

signals to your adrenal glands.

- SIDE EFFECTS: Nausea, upset stomach, headache, dizziness, or

drowsiness may occur.
Mitotane (LYSODREN®)

- works by killing or slowing the growth of adrenal gland cells and also
reverses the side effects caused by too much hormone production.

- Tablets 500 mg

- Take this medication by mouth with or without food, usually 3 or 4 times

daily or as directed by your doctor.

- SIDE EFFECTS: Dizziness, drowsiness, nausea, diarrhea, loss of

appetite,headache, or unusual weakness may occur.

Aminoglutethimide(Cytadren)

- Aminoglutethimide is indicated in conjunction with other drugs for the

suppression ofadrenal function in patients with Cushing's syndrome.

- Take this medication by mouth with or without food, usually 4 times

a day (every 6 hours) or as directed by your doctor.

- SIDE EFFECTS: Drowsiness, dizziness, headache, nausea, vomiting, or

loss of appetite may occur.
DIAGNOSTIC TESTS

• 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. The midnight plasma cortisol test measures cortisol
concentrations in the blood.

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 nanomoles per liter (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.

• Low-dose dexamethasone suppression test (LDDST). In the LDDST, a

person is given a low dose of dexamethasone, a synthetic glucocorticoid,
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.

• Dexamethasone-corticotropin-releasing hormone (CRH) test. Some

people have high cortisol levels but do not develop the progressive effects
of Cushing’s syndrome, such as muscle weakness, fractures, and thinning
of the skin.

These people 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. In the CRH stimulation test, an injection of CRH causes the
pituitary to secrete ACTH.

Pretreatment with dexamethasone prevents CRH from causing an increase

in cortisol in people with pseudo-Cushing’s. Elevations of cortisol during
this test suggest Cushing’s syndrome.
MNEMONIC

C - Central obesity, Cervical fat pads, Collagen fibre

weakness, Comedones (acne)
U - Urinary free cortisol and glucose increase
S - Striae, Suppressed immunity
H - Hypercortisolism, Hypertension, Hyperglycaemia, Hirsutism
I - Iatrogenic (Increased administration of corticosteroids)
N - Noniatrogenic (Neoplasms)
G - Glucose intolerance, Growth retardation
REFERENCES

http://emedicine.medscape.com/article/117365-treatment

http://www.uptodate.com/contents/patient-information-cushings-syndrome-
treatment

Suzzane C. Smeltzer, et.al.Medical-Surgical Nursing, 12th ed.Lippincott

Williams and Wilkins.2010.pp1281-1286
Cushing’s syndrome

And

Addison’s disease
 Submitted by:

Arnel John Marcera

Eloisa Dajes

Johayrah Macadato

Zoren Kier Sabellina

Joy Cheryl Pabololot

Rolin Theresa Sabio

Lorry Calisagan

Submitted to:

Ms. Dolly Banluta,RN