CUSHING SYNDROME

First described by the physician, Harvey Cushing, in 1912, Cushing’s syndrome (sometimes called
hypercortisolism)

Normally, the production of cortisol follows a precise chain of events, first the hypothalamus
sends corticotrophins releasing hormone (CRH) to the pituitary gland, and CRH causes the
pituitary to secrete Adrenocorticotropic hormone (ACTH) which stimulates the adrenal gland.
Adrenal gland responds by releasing cortisol in the blood stream.

The adrenal medulla, which accounts for 20% of weight, secretes epinephrine, nor epinephrine &
dopamine.

The adrenal cortex accounts for 80% of the weight of the adult gland, the adrenal cortex secretes
mineral corticoids, adrenal androgens and estrogens & the glucocortcoids. Theses hormones are
synthesized from cholesterol, the cells of the adrenal cortex must be stimulated by the extra
adrenal regulator- Adrenocorticotropic hormone (ACTH) for cholesterol to be used in
steriodogensis.

Functions of Glucocortcoids

 Metabolic.
 Anti-inflammatory.
 Growth suppressing.
 Influence levels awareness & sleep.
 It increases blood glucose concentration by promoting gluconeogenesis in
the liver & by decreasing use of glucose in muscle, adipose tissue &
lymphatic tissue.
 Intrahepatic tissue it stimulates protein catabolism.
 In hepatic tissue stimulates glucose formation.

Aldosterone: Aldosterone is the most potent of the naturally occurring mineral corticoid. The
primary role of aldosterone is to conserve water and sodium. In the kidney, aldosterone acts on
the ascending portion of loop of henle, the distal convoluted tubules, and the collecting tubules to
increase potassium & hydrogen ion excretion. High levels of aldosterone may result in alkalosis
& hypokalemia, hypertension, & skeletal muscle weakness.

Adrenal estrogens & androgens:

Estrogen secretion by the normal adrenal cortex is so minimal as to be considered

physiologically unimportant. The adrenal cortex also secretes androgens, some of the weakly
androgenic substances secreted by the cortex are then converted by peripheral tissues to stronger
androgens such as testosterone. An increased capacity for peripheral conversion of adrenal
androgen to estrogen occurs in some cases.
Hypersecretion of estrogen causes feminization, the development of female sex characteristics.
Hypersecretion of androgens results in virilization.

CUSHING SYNDROME

Adrenal cortex secretes three hormones

1. Glucocorticoid- Cortisol

2. Mineralocorticoid- aldosterone

3. Adrenal androgens.

Distinct clinical syndrome is produced when excess amounts of principal andreno cortical
hormones are secreted, thus excessive secretion of glucocorticoid results in Cushing syndrome.

Excessive secretion of mineral corticoid (aldosterone) results in clinical & chemical

manifestations of Hyperaldosteronism.

Excessive production of adrenal androgens leads to Adrenal virilism.

DEFINITION

“Cushing syndrome refers to chronic hyper cortolism (excessive levels of circulating cortisol)
caused by hyperfunction of the adrenal cortex, with or without pituitary involvement “

“Cushing disease refers specifically to pituitary dependent hypercortolism.”

“Additionally, a Cushing like syndrome may develops as a result of the exogenous

administration of cortisol.”

INCIDENCE

The annual incidence of Cushing syndrome has been estimated at 13 cases per million
individuals of these cases.

Approximately 70% are due to Cushing disease,

15% ectopic ACTH,

15% due to primary adrenal tumor,

55% tumors are benign in nature,

15% tumors are malignant in nature.

MORTALITY/MORBIDITY

Adrenocortical carcinomas are associated with a 5 years survival rate of 30% or less.

SEX

The female to male incidence is approximately 5:1 for Cushing syndrome due to adrenal or
pituitary tumor.

Ectopic ACTH production is more frequent in men than in women, because of increased
incidence of lung tumors in the population.

AGE: The peak incidence of Cushing syndrome due to either an adrenal or pituitary adenoma is
in persons aged 25-40 years.

Ectopic ACTH production due to lung cancer occurs later in life.

CAUSES OF CUSHING SYNDROME

Cushing syndrome occurs when the body’s tissue are exposed to excessive levels of cortisol for
long periods of time, either there will be over production of cortisol by the body or exogenous
administration of steroids.

I. Endogenous glucocorticoid over production.

II. Ectopic ACTH production.
III. Exogenous steroid administration.

I. Endogenous glucocorticoid over production.

a) ACTH producing pituitary adenoma

Pituitary adenoma that secrete ACTH are derived from corticotrophin in the anterior pituitary.
ACTH produced by the corticotrophins are released in to the blood stream and acts on the
adrenal cortex and stimulate the secretions of adrenal steroids, they are benign or malignant
tumors of the pituitary gland, this form of syndrome is known as “Cushing syndrome”

b) Primary adrenal lesions

Sometimes the abnormality of the adrenal glands, most often an adrenal tumor, cause Cushing
syndrome.

Over production of glucocortcoids may be due to an adrenal adenoma, adrenal carcinoma or

macro nodular hyperplasia.
The zona fasciculate and zona reticularis layers of adrenal cortex mainly produce glucocortcoids
and androgens. Glucocortcoids are derived from these cells and they may secrete both
glucocortcoids and androgens & these glucocorticoid producing tumors generally do not secrete
aldosterone which is produced in the zona glomerulosa layer of the adrenal gland.

Carney complex is a familial form of micro nodular hyperplasia of adrenal gland (an auto somal
dominant disorder)

II. Ectopic ACTH production

Some benign, or more often malignant tumors that arise out side the pituitary can produce
ACTH, this condition is known as Ectopic ACTH syndrome.

Lung cancer cause more than half of these cases, the most common form of ACTH producing
tumors are small cell lung carcinoma(Oat cell carcinoma).

Other less common types of tumors that can produce ACTH are thymomas, pancreatic islet
tumors and medullary carcinomas of thyroid.

III. Exogenous steroids administration.

Administration of exogenous steroids may lead to the development of Cushing syndrome in

patients with such disorders include a wide variety of rheumatic, pulmonary, neurological and
nephrogenic disease.

Patient who under gone organ transplant are also at risk for developing Cushing syndrome due to
exogenous steroids, required as a part of graft anti rejection medication regimen.

PATHOPHYSIOLOGY

Cause of hypercortisolism often involves excessive circulating ACTH, which may result from a
variety of pathophysiologic alterations. Dysregulation hypothalamic or anterior pituitary
hormones may lead to increased levels of ACTH.

Autonomous, ectopic ACTH secretion by a tumor outside the pituitary, usually a malignant
tumor, & frequently an oat cell carcinoma of the lung, also may cause the development of
Cushing syndrome. Elevated levels of ACTH account for approximately 95-80% of all cases of
Cushing syndrome. Autonomous secretion of cortisol by an adrenal neoplasm, which may be
either benign or malignant account for approximately 10% of the cases of hypercortico
adrenalism.

Whatever the cause, two observations consistently apply to individuals with Cushing syndrome.

1. They do not have diurnal or circadian secretion pattern of ACTH & cortisol.

2. They do not increase ACTH &cortisol secretion in response to stressor.

In individuals with ACTH stimulated hypercorticoadrenalism, secretion of both cortisol&adrenal
androgens is increased. Hormone secreting tumors of the adrenal cortex however generally only
secrete cortisol by the tumor exceeds normal cortisol levels, symptoms of hypercortisolism
develops.

CLINICAL MANIFESTATIONS

Most of the clinical manifestations of Cushing syndrome are caused by hypercortisolism

knowledge of the physiologic effects of glucocortcoids shows that most of the signs and
symptoms logically follow.

Hypercortisolism promotes deposition of fats in characteristic sites notably in the upper part of
the face, the typical moon face; in the scapular area- the buffalo hump and in the mesenteric bed-
where it produces classic truncal obesity. The ultimate effect is weight gain resulting from
accumulation of adipose tissue.

It also causes transient weight gain from sodium& water retention because of the mineralo
corticoid effect of cortisol. Glucose tolerance occurs because of cortisol induced insulin
resistance & increased gluconeogenesis & glycogen storage by the liver. Overt diabetes mellitus
develops in approximately 20% of individuals with hypercortisolism. Polyuria, which is
sometimes seen in hypercortolism, is a manifestation of hyperglycemia & resultant glycosuria.

Protein wasting is commonly observed in hypercortisolism & is caused by the catabolic effects
of cortisol on peripheral tissues. Muscle wasting, especially obvious in the muscles of the
extremities, leads to muscle weakness.

In bone, loss of protein matrix leads to osteoporosis with pathologic fractures, bone & back pain,
kyphosis & reduced height. Bone disease may contribute to hypercalcinuria & renal stones,
which are experienced by 20% of individuals with Cushing syndrome. Loss of collagen also
leads to thin, weakened integumetry tissue through which capillaries are more visible & which
are easily stretched by adipose deposits. Together these changes account for the characteristic
purple striae most frequently observed in the trunk area. Loss of collagen support around small
vessels makes them susceptible to rupture, leading to easy bruising, even with minor trauma.
Thin atrophied skin is also easily damaged, leading to skin breaks and ulcerations. Hyper
pigmentation in cushing syndrome is associated high serum levels of ACTH. The precise
hormonal basis for this hyper pigmentation is still undetermined, however current speculation
focuses on the melanotropic activity of ACTH .The pigmentation involves mucus membrane,
hair & skin all of which acquire a characteristic brownish or bronze colour.

Cortisol has a permissive effect on the actions of the catecholamine’s, with elevated cortisol
levels, vascular sensitivity to catecholamine’s is significantly increased leading to
vasoconstriction & hypertension. Elevated blood pressure occurs in most individuals with
Cushing syndrome.
Chronically elevated cortisol levels also cause suppression of immune system & increased
susceptibility to infections.

Approximately 50% of individuals with cushing syndrome experience alterations in their mental
status, these may range from irritability & depression to severe psychiatric disturbances such as
schizophrenia.

Females may experience symptoms of increased adrenal androgen levels, increased hair growth
(especially facial hair) acne & oligomenorrhoea. Rarely do androgen levels becomes high
enough to cause changes of the voice, recession of hair line,& clitorial hypertrophy unless an
adrenal carcinoma is involved. Routine laboratory examination may reveal hyperglycemia,
glycosuria, hypokalemia, & metabolic alkalosis.

DIAGNOSIS

Varieties of laboratory tests are used to diagnose Cushing syndrome. These include urinary free
cortisol (17 hydroxy cortisol) greater than 100 mg/24 hrs & plasma cortisol obtained late in the
evening greater than 20mg/dl.

 Patient characteristically shows mild neutrophylic Leucocytosis.

 Serum sodium concentration is usually normal.
 In cases of marked Hypersecretion hypokalemia, hypochloremia & metabolic alkalosis
occurs.

Intermittent glycosuria is seen < ¾% of patients.

Some patients may have frank symptoms of diabetes necessitating insulin therapy.

 X-ray studies usually reveal generalized osteoporosis most marked in spine pelvis &
skull. Fractures are often seen in ribs & vertebrae.
 Serum electrolytes and glucose are measured to identify electrolyte imbalance.

The diagnosis of cushing syndrome depends on the direct on indirect demonstration in the
absence of stress.

1. For initial screening purposes a rapid overnight Dexamethasone suppression test is done.

Dexamethasone (Decadron) 2 mg is administered at 2300 hrs to suppress secretion of

corticotrophin releasing hormone (CRH).Plasma cortisol sample is drawn at 0800 hrs. Cortisol
level < 5mg/dl indicates normal response.

 Ensure that patient has fasted before collection of plasma cortisol sample.
 Observe venipuncture site for bleeding & hematoma formation.
 Drugs such as estrogen & glucocortcoids may give false positive result.
  Ensure accurate timing of medication & sample collection.

2. Base line 24hr urine 17- hydroxy steroid & 17- ketosteriod should be carried out. Values in
excess of 10/mg day of urine 17-hydroxy steroid justify further evaluation.

An ancillary screening procedure is to determine the diurnal excretion pattern for urine between
9Am to 9Pm, & 9Pm to 9Am.

The patient with Cushing syndrome will generally excrete an equivalent or greater amount of 17-
hydroxy steroid in the night collection in contrast to most normal subjects.

If it is demonstrated that the diurnal cycle of steroid excretion is reversed, i e night urine 17-
hydroxy steroid are almost equal to or greater than day time excretion, one then knows that
excessive cortisol is being continuously released around the clock.

 Pituitary CT has a sensitivity of about 50% for identifying micro adenomas

 MRI has increased sensitivity but is not 100% predictive

 If diagnostic doubt need bilateral inferior petrosal sinus sampling for ACTH

 Adrenal ultrasonography---first choice

 Abdominal CT will allow identification of adrenal pathology.

TREATMENT

Treatment depends on the specific reason for cortisol excess and may include surgery, radiation,
chemotherapy or use of cortisol inhibition drugs.

I. When an adenoma or carcinoma is suspected adrenal exploration is performed, with excision

of the tumor. Since cortisol production by the tumor generally causes atrophy of the
contralateral gland , if an atrophied gland is noted on the initial side of exploration, the tumor
must be on the opposite side. Because of the probable atrophy of the contralateral adrenal,
the patient is prepared and treated pre & post operatively for total adrenalectomy.
II. In patients with a severe form of Cushing syndrome due to adrenal hyperplasia, with features
of hypertension, overt diabetes, psychosis & osteoporosis with pathologic fractures, & in the
absence of an enlarged sella turcica, a complete total bilateral adrenalectomy is performed.
III. If the underlying cause is a pituitary adenoma, the standard treatment is surgical removal of
the pituitary tumor using the transphenoidal approach.
IV. Radiation to the pituitary adenoma may be necessary if surgical outcomes are not optimal or
if the patient is not a good candidate for surgery.
V. Drug therapy as a treatment measure for Cushing syndrome is usually indicated when
surgery is contraindicated. The goal of the therapy is the inhibition of adrenal function. The
principal antitumor drug used to chemically inhibit adrenal cortisol function due to
 carcinoma, the drug is a,p-DDD (2,2bis-2 cholorophenyl 4 cholorophenyl) 1,1 dicholoro
ethane an isomer of insecticide DDT (MITOTANE).

This drug suppress cortisol production & decreases plasma & urine steroid levels. The usual dose
is 8 to 10 gms daily given in three or four divided doses. Side effects include GIT( anorexia,
diarrhea, or vomiting ) or neuromuscular (lethargy, somnolence& dizziness).

All patients should be placed on long term glucocorticoid & Mineralocorticoid replacement
therapy.

Other drugs like Metyrapone, ketaconazole (Nizoral) & Aminoglutethiamide (Cytaden) are used
to inhibit cortisol synthesis.

VI. If cushing syndrome has developed during the course of prolonged administration of
corticosteroids (Prednisolone) one or more of the following alternatives may be tried.
 Gradual discontinuation of glucocorticoid therapy.
 Reduction of the dose of the steroids.
 Conversion to an alternative drug regimen.
VII. Patients with ectopic ACTH secreting tumors are managed by treating the primary neoplasm.

In some patients, pituitary irradiation is the primary treatment of bilateral hyperplasia.

NURSING DIAGNOSIS

1) Risk for infection r/t lowered resistance to stress and suppress of immune system.

2) Imbalanced nutrition: more than body requirement r/t increased appetite, high calorie intake &
inactivity, manifested by statement of increased appetite.

3) Disturbed self-esteem R/T altered body image.

4) Impaired skin integrity R/T excess corticosteroids.