Cho-Cho & Sophia

Cushing's syndrome ( hyperadrenocorticism or hypercorticism ) #1
is a hormone disorder caused by high levels of cortisol in the blood.
This can be caused by taking glucocorticoid drugs, or by tumors that produce cortisol or adrenocorticotropic hormone (ACTH) or CRH.

Cushing's disease refers to one specific cause of the syndrome:
a tumor (adenoma) in the pituitary gland that produces large amounts of ACTH, which in turn elevates cortisol.
It is the most common cause of Cushing's syndrome, responsible for 70% of cases excluding glucocorticoid related cases.

Cause
There are several possible causes of Cushing's syndrome.
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).

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 disease and is seen in diseases like small cell lung cancer.

Pathophysiology
The hypothalamus is in the brain and the pituitary gland sits just below it.
The paraventricular nucleus (PVN) of the hypothalamus releases corticotropin-releasing hormone (CRH), which stimulates the pituitary gland to release adrenocorticotropin (ACTH).
ACTH travels via the blood to the adrenal gland, where it stimulates the release of cortisol.
Cortisol is secreted by the cortex of the adrenal gland from a region called the zona fasciculata in response to ACTH.
Elevated levels of cortisol exert negative feedback on the pituitary, which decreases the amount of ACTH released from the pituitary gland.

Strictly, Cushing's syndrome refers to excess cortisol of any etiology.
One of the causes of Cushing's syndrome is a cortisol secreting adenoma in the cortex of the adrenal gland.
The adenoma causes cortisol levels in the blood to be very high, and negative feedback on the pituitary from the high cortisol levels causes ACTH levels to be very low.

Cushing's disease refers only to hypercortisolism secondary to excess production of ACTH from a corticotrophic pituitary adenoma.
This causes the blood ACTH levels to be elevated along with cortisol from the adrenal gland.
The ACTH levels remain high because a tumor causes the pituitary to be unresponsive to negative feedback from high cortisol levels.


Cushing's disease #2
is a cause of Cushing's Syndrome characterised by increased secretion of adrenocorticotropic hormone (ACTH) from the anterior pituitary.
This is most often as a result of a pituitary adenoma.
Pituitary adenomas are responsible for 70% of endogenous Cushing's syndrome, that is,
when excluding Cushing's syndrome from exogenously administered corticosteroids,
which is the major cause of Cushing's syndrome.

Signs and Symptoms
The condition is characterised by mainly the same features as Cushing's Syndrome
with the added condition that ACTH levels are also elevated,
despite the elevated levels of glucocorticoids such as cortisol

Diagnosis
Diagnosis is made first by diagnosis of Cushing's Syndrome which involves the 1 mg dexamethasone suppression test. (LDDST)
If the patient has Cushing's Syndrome, the 8 mg dexamethasone suppression test (HDDST ) is carried out which will confirm the aetiology of the disease.

Following the 8 mg dexamethasone suppression test plasma cortisol should be low;
while plasma ACTH should be at the higher end of normal or should exceed the reference range.
This will distinguish whether the cause is an ectopic ACTH secreting tumour, an adrenal carcinoma or an adrenal adenoma - ranges differ between different labs.

A CT or MRI of the pituitary may also show the ACTH secreting tumour if present.
Administration of corticotropin releasing hormone (CRH) can differentiate this condition from ectopic ACTH secretion.
If ectopic, the plasma ACTH and cortisol levels should remain unchanged;
if this is pituitary related, levels of both would rise.

Corticosteroids #3
 are a class of steroid hormones that are produced in the adrenal cortex.
The corticosteroids are synthesized from cholesterol within the adrenal cortex.
Corticosteroids are involved in a wide range of physiologic systems such as stress response, immune response and regulation of inflammation,
carbohydrate metabolism, protein catabolism, blood electrolyte levels, and behavior.

• Glucocorticoids such as cortisol control carbohydrate, fat and protein metabolism and are anti-inflammatory by preventing phospholipid release,
 decreasing eosinophil action and a number of other mechanisms.
• Mineralocorticoids such as aldosterone control electrolyte and water levels, mainly by promoting sodium retention in the kidney.


Glucocorticoids (GC)  #4
are a class of steroid hormones that bind to the glucocorticoid receptor (GR), 
which is present in almost every vertebrate animal cell.
The name glucocorticoid (glucose + cortex + steroid) derives from their role in the regulation of the metabolism of glucose,
their synthesis in the adrenal cortex, and their steroidal structure.

In technical terms, corticosteroid refers to both glucocorticoids and mineralocorticoids (as both are mimics of hormones produced by the adrenal cortex),
but is often used as a synonym for glucocorticoid.

Cortisol (or hydrocortisone) is the most important human glucocorticoid.
It is essential for life, and it regulates or supports a variety of important cardiovascular, metabolic, immunologic, and homeostatic functions.
Various synthetic glucocorticoids are available;
these are used either as replacement therapy in glucocorticoid deficiency or to suppress the immune system.

The combination of clinical problems produced by prolonged, excess glucocorticoids, whether synthetic or endogenous, is termed Cushing's syndrome.

Use of high-dose steroids for more than a week begins to produce suppression of the patient's adrenal glands
because the exogenous glucocorticoids suppress hypothalamic corticotropin-releasing hormone (CRH) and pituitary adrenocorticotropic hormone (ACTH).
With prolonged suppression, the adrenal glands atrophy (physically shrink), and can take months to recover full function after discontinuation of the exogenous glucocorticoid.


Cortisol(hydrocortisone)  #5
is a steroid hormone, or glucocorticoid, produced by the adrenal gland.
It is released in response to stress and a low level of blood glucocorticoids.

Its primary functions are to
•increase blood sugar through gluconeogenesis;
•suppress the immune system;
•aiding in fat, protein and carbohydrate metabolism.
•It also decreases bone formation.
Cortisol prevents the release of substances in the body that cause inflammation.
It stimulates gluconeogenesis (the breakdown of protein and fat to provide metabolites that can be converted to glucose in the liver)
and it activates anti-stress and anti-inflammatory pathways.

Cortisol is produced by the adrenal gland in the zona fasciculata,
the second of three layers comprising the outer adrenal cortex.
This release is controlled by the hypothalamus, a part of the brain.
The secretion of corticotropin-releasing hormone (CRH) by the hypothalamus triggers anterior pituitary secretion of adrenocorticotropic hormone (ACTH).
ACTH is carried by the blood to the adrenal cortex, where it triggers glucocorticoid secretion.

The amount of cortisol present in the blood undergoes diurnal variation;
the level peaks in the early morning (approximately 8 am) and reaches its lowest level at about midnight-4 am,
or three to five hours after the onset of sleep.
Changed patterns of serum cortisol levels have been observed in connection with abnormal ACTH levels, clinical depression, psychological stress, and physiological stressors
such as hypoglycemia, illness, fever, trauma, surgery, fear, pain, physical exertion, or temperature extremes.

The relationship between cortisol and ACTH, and some consequent conditions, are as follows:

THE DISORDERS OF CORTISOL SECRETION