Cushing's Syndrome is the resulting set of symptoms observed when the body is exposed to excess cortisone (or related hormones) over a long period of time. Cortisone, or more correctly Cortisol,  is a hormone produced by the adrenal glands which are located atop the kidneys. Cortisol is stored in the adrenal gland and released in times of stress where it helps our bodies prepare for a fight or flight situation. It adjusts the metabolism to expect physical exertion by mobilizing fat and sugar stores and retaining sodium and water. It puts us in a state of break down so that our stored resources can be used quickly. If the body is exposed to this hormone most of the time instead of during short stressful periods, the state of break down becomes debilitating.
There are several mechanisms which can lead to Cushing¡¦s syndrome and, as they are treated differently, it is important to determine which one is at work in a given animal.
In the normal body, the pituitary gland, located at the base of the brain, can detect when cortisol levels in the blood are declining. In response, the pituitary secretes a stimulating substance which causes the adrenal gland to release more cortisol. When the pituitary gland detects that cortisol levels are again appropriate, it stops its stimulatory message.
You can think of the pituitary gland as a sort of a thermostat for cortisol. This raising and lowering of cortisol blood level is regulated throughout the day and occurs rapidly.

PITUITARY-DEPENDENT CUSHING'S SYNDROME
This accounts for 85% of dogs with Cushing's syndrome. Basically, the pituitary gland grows a tumor, generally microscopic and generally benign. This tumor, however, over-produces its stimulatory message thus leading to enlargement of both adrenal glands and an over-production of cortisone. Occasionally (10% of pituitary-dependent Cushing's dogs), these benign pituitary tumors are large enough to compress the brain. In these cases, neurological signs may be observed; these cases are unusual but very hard to treat.

ADRENAL-DEPENDENT CUSHING'S SYNDROME
In 15% of dogs with Cushing's syndrome, an adrenal tumor is directly over-producing cortisone. The tumor is often large enough to see with radiographs or ultrasound and may be malignant.

OVERUSE OF CORTISONE-TYPE HORMONES
Cortisone derivatives may well be the most over-used drugs in veterinary medicine. Their anti-inflammatory actions soothes such common maladies as allergic skin disease (especially flea allergic dermatitis) and degenerative arthritis. Relief is usually rapid and and many owners find themselves requesting "cortisone" shots or pills over and over again. In time, Cushing's syndrome results, not from any inherent disease in the pet's system but from the effects of the hormones given.

The pituitary gland perceives the high steroid levels yielded by the medication and does not send a stimulation to the adrenal glands. In time, the adrenal glands atrophy and are not able to release cortisone for a period of three months after the medication is discontinued. To allow the adrenal to gradually recover, cortisone pills are usually prescribed in a decreasing dose and an owner should never discontinue the pills suddenly.

Commonly prescribed cortisone derivatives include: vetalog, azium, prednisone, prednisolone, dexamethasone, depomedrol and others.

SPECIFIC TESTS TO CONFIRM
CUSHING'S DISEASE
THE LOW DOSE DEXAMETHASONE SUPPRESSION TEST
Dexamethasone is a cortisone-type hormone which is used therapeutically for numerous conditions. The dog¡¦s pituitary gland will perceive the presence of dexamethasone and shut off its stimulatory message to the adrenal glands. In the normal animal, this means that a drop in blood cortisol level will be seen 8 hours after a tiny dose of dexamethasone is given.
If a pituitary tumor is present, the pituitary is not about to shut off its stimulatory message and ignores the presence of the dexamethasone. No drop in cortisol level is seen at the end of eight hours.

THIS TEST IS CURRENTLY CONSIDERED THE MOST ACCURATE IN THE CONFIRMATION OF CUSHING'S DISEASE.
TO RUN THIS TEST

Ideally this test is run in the morning. A baseline cortisol level is measured, a low dose of dexamethasone is given intravenously, and blood samples are checked again in 8 hours. Sometimes a 4 hour sample is also drawn as the pattern of suppression over the entire 8 hours may help classify the type of Cushing¡¦s disease. The pet will require at least 8 hours in the hospital.

THE ACTH STIM TEST
Central to the concept of Cushing¡¦s disease is the over-production of cortisol. It follows then that the adrenal glands of the Cushing¡¦s patient would possess large amounts of stored hormone due to their chronic stimulation.
We have been talking about the stimulatory message sent from the pituitary gland to the adrenal glands. This message consists of a hormone called Adrenocorticotrophic hormone or ACTH.   In this test, a dose of ACTH is given to the patient. If a larger than expected, rise in cortisol levels is measured in 2 hours we may diagnose Cushing's syndrome.

TO RUN THIS TEST
Ideally, the patient is fasted overnight and the test is performed in the morning between 8 A.M. and 10 A.M. A blood sample is drawn, a dose of ACTH is given, and two hours later a second blood sample is drawn.

WHEN WOULD WE RUN THIS TEST?
Given that the Low Dose Dexamethasone Suppression test is more accurate, when might we run this test instead? It turns out that this is the only test that can be used if the iatrogenic form of Cushing¡¦s disease is suspected. This test is also crucial in monitoring patients with Cushing¡¦s disease, depending on which medications are used.

THE URINE CORTISOL/CREATININE RATIO
This is a screening test for Cushing's disease; a positive test here does NOT confirm Cushing's syndrome but a negative test here DOES rule it out. In this test a single urine sample is collected and the relative amounts of cortisol and creatinine (creatinine is a protein metabolyte that is excreted in urine constantly). If there is a high ratio (a

ADRENAL OR PITUITARY CUSHINGS?
WHY DO WE CARE?
Once a pet has been confirmed as having Cushing's syndrome, the next step is to determine which form of Cushing's syndrome the pet has since treatment is different for each form. 
If an adrenal tumor is present, there is a 50% chance that it is a malignant tumor. Surgical exploration is generally warranted so that the tumor may be removed. 
Adrenal tumors can be treated with medications just as pituitary tumors can be but the protocols are completely different so it is imperative that classification be complete.

SO WHAT TESTS WILL TELL US
WHAT TYPE OF CUSHING'S SYNDROME IS PRESENT?
THE LOW DOSE DEXAMETHASONE SUPPRESSION TEST
If one is lucky, the same test used to determine if Cushing's disease is present or not can also classify the Cushing's disease so that no further tests are needed. If a 4-hour sample is drawn in addition to the pre-dexamethasone sample and the 8-hour sample, more information can be determined about the cortisol suppression pattern. Some patterns are characteristic of pituitary or adrenal Cushing's disease. If your pet fits into this category, then no further testing is needed to classify the Cushing's disease.

IMAGING
Imaging such as ultrasound, MRI, CT scan, or nuclear medicine studies may be helpful in classifying Cushing's syndrome. Probably ultrasound is the most readily available. If a Low Dose Dexamethasone Suppression test has confirmed Cushing's syndrome but not confirmed which type, imaging of the adrenal glands can provide the information needed to complete classification. Two large or normal sized adrenal glands are typically present with the presence of a pituitary tumor as both adrenal glands will be equally stimulated by ACTH production. Other imaging results should be followed by either of the blood tests described below.
If one adrenal gland looks large and the other is not visible, an adrenal tumor may be suspected (remember, the non-tumorous gland will atrophy). In the event of an adrenal tumor, ultrasound is also helpful to determine the extent of tumor spread, which is crucial to deciding for or against surgical removal of the tumor.

THE HIGH DOSE DEXAMETHASONE SUPPRESSION TEST
This test is similar to the low dose dexamethasone suppression test except that a higher dose of dexamethasone is used and the patient having the test is already known to have Cushing's disease through prior testing. In this case, a patient with a pituitary tumor will show suppression in circulating cortisol when exposed to the high dose of dexamethasone (though suppression does not occur with the low dose). If an adrenal tumor is present, suppression does not occur.

ENDOGENOUS ACTH LEVEL
This test is felt by many to be the most accurate method of classifying Cushing's syndrome but the problem is that the test is technically challenging to run. Serum from the patient must be frozen when transported to the laboratory and may not thaw. The hormone ACTH is very fragile and may not survive the trip to the lab. The idea with this test is that a patient with a pituitary tumor will have high ACTH levels, as this is what the tumor is secreting. A patient with low or no measurable ACTH levels has an adrenal tumor as the pituitary is trying its best not to stimulate the over-active adrenal tumor.