The adrenal glands are two small endocrine organs located near each kidney. The glands have two separate parts: the cortex (outer layer) and the medulla (inner layer). The adrenal cortex is the layer that is responsible for glucocorticoid or cortisol production. Normally, the adrenal gland's production of glucocorticoids is regulated by higher functions in the brain. The area of the brain called the hypothalamus secretes the hormone CRH (corticotrophin releasing hormone). CRH then stimulates the pituitary gland to produce ACTH (adrenocorticotropic hormone), which in turn stimulates the production of glucocorticoids by the adrenal cortex. Elevated glucocorticoid levels normally lead to suppression of ACTH production, thus maintaining homeostasis.

In feline Cushing's disease, elevated cortisol levels are caused by either a pituitary tumor producing increased ACTH or by an adrenocortical tumor directly producing elevations in cortisol. Chronically elevated cortisol levels may predispose a cat to become a diabetic; cause muscle atrophy and weakness; cause skin to be more fragile – even to the extent of bruising or tearing with minor manipulation; cause suppression of the immune system; and changes in the body conformation.

Other diseases that might cause similar clinical signs include:

Diabetes mellitus. The vast majority of cats that have Cushing's disease are diabetic. If a cat is not a diabetic, it is unlikely (but possible) that the disease is cushingoid.

Feline acromegaly. Acromegaly or an excess of growth hormone is caused by a growth hormone secreting tumor in the pituitary gland. Cats usually present as insulin resistant diabetics with body conformational changes. Typical changes include an increase in the cat's head and paw size. The lower jaw may also protrude.

Hyperthyroidism. Elevated levels of thyroid hormones may cause cats to eat and drink excessively, urinate more and lose weight. Hyperthyroid cats may also have poor hair coats and have generalized muscle atrophy.

Liver disease may cause an enlarged liver and a protruding abdomen. Many cats drink excessively and have a poor hair coat with liver disease.

Feline fragile skin syndrome. Fragile skin syndrome is a condition that causes the cat's skin becomes thinner and weaker. It may be associated with metabolic or neoplastic conditions. Its exact cause is unknown.