The most common cause of Cushing's syndrome is the long-term use of glucocorticoid hormones in medications. Medications such as prednisone are used in a number of inflammatory conditions. Such conditions include rheumatoid arthritis, asthma, vasculitis, lupus, and a variety of other autoimmune disorders in which the body's immune cells accidentally attack some part of the body itself. In these disorders, the glucocorticoids are used to dampen the immune response, thereby decreasing damage to the body.

Cushing's syndrome can also be caused by three different categories of disease:

• a pituitary tumor producing abnormally large quantities of ACTH
• the abnormal production of ACTH by some source other than the pituitary
• a tumor within the adrenal gland overproducing cortisol

Although it is rare, about two-thirds of endogenous (occurring within the body rather than from a source outside the body, like a medication) Cushing's syndrome is a result of Cushing's disease. The term "Cushing's disease" refers to Cushing's syndrome, which is caused by excessive secretion of ACTH by a pituitary tumor, usually an adenoma (noncancerous tumor). The pituitary tumor causes increased growth of the adrenal cortex (hyperplasia) and increased cortisol production. Cushing's disease affects women more often than men.

Tumors in locations other than the pituitary can also produce ACTH. This is called ectopic ACTH syndrome ("ectopic" refers to something existing out of its normal place). Tumors in the lung account for more than half of all cases of ectopic ACTH syndrome. Other types of tumors that may produce ACTH include tumors of the thymus, the pancreas, the thyroid, and the adrenal gland. Nearly all adrenal gland tumors are benign (noncancerous), although in rare instances a tumor may actually be cancerous.

Symptoms of cortisol excess (resulting from medication or from the body's excess production of the hormone) include:

• weight gain
• an abnormal accumulation of fatty pads in the face (creating the distinctive "moon face" of Cushing's syndrome); in the trunk (termed "truncal obesity"); and over the upper back and the back of the neck (giving the individual what has been called a "buffalo hump")
• purple and pink stretch marks across the abdomen and flanks
• high blood pressure
• weak, thinning bones (osteoporosis)
• weak muscles
• low energy
• thin, fragile skin, with a tendency toward both bruising and slow healing
• abnormalities in the processing of sugars (glucose), with occasional development of actual diabetes
• kidney stones
• increased risk of infections
• emotional disturbances, including mood swings, depression, irritability, confusion, or even a complete break with reality (psychosis)
• irregular menstrual periods in women
• decreased sex drive in men and difficulty maintaining an erection
• abormal hair growth in women (in a male pattern, such as in the beard and mustache area), as well as loss of hair from the head (receding hair line).