The majority of CS cases are due to exogenous corticosteroid medication. It occurs in approximately 13 per million people. Endogenous CS occurs with an incidence of approximately 0.7–2.4 per million population per year. When the disorder is endogenous and caused by either an adrenal or pituitary tumor, females are five times more likely to be affected than males. However, males are affected three times more than females by  the ectopic production of adrenocorticotropin hormone (ACTH), which is a hormone that stimulates cortisol production, due to lung cancer later in life.

Exogenous CS: This is due to long-term administration of a cortisol-like drug therapy either used to treat another medical condition, such as arthritis or lupus, or other inflammatory diseases, such as leukemia or asthma. 

Endogenous CS: The pituitary gland in the brain produces a hormone called adrenocorticotropic hormone (ACTH) which enters and travels in the blood stream until it reaches the adrenal glands which are located on top of the kidneys. Secretion of ACTH is managed by three regions of the body, the hypothalamus, pituitary gland and adrenal glands. These regions form the hypothalamic-pituitary-adrenal (HPA) axis. When cortisol levels are low in the blood, the hypothalamus will release a hormone called the corticotrophin-releasing hormone that stimulates the pituitary gland to secrete ACTH into the bloodstream. High levels of ACTH are then detected by the adrenal gland receptors. These receptors respond by stimulating the secretion of cortisol, and this then increases cortisol levels in the blood. As these levels rise, this in turn reduces the release of the cortiocotrophin-releasing hormone and ACTH from the pituitary gland. Because the ACTH levels begin to fall, so do cortisol levels. Therefore, excessive cortisol production can occur in the context of abnormally elevated ACTH levels that stimulate healthy adrenal glands to produce more cortisol or in the context of defective adrenal glands that produce excessive cortisol despite low or normal ACTH levels. Approximately 70% of Cushing syndrome cases are the result of Cushing disease. When there is excess ACTH production from a benign pituitary tumor (adenoma), the adrenal glands produce excess amounts of cortisol. Approximately 10-15% of endogenous cases are due to non-pituitary tumors that secrete excessive ACTH. Benign or malignant tumors commonly found in the chest cavity or abdomen cause the excessive ACTH production. Other types of ACTH-producing tumors include medullary carcinomas of the thyroid or pancreatic islet cell tumors. Some patients (approx. 10-15%) have benign or malignant tumors of the adrenal glands resulting in excessive cortisol production. 

While the majority of cases are not inherited, some cases of CS are the result of an inherited tendency to develop tumors in one or more hormone-secreting glands, such as the adrenal glands. 

The condition can affect many different parts of the body and can cause a range of symptoms, which include:

• A rounded face

• Dorsal fat pad or so-called Buffalo hump - a mound of fat formed at the base of the neck

• Weight gain especially in the abdomen, while arms and legs become slender

• Increased body hair

• Thinning skin

• Acne

• Easy bruising 

• Leg swelling

• Purple stretch marks on abdomen and legs

• Constant rosy cheeks

• Diabetes 

• Hypertension

• Mood changes including feeling hyperactive or sudden mood swings

• Muscle weakness

• Irregular menstruation

In addition to assessing a patient’s medical history, a patient with CS is commonly diagnosed by a physical examination and certain laboratory tests. If a diagnosis is made, the next step to follow is to determine what is causing the condition. For example, it could be caused by an adrenal tumor (adrenal Cushing’s), a pituitary tumor (Cushing’s disease), or a tumor elsewhere in the body (ectopic ACTH-producing tumor).

Tests used to diagnose Cushing syndrome include:

• Blood (plasma) test to measure ACTH levels and cortisol levels. 

• Radiologic imaging may be used to identify ACTH-producing tumors

• Magnetic resonance imaging (MRI) may be used to identify a tumor in the pituitary gland

• 24-hour urine cortisol test can be used to measure overall cortisol levels in a patient’s urine for an entire day and to determine any abnormal levels.

• Salivary cortisol test involves swabbing inside of the patient’s mouth before going to bed and measuring cortisol levels in the saliva.

If the above tests are performed and the patient appears to be making too much cortisol, a low dose dexamethasone suppression test may be used. This test involves the administration of a pill containing 1 mg of Dexamethasone (artificial steroid) at 11pm and then checking the blood cortisol level the following morning. If the level does not drop, then this can confirm elevated levels of blood cortisol and help to confirm a CS diagnosis.

Treatment depends on the cause and can include surgery, targeted radiation, chemotherapy, or cortisol-reducing medications. 

If the cause is the result of long-term glucocorticoid use to treat another disease, a physician will likely reduce the dosage to the lowest dose to help manage cortisol levels but to also keep treating the other disease. In some cases, non-glucocorticoid medication may be used instead if disease treatment doesn’t require glucocorticoids.

Ectopic ACTH-producing tumors are typically first treated through surgical removal of the ectopic tumor. If the tumor is cancerous and has already spread, treatment may extend to chemotherapy, radiation or other treatment options. 

When a patient has been diagnosed with Cushing’s disease, and the pituitary tumor is benign, treatment would likely involve removal of the tumor by a neurosurgeon, or in some cases directed radiation treatment. If surgery and medications are unsuccessful, a patient may need to have both adrenal glands removed. 

When a patient has CS due to an adrenal tumor, the treatment typically involves removal of either one of both adrenal glands. If a patient has just one hyperactive adrenal gland, then the other gland typically shuts down temporarily. Therefore, when the hyperactive adrenal gland is removed, extra steroids through IV and pills will be used temporarily to assist in kickstarting the remaining adrenal gland to function properly again.

If both adrenal glands need to be removed, medication will be required for life to replace the cortisol and other hormones produced by the adrenal glands.

The prognosis for patients diagnosed with CS varies due the range of treatment options depending on the cause of the disease and it being exogenous or endogenous. In cases where patients have persistent hypercortisolism, CS is associated with a high number of metabolic, cardiovascular and cognitive complications, which can affect both quality of life and a patient’s prognosis. 

Aulinas A., Valassi E., and Webb S. M. Prognosis of Patients treated for Cushing syndrome. Endocrinología y Nutrición (English Edition). 2014; 61: (1): 1-64. DOI: 10.1016/j.endoen.2014.01.004

Columbia Surgery, Columbia Adrenal Center. N.d. Cushing’s Syndrome. Available from: https://columbiasurgery.org/conditions-and-treatments/cushings-syndrome 

National Institute of Diabetes and Digestive Kidney Diseases. 2018. Cushing’s Syndrome. Available from: https://www.niddk.nih.gov/health-information/endocrine-diseases/cushings-syndrome 

National Organization for Rare Disorders. 2017. Cushing Syndrome. Available from: https://rarediseases.org/rare-diseases/cushing-syndrome/ 

You and Your Hormones. 2020. Adrenocorticotropic hormone. Available from: https://www.yourhormones.info/hormones/adrenocorticotropic-hormone/