Cushing’s syndrome is a group of signs and symptoms caused by overexposure to a hormone called cortisol. This hormone is produced in the body by the adrenal glands. There are two adrenal glands, one on top of each kidney. The control of production of cortisol from the adrenal glands comes from an area in the lower part of the brain called the pituitary gland. This secretes a hormone called adrenocorticotrophic hormone (ACTH). This hormone stimulates the adrenal glands to produce cortisol. The pituitary gland itself and its production of ACTH are controlled in turn by an area of the brain called the hypothalamus. When the cortisol concentration in the blood is low the hypothalamus secretes a hormone called corticotrophin releasing hormone (CRH) which in turns stimulates the pituitary gland to secrete ACTH.
Cushing’s syndrome can therefore be caused by a variety of problems. The adrenal gland may itself be producing too much cortisol, or the gland could be being stimulated by excess ACTH which in turn causes the adrenals to produce too much cortisol. This may be due to problems with the pituitary gland itself but may also be caused by tumours outside these areas producing large amounts of CRH or ACTH. Finally, Cushing’s syndrome can also be caused by a patient taking too much of a synthetic glucocorticoid (a steroid like cortisol e.g. prednisolone, dexamethasone) for another clinical condition. This is the most common cause of Cushing’s syndrome.
As there are several possible causes of Cushing’s syndrome, for simplicity it is easier to divide them into those caused by excess ACTH production and those without.
Causes Related to Excess ACTH production
- Cushing’s disease. A pituitary tumour that produces large amounts of adrenocorticotrophic hormone ACTH is known as Cushing’s disease. This is the most common cause of Cushing’s syndrome in this category (i.e. where there is excess ACTH production). In most cases the cause of the tumour cannot be found. In a small number of cases, the pituitary tumour that causes Cushing’s disease is part of an inherited condition known as multiple endocrine neoplasia type 1.
- Ectopic ACTH. A tumour in the body not associated with the pituitary gland, which produces too much ACTH. This ACTH stimulates the adrenal glands to produce too much cortisol. This may be seen in lung cancer.
- Ectopic CRH. A tumour in the body not associated with the hypothalamus that produces too much corticotrophin releasing hormone (CRH). This stimulates the pituitary to secrete large amounts of ACTH that in turn stimulates the adrenal glands to produce too much cortisol. This is commonly seen with small-cell carcinoma of the lung and bronchial carcinoid tumours but can occur with other tumours in the endocrine system.
Non excess ACTH related causes
- Iatrogenic Cushing’s syndrome. Caused by taking synthetic glucocorticoids. These drugs, such as prednisolone and dexamethasone, act like cortisol.
- Adrenal tumour. A tumour in the adrenal gland that produces too much cortisol. This is most often on one side (unilateral). These may be cancerous (carcinoma) or non-cancerous (adenoma).
- Adrenal nodular hyperplasia. When groups of cells, or nodules, in the adrenal gland produce too much cortisol.
- Genetic mutations. In some rare cases Cushing’s syndrome may develop because of gene mutations associated with other clinical conditions such as McCune-Albright syndrome.
Cushing’s syndrome can occur in anyone but is more common in certain groups of people, depending on the cause of the excess cortisol production. Pituitary tumours and adrenal tumours for example are more common in women usually occurs between the ages of 25 and 40 years. It can however occasionally occur in children. Excess ACTH or CRH production due to lung cancers however would usually be found in the elderly. Cushing’s syndrome is also more common in patients with diabetes, hypertension, obesity and osteoporosis. This is because Cushing’s syndrome can affect the body in such a way that these complications develop i.e. these diseases can be a result of the Cushing’s Syndrome.