Cushing’s Disease And Syndrome

The most common form of overproduction of the adrenal gland cortex is Cushing’s Disease and Cushing’s Syndrome.

Here the hormone cortisol is overproduced, either from the adrenal cortex itself (Cushing’s disease) or because of overstimulation from ACTH production in the pituitary gland. This produces adrenal cortex stimulation (Cushing’s syndrome) secondarily.

The table below depicts this again. Sometimes, in a clinical setting, it can be very confusing as the clinical presentation of these two entities can look identical, but without further testing some subtle hints can be missed, which are essential to tell the physician how to treat the condition successfully. It is vital to be certain whether or not ACTH production is normal or elevated to distinguish the primary condition (Cushing’s disease) from the secondary condition (Cushing’s syndrome).

Hyperfunctions of the adrenal glands

Signs and symptoms

The characteristic moon face (rounded) with obesity around the trunk and an association of muscle wasting in the extremities is the main presentation. Skin texture is thin and there are purple breaks in the skin (striae) on the abdomen like with pregnancy.

Other symptoms are an elevation of blood pressure, osteoporosis, kidney stones and proneness to infection. In children there is growth retardation (=lack of growth). In women there are menstruation irregularities. If there is an adrenal gland tumor and production of testosterone like substances, there can be body hair growth, premature male pattern baldness and male pattern hair growth in females. With pituitary adenomas headaches can occur and there is a danger of loss of sight because of optic nerve damage.

Cushing’s Disease And Syndrome

Diagnostic tests

Normally there is a variation of cortisol levels with high levels in the morning and lower levels in the evening. This pattern is lost, so there are high levels in the evening. Also the 24 hour cortisol urine test is elevated. The following hormone tests are commonly ordered by the endocrinologist:

• Standard overnight dexamethasone suppression test
  After  a morning dosage of 1mg of this potent artificial corticosteroid plasma cortisol levels are obtained in the late night and the morning. This value is normally low as the negative feedback cycle to the anterior pituitary gland will suppress the body’s own ACTH hormone secretion. Overnight this clamps down on the morning production of cortisol. However, with non-pituitary Cushing’s syndrome this test is not suppressed as there is no reduction of the ACTH production from lung cancer cells when dexamethasone is given.
• The “low dose” two day dexamethasone test (= 0.5mg four times daily for 2 days) will normally be enough to suppress ACTH production in the pituitary gland leading to low morning cortisol levels for two consecutive days. With Cushing’s disease the ACTH production of the pituitary adenoma will usually not get suppressed thus suggesting a pituitary cause for the Cushing’s disease.
• In contrast, the “high dose” two day dexamethasone test(= 2 mg four times daily for 2 days) will reduce the cortisol production by 50% in the case of a pituitary adenoma that caused the Cushing’s disease.
• Metyrapone is used for another special test to distinguish whether the Cushing’s syndrome is due to a pituitary or non-pituitary cause.
• Occasionally the endocrinologist may order an ACTH stimulation test. In the case of adrenal gland hyperplasia there is an increase in cortisol production, but with a adrenal carcinoma there is no response.
• CRH test:The hypothalamic hormone corticotropin-releasing hormone(= CRH) is available in pure form and can be given to test whether ACTH that is found in the blood is produced by the pituitary gland (large increase of ACTH and cortisol) or whether it is from an adenoma of the adrenal glands or ectopic ACTH (no increase of ACTH or cortisol in these cases). This test is most meaningful in connection with a dexamethasone suppression test.

In a patient with an adrenal gland tumor producing cortisol the dexamethasone tests will not show suppression. Similarly, most Cushing’s syndromes with ectopic (= not in the pituitary gland produced) ACTH will also not show changes in cortisol production. This makes the dexamethasone test a handy tool to distinguish between a pituitary cause of Cushing’s disease versus a non-pituitary cause of Cushing’s syndrome. The other tests are used to further define these findings. Other tests used are CT and MRI scans of the pituitary gland and the adrenal glands. For more details on pituitary adenomas a gadolinium enhanced high resolution MRI scan shows more details.

Other blood tests are also done to rule out other hormone abnormalities including thyroid, growth hormones, gonadotropins and other adrenal gland hormones, particularly aldosterone.

Cushing’s disease treatment

In the beginning the patient with a pituitary adenoma needs to be stabilized prior to surgery. This can be achieved with ketoconazole, which is an antifungal medication, but has a cortisol inhibiting effect.

In about 70% the pituitary adenoma can be removed by a skilled neurosurgeon who does a lot of these procedures. The best results seem to occur with microadenomas of less than 1 cm (= 0.4″) in diameter. The approach is through the sphenoid sinus, which is located just underneath the pituitary gland (=”transsphenoidal partial hypophysectomy”).

After this procedure the patient is in the Intensive Care Unit and is closely observed. The procedure is mostly very well tolerated and can be done during pregnancy as well. However, there is about a 20% recurrence rate as any cells that stay behind can regrow into another ACTH producing adenoma. It is a benign tumor, but it is potentially harmful, as in the past without removal it has caused partial blindness in many people. The pituitary gland is in close proximity to the optic nerves, where they cross and then disappear into the brain. Pressure on his vulnerable spot by an enlarging pituitary gland can cause a lot of harm.

If the tumor has been removed, but subsequently regrew, often a total hypophysectomy (= removal of all of the pituitary gland) is done. Alternatively the specialist might decide to ask a radiotherapist to irradiate the pituitary gland with crossing external radiotherapy beams. It can take several months for the full effect of radiation to occur, which is followed with serial blood tests.

Occasionally the patient who does not respond to all these measures might have to have both adrenal glands surgically removed (= bilateral adrenalectomy). The endocrinologist will closely monitor this patient, as the patient now needs careful hormone replacement similar to a patient with Addison’s disease. Other potent medications are available, but the endocrinologist would follow the patient on an ongoing basis with blood tests.

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