Cushing's
Disease and Cushing's Syndrome The most common form of overproduction
of the adrenal gland cortex is Cushing's disease. 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).
| Hyperfunction types
of the adrenal glands | | Name
of hyperfunction: | Description
of underlying pathology: | | Cushing's
disease | cortisol excess from adrenal gland overproduction |
| Cushing's syndrome | hypersecretion
of ACTH from pituitary gland adenoma or ectopic ACTH production such as with lung
carcinoma | Signs and symptoms: The
characteristic moon face (rounded) associated with obesity around the trunk, but
associated with slim muscle wasted 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 elevated blood pressure, osteoporosis,
kidney stones and proneness to infection. In children there is growth retardation
(=lack of growth). In women there are irregularities regarding menstruation. If
there is an adrenal gland tumor and testosterone like substances are also produced,
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.
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:
-
With the standard overnight dexamethasone
suppression test
(= dosage of 1mg) this potent artificial
corticosteroid is given in the late night and the morning plasma cortisol is determined.
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. Â 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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