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Cushing's Syndrome, Cushing's Disease Print E-mail

Dr. Kennedy What is now known as Cushing's syndrome was described by Harvey Cushing (1869-1939), an American physician, surgeon and endocrinologist. He reported this syndrome in the literature in 1932. Also called hypercortisolism and hyperadrenocorticism is an complex of symptoms commonly caused by high levels of cortisol in the blood from a variety of causes, including pituitary adenoma (known as Cushing's disease), adrenal hyperplasia or neoplasia, ectopic adrenocorticotropic hormone (ACTH) production (e.g., from a small cell lung cancer), and iatrogenic (doctor induced by steroid prescription). (The opposite of Cushing's syndrome is Addison's disease.)

Normally, cortisol is released from the adrenal gland in response to ACTH from the pituitary gland. Both Cushing's syndrome and Cushing's disease are characterized by elevated levels of cortisol in the blood, but the cause of elevated cortisol differs between the two. Cushing's disease specifically refers to a tumor in the pituitary gland that releases large amounts of ACTH which stimulates excessive cortisol from the adrenal gland. In Cushing's disease, ACTH levels do not respond to negative feedback from the high levels of cortisol.

Epidemiology

Iatrogenic Cushing's (caused by treatment with doctor prescribed corticosteroids) is the most common form of Cushing's syndrome. The incidence of pituitary tumors is as much as one in five people, but only a minute fraction are active and produce excessive hormones. (Cushing's syndrome is not confined to humans: it is also a relatively common condition in domestic dogs and horses.)

Symptoms may include:

  • rapid weight gain, particularly of the trunk and face with sparing of the limbs (central obesity), a round face often referred to as a "moon face"
  • hirsutism (facial male-pattern hair growth)
  • excess sweating
  • gastrointestinal disturbances
  • telangiectasia (dilation of capillaries)
  • thinning of the skin (which causes easy bruising) and other mucous membranes
  • purple or red striae (the weight gain in Cushing's stretches the skin, which is thin and weakened, causing it to hemorrhage) on the trunk, buttocks, arms, legs or breasts, proximal muscle weakness (hips, shoulders)
  • fat pads along the collar bone and on the back of the neck (known as a lipodystrophy)
  • hyperpigmentation (due to Melanocyte-Stimulating Hormone production as a byproduct of ACTH synthesis)
  • cortisol can also exhibit mineralcorticoid activity in high concentrations, worsening the hypertension and leading to hypokalemia (common in ectopic ACTH secretion)
  • opportunistic infections
  • impaired wound healing

Excess cortisol may also affect other endocrine systems and cause:

  • impotence
  • insomnia
  • reduced libido
  • amenorrhea
  • infertility
  • various psychological disturbances, ranging from euphoria to psychosis, including depression and anxiety
  • polydipsia and polyuria (excessive drinking and urination)
  • persistent hypertension (due to cortisol's enhancement of epinephrine's vasoconstrictive effect by cortisol)
  • insulin resistance (especially common in ectopic ACTH production), leading to hyperglycemia (high blood sugars) which can lead to diabetes mellitus.

Untreated Cushing's syndrome can lead to:

  • osteoporosis (mechanism not clear, but corrtisol may inhibit bone biliding cells called osteoblasts)
  • heart disease
  • increased mortality
  • depression the immune system
  • suppression of inflammatory responses
  • hirsuitism (male-pattern hair growth in a female)
  • oligomenorrhea (decreased frequency of menstruation due to elevations in male sex hormones

Endogenous vs. Exogenous

In endogenous disease, excess cortisol production within the body is the cause, while in exogenous disease the causal factor is typically steroid medication (p[rescribed or unprescribed) which mimics cortisol's activity. The signs and symptoms are virtually identical, except for those induced by ACTH in pituitary-dependent disease and ectopic ACTH-producing tumours (such as hyperpigmentation). The exogenous route is by far the most common cause of Cushing’s syndrome. Examples of such exogenous steroid medications are those used to treat inflammatory disorders such as asthma and rheumatoid arthritis, or to suppress the immune system. for example after an organ transplant. This type of Cushing’s is temporary and goes away after the patient no longer is taking cortisol-like medications. Endogenous Cushing’s syndrome is unusual, it usually comes on slowly and can be difficult to diagnose.

Diagnosis

When Cushing's (disease or syndrome) is suspected, a 24-hour urinary measurement for cortisol is easily obtained and is the most accurate test. The Dexamthasone stimulation test can also be used, but is somewhat endocrinologically invasive. Therefore, I avoid it. Another approach, recently cleared by the FDA, is sampling cortisol in saliva over 24 hours, which may be equally sensitive, as late night levels of salivary cortisol are high in Cushingoid patients. Other pituitary hormone levels may need to be ascertained. Performing a physical examination to determine any visual field defect may be necessary if a pituitary lesion is suspected, which may compress the optic chiasm causing typical bitemporal hemianopia (blind areas on both sides in the upper outer qaudrants). When any of these tests are positive, CT scanning of the adrenal gland and MRI of the pituitary should be performed to detect the presence of any adrenal or pituitary adenomas or harmless lesions. Scintigraphy of the adrenal gland with iodocholesterol scan is occasionally necessary. Very rarely, determining the cortisol levels in various veins in the body by venous catheterization, working towards the pituitary (petrosal sinus sampling) is necessary.

Treatment

One must remember that the vast majority of cases of Cushing's syndrome are caused by steroid medications. We must, therefore, remember to check patients' medications first, as tapering (and eventually stopping) the dose will usually resolve the problem. (Steroid medication must never be stopped suddenly.) If an adrenal adenoma (a benign tumor of the adrenal gland) is identified it may be removed by surgery. An ACTH-secreting corticotrophic pituitary adenoma should be removed after diagnosis. Most patients will require steroid replacement postoperatively at least in the interim because long-term suppression of pituitary ACTH and normal adrenal tissue does not recover immediately. If both adrenals are removed, replacement with hydrocortisone is required. In those patients not suitable for or unwilling to have surgery, several drugs have been found to inhibit cortisol synthesis (e.g. ketoconazole, metyrapone) but they are of limited efficacy. Removal of the adrenals in the absence of a known tumor is occasionally performed to eliminate the production of excess cortisol. In some occasions, this removes negative feedback from an undetected pituitary adenoma, which then begins to grow rapidy and produces extreme levels of ACTH, leading to hyperpigmentation. This is known as Nelson's syndrome.



The information in this article is not meant to be medical advice.�Treatment for a medical condition should come at the recommendation of your personal physician.

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