Cushing's syndrome
Cushing's syndrome | |
---|---|
Other names | Hypercortisolism, Itsenko-Cushing syndrome, hyperadrenocorticism |
round face, often reddened due to facial plethora, fat lump between the shoulders, weak muscles, acne, fragile skin[2] | |
Complications | High blood pressure (hypertension), Type 2 diabetes, Frequent or unusual infections, Loss of muscle mass and strength, Bone loss (osteoporosis).[3] |
Usual onset | 20–50 years[4] |
Causes | Prolonged exposure to cortisol[4] |
Diagnostic method | Requires a number of steps[5] |
Treatment | Based on underlying cause[6] |
Prognosis | Generally good with treatment[7] |
Frequency | 2–3 per million people per year[8] (from 1/333,333 to 1/500,000 people) |
Cushing's syndrome is a collection of signs and symptoms due to prolonged exposure to
Cushing's syndrome is caused by either excessive cortisol-like medication, such as
Most cases can be treated and cured.[7] If due to medications, these can often be slowly decreased if still required or slowly stopped.[6][15] If caused by a tumor, it may be treated by a combination of surgery, chemotherapy, and/or radiation.[6] If the pituitary was affected, other medications may be required to replace its lost function.[6] With treatment, life expectancy is usually normal.[7] Some, in whom surgery is unable to remove the entire tumor, have an increased risk of death.[16]
About two to three cases per million persons are caused overtly by a tumor.[8] It most commonly affects people who are 20 to 50 years of age.[4] Women are affected three times more often than men.[8] A mild degree of overproduction of cortisol without obvious symptoms, however, is more common.[17] Cushing's syndrome was first described by American neurosurgeon Harvey Cushing in 1932.[18] Cushing's syndrome may also occur in other animals including cats, dogs, and horses.[19][20]
Signs and symptoms
Symptoms include rapid
Many of the features of Cushing's are those seen in metabolic syndrome, including insulin resistance, hypertension, obesity, and elevated blood levels of triglycerides.[24]
Cognitive conditions, including memory and attention dysfunctions, as well as depression, are commonly associated with elevated cortisol,
Other striking and distressing skin changes that may appear in Cushing's syndrome include facial acne, susceptibility to superficial fungus (dermatophyte and malassezia) infections, and the characteristic purplish, atrophic striae on the abdomen.[27]: 500
Other signs include
Brain changes such as cerebral atrophy may occur.[28] This atrophy is associated with areas of high glucocorticoid receptor concentrations such as the hippocampus and correlates highly with psychopathological personality changes.[29][30][31][32]
- Rapid weight gain
- Moodiness, irritability, or depression
- Muscle and bone weakness
- Memory and attention dysfunction
- Osteoporosis
- Diabetes mellitus
- Hypertension
- Immune suppression
- Sleep disturbances
- Menstrual disorders such as amenorrhea in women
- Infertility in women
- Impotencein men
- Hirsutism
- Baldness
- Hypercholesterolemia
Hyperpigmentation
Cushing's syndrome due to excess
When Cushing's syndrome is caused by an increase of cortisol at the level of the adrenal glands (via an adenoma or hyperplasia), negative feedback ultimately reduces ACTH production in the pituitary. In these cases, ACTH levels remain low and no hyperpigmentation develops.[33]
Causes
Cushing's syndrome may result from any cause of increased glucocorticoid levels, whether due to medication or internal processes.[10][34] Some sources however do not consider the glucocorticoid medication-induced condition as "Cushing's syndrome" proper, instead using the term "Cushingoid" to describe the medication's side effects which mimic the endogenous condition.[35][34][36]
Cushing's disease is a specific type of Cushing's syndrome caused by a pituitary tumor leading to excessive production of
Exogenous
The most common cause of Cushing's syndrome is the use of prescribed glucocorticoids to treat other diseases (iatrogenic Cushing's syndrome). Glucocorticoids are used in treatment of a variety of disorders, including asthma and rheumatoid arthritis, and also used for immunosuppression after organ transplants. Administration of synthetic ACTH is also possible, but ACTH is less often prescribed due to cost and lesser utility. Rarely, Cushing's syndrome can also be due to the use of medroxyprogesterone acetate.[40][41] In exogenous Cushing's, the adrenal glands may often gradually atrophy due to lack of stimulation by ACTH, the production of which is suppressed by glucocorticoid medication. Abruptly stopping the medication can thus result in acute and potentially life-threatening adrenal insufficiency and the dose must hence be slowly and carefully tapered off to allow internal cortisol production to pick up. In some cases, patients never recover sufficient levels of internal production and must continue taking glucocorticoids at physiological doses for life.[35][42]
Cushing's syndrome in childhood is especially rare and usually results from use of glucocorticoid medication.[43]
Endogenous
- In pituitary Cushing's, a benign pituitary adenoma secretes ACTH. This is also known as Cushing's disease and is responsible for 70% of endogenous Cushing's syndrome.[44]
- In adrenal Cushing's, excess cortisol is produced by adrenal gland tumors, hyperplastic adrenal glands, or adrenal glands with nodular adrenal hyperplasia.
- Tumors outside the normal pituitary-adrenal system can produce ACTH (occasionally with CRH) that affects the adrenal glands. This etiology is called ectopic or small cell lung cancer.[45]
- Finally, rare cases of CRH-secreting tumors (without ACTH secretion) have been reported, which stimulates pituitary ACTH production.[46]
Pseudo-Cushing's syndrome
Elevated levels of total cortisol can also be due to estrogen found in oral contraceptive pills that contain a mixture of estrogen and progesterone, leading to pseudo-Cushing's syndrome. Estrogen can cause an increase of cortisol-binding globulin and thereby cause the total cortisol level to be elevated. However, the total free cortisol, which is the active hormone in the body, as measured by a 24-hour urine collection for urinary free cortisol, is normal.[47]
Pathophysiology
The
Strictly, Cushing's syndrome refers to excess cortisol of any etiology (as syndrome means a group of symptoms). One of the causes of Cushing's syndrome is a cortisol-secreting adenoma in the cortex of the adrenal gland (primary hypercortisolism/hypercorticism). The adenoma causes cortisol levels in the blood to be very high, and negative feedback on the pituitary from the high cortisol levels causes ACTH levels to be very low.[citation needed]
When Cushing's syndrome is due to extra
When Cushing's syndrome is suspected, either a
When any of these tests is positive,
Plasma CRH levels are inadequate at diagnosis (with the possible exception of tumors secreting CRH) because of peripheral dilution and binding to CRHBP.[51]
Diagnosis
Cushing's syndrome can be ascertained via a variety of tests which include the following:[53]
- 24-hour urine free cortisol
- Dexamethasone suppression test
- Saliva cortisol level
Treatment
Most cases of Cushingoid symptoms are caused by corticosteroid medications, such as those used for asthma, arthritis, eczema and other inflammatory conditions. Consequently, most patients are effectively treated by carefully tapering off (and eventually stopping) the medication that causes the symptoms.[citation needed]
If an adrenal adenoma is identified, it may be removed by surgery. An ACTH-secreting corticotrophic pituitary adenoma should be removed after diagnosis. Regardless of the adenoma's location, most patients require steroid replacement postoperatively at least in the interim, as long-term suppression of pituitary ACTH and normal adrenal tissue does not recover immediately. Clearly, if both adrenals are removed, replacement with hydrocortisone or prednisolone is imperative.[citation needed]
In those patients not suited for or unwilling to undergo surgery, several drugs have been found to inhibit cortisol synthesis (e.g. ketoconazole, metyrapone) but they are of limited efficacy.[citation needed] Mifepristone is a powerful glucocorticoid type II receptor antagonist and, since it does not interfere with normal cortisol homeostasis type I receptor transmission, may be especially useful for treating the cognitive effects of Cushing's syndrome.[54] However, the medication faces considerable controversy due to its use as an abortifacient. In February 2012, the FDA approved mifepristone to control high blood sugar levels (hyperglycemia) in adult patients who are not candidates for surgery, or who did not respond to prior surgery, with the warning that mifepristone should never be used by pregnant women- although pregnancy is extremely rare during the course of Cushing's Syndrome[55][56][57] [58] In March 2020, Isturisa (osilodrostat) oral tablets a 11-beta-hydroxylase enzyme inhibitor was approved by FDA for treating those patients who cannot undergo pituitary surgery or for patients who underwent surgery but continue to have the disease.[59]
Removal of the adrenals in the absence of a known tumor is occasionally performed to eliminate the production of excess cortisol.[60] In some occasions, this removes negative feedback from a previously occult pituitary adenoma, which starts growing rapidly and produces extreme levels of ACTH, leading to hyperpigmentation. This clinical situation is known as Nelson's syndrome.[61]
Epidemiology
Cushing's syndrome caused by treatment with corticosteroids is the most common form. Cushing's disease is rare; a Danish study found an incidence of less than one case per million people per year.[62] However, asymptomatic microadenomas (less than 10 mm in size) of the pituitary are found in about one in six individuals.[63]
About 0.9 to 1% of those with Cushing's syndrome have a tendency to develop venous thrombosis. Other factors such as surgery and obesity also increase the chance of getting thrombosis.[64]
See also
- Addison's disease
- Adrenal insufficiency (hypocortisolism)
- Corticosteroid-induced lipodystrophy
- pituitary pars intermedia dysfunction
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{{cite journal}}
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External links
- "Cushing's Syndrome". MedlinePlus. U.S. National Library of Medicine.