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Cushing's syndrome describes the signs and symptoms associated with prolonged exposure to inappropriately high levels of the hormone cortisol. This can be caused by taking glucocorticoid drugs, or diseases that result in excess cortisol, adrenocorticotropic hormone (ACTH), or CRH levels.
Cushing's disease refers to a pituitary-dependent cause of Cushing's syndrome: a tumor (adenoma) in the pituitary gland produces large amounts of ACTH, causing the adrenal glands to produce elevated levels of cortisol. It is the most common non-iatrogenic cause of Cushing's syndrome, responsible for 70% of cases excluding glucocorticoid related cases.
Signs and symptoms
Symptoms include rapid weight gain, particularly of the trunk and face with sparing of the limbs (central obesity). A common sign is the growth of fat pads along the collarbone and on the back of the neck and a round face often referred to as a "moon face." Other symptoms include hyperhidrosis (excess sweating), telangiectasia (dilation of capillaries), thinning of the skin (which causes easy bruising and dryness, particularly the hands) and other mucous membranes, purple or red striae (the weight gain in Cushing's syndrome 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), and hirsutism (facial male-pattern hair growth), baldness and/or extremely dry and brittle hair. In rare cases, Cushing's can cause hypocalcemia. The excess cortisol may also affect other endocrine systems and cause, for example, insomnia, inhibited aromatase, reduced libido, impotence in men, amenorrhoea/oligomenorrhea and infertility in women due to elevations in androgens. Studies have also shown that the resultant amenorrhea is due to hypercortisolism, which feeds back onto the hypothalamus resulting in decreased levels of GnRH release.
Cognitive conditions, including memory and attention dysfunctions, as well as depression are commonly associated with elevated cortisol and may be early indicators of exogenous or endogenous Cushing's. Patients frequently suffer various psychological disturbances, ranging from euphoria to psychosis. Depression and anxiety are also common.
Other striking and distressing skin changes that may appear in Cushing's syndrome include facial acne, susceptibility to superficial dermatophyte and malassezia infections, and the characteristic purplish, atrophic striae on the abdomen.:500
Other signs include polyuria (and accompanying polydipsia), persistent hypertension (due to cortisol's enhancement of epinephrine's vasoconstrictive effect) and insulin resistance (especially common in ectopic ACTH production), leading to hyperglycemia (high blood sugar) and insulin resistance which can lead to diabetes mellitus. Insulin resistance is accompanied by skin changes such as acanthosis nigricans in the axilla and around the neck, as well as skin tags in the axilla. Untreated Cushing's syndrome can lead to heart disease and increased mortality. Cushing's disease due to excess ACTH may also result in hyperpigmentation. This is due to Melanocyte-Stimulating Hormone production as a byproduct of ACTH synthesis from Pro-opiomelanocortin (POMC). Cortisol can also exhibit mineralcorticoid activity in high concentrations, worsening the hypertension and leading to hypokalemia (common in ectopic ACTH secretion). Furthermore, gastrointestinal disturbances, opportunistic infections and impaired wound healing (cortisol is a stress hormone, so it depresses the immune and inflammatory responses). Osteoporosis is also an issue in Cushing's syndrome since osteoblast activity is inhibited. Additionally, Cushing's may cause sore and aching joints, particularly in the hip, shoulders, and lower back. Cushing’s syndrome includes all the causes of increased cortisol leading to the diseased state. Cushing’s disease is a subset of Cushing’s syndrome that refers to Cushing’s syndrome caused by a pituitary tumor. When this occurs, ACTH levels are high which ultimately leads to increased cortisol production by the adrenal glands. Ectopic ACTH production (e.g. by a small cell lung cancer) is another cause of Cushing’s syndrome that has high ACTH. When Cushing's syndrome is caused by an increase of cortisol at the level of the adrenal glands (via an adenoma or hyperplasia), this causes negative feedback which ultimately reduces ACTH production in the pituitary. This type of Cushing's syndrome doesn't cause hyperpigmentation because there is no excess of ACTH. Again, Cushing's disease is an excess of ACTH at the pituitary level which causes increase cortisol release from the adrenals. This increased ACTH may cause hyperpigmentation as previously described. While all Cushing’s disease is Cushing’s syndrome, not all Cushing’s syndrome is Cushing’s disease.
- Extreme weight gain
- Moodiness, irritability, or depression
- Muscle and bone weakness
- Memory and attention dysfunction
- Diabetes mellitus
- Immune suppression
- Sleep disturbances
- Menstrual disorders such as amenorrhea in women and decreased fertility in men
There are several possible causes of Cushing's syndrome.
Exogenous vs. endogenous
The most common cause of Cushing's syndrome is exogenous administration of glucocorticoids prescribed by a health care practitioner to treat other diseases (called iatrogenic Cushing's syndrome). This can be an effect of corticosteroid treatment of a variety of disorders such as asthma and rheumatoid arthritis, or in immunosuppression after an organ transplant. Administration of synthetic ACTH is also possible, but ACTH is less often prescribed due to cost and lesser utility. Although rare, Cushing's syndrome can also be due to the use of medroxyprogesterone. In this form of Cushing's, the adrenal glands atrophy due to lack of stimulation by ACTH, since glucocorticoids downregulate production of ACTH.
Endogenous Cushing's syndrome results from some derangement of the body's own system of secreting cortisol. Normally, ACTH is released from the pituitary gland when necessary to stimulate the release of cortisol from the adrenal glands.
- 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.
- 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 paraneoplastic Cushing's disease and is seen in diseases like small cell lung cancer.
- Finally, rare cases of CRH-secreting tumors (without ACTH secretion) have been reported, which stimulates pituitary ACTH production.
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.
Iatrogenic Cushing's syndrome (caused by treatment with corticosteroids) is the most common form of Cushing's syndrome. The incidence of pituitary tumors may be relatively high, as much as one in five people, but only a minute fraction are active and produce excessive hormones.
The hypothalamus is in the brain and the pituitary gland sits just below it. The paraventricular nucleus (PVN) of the hypothalamus releases corticotropin-releasing hormone (CRH), which stimulates the pituitary gland to release adrenocorticotropin (ACTH). ACTH travels via the blood to the adrenal gland, where it stimulates the release of cortisol. Cortisol is secreted by the cortex of the adrenal gland from a region called the zona fasciculata in response to ACTH. Elevated levels of cortisol exert negative feedback on the pituitary, which decreases the amount of ACTH released from the pituitary gland.
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.
On the other hand, Cushing's disease refers only to hypercortisolism secondary to excess production of ACTH from a corticotroph pituitary adenoma (secondary hypercortisolism/hypercorticism) or due to excess production of hypothalamus CRH (Corticotropin releasing hormone) (tertiary hypercortisolism/hypercorticism). This causes the blood ACTH levels to be elevated along with cortisol from the adrenal gland. The ACTH levels remain high because the tumor is unresponsive to negative feedback from high cortisol levels.
Cushing's Syndrome was also the first autoimmune disease identified in humans.
When Cushing's syndrome is suspected, either a dexamethasone suppression test (administration of dexamethasone and frequent determination of cortisol and ACTH level), or a 24-hour urinary measurement for cortisol offer equal detection rates. Dexamethasone is a glucocorticoid and simulates the effects of cortisol, including negative feedback on the pituitary gland. When dexamethasone is administered and a blood sample is tested, cortisol levels >50nmol/L (1.81 µg/dL) would be indicative of Cushing's syndrome because there is an ectopic source of cortisol or ACTH (such as adrenal adenoma) that is not inhibited by the dexamethasone. A novel approach, recently cleared by the US 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.
When any of these tests are positive, CT scanning of the adrenal gland and MRI of the pituitary gland are performed to detect the presence of any adrenal or pituitary adenomas or incidentalomas (the incidental discovery of harmless lesions). Scintigraphy of the adrenal gland with iodocholesterol scan is occasionally necessary. Very rarely, determining the ACTH levels in various veins in the body by venous catheterization, working towards the pituitary (petrosal sinus sampling) is necessary.
C - Central obesity, Clavical fat pads, Collagen fibre weakness, Comedones (acne)
U - Urinary free cortisol and glucose increase
S - Striae, Suppressed immunity
H - Hypercortisolism, Hypertension, Hyperglycemia, Hypercholesterolemia, Hirsutism, Hypernatremia, Hypokalemia
I - Iatrogenic (Increased administration of corticosteroids)
N - Noniatrogenic (Neoplasms)
G - Glucose intolerance, Growth retardation
Most Cushing's syndrome cases are caused by corticosteroid medications (iatrogenic), such as those used for asthma, arthritis, and other inflammatory conditions. Consequently, most patients are effectively treated by carefully tapering off (and eventually stopping) the medication that causes the symptoms.
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 will 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.
In those patients not suitable 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. Mifepristone is a powerful glucocorticoid type II receptor antagonist and, since it does not interfere with normal cortisol homeostatis type I receptor transmission, may be especially useful for treating the cognitive effects of Cushing's syndrome. However, the medication faces considerable controversy due to its use as an abortifacient. In February 2012 the FDA approved mifepristone in order to control high blood sugar level (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.
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 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.
- Kumar, Abbas, Fausto. Robbins and Cotran Pathologic Basis of Disease, 7th ed. Elsevier-Saunders; New York, 2005.
- Schwartz's principles of surgery, 8th ed., p.1455.
- Cushing's Syndrome at The National Endocrine and Metabolic Diseases Information Service. July 2008. Citing: Nieman LK, Ilias I. "Evaluation and treatment of Cushing's syndrome". The Journal of American Medicine 2005; 118(12), 1340–1346.
- Cushing, HW (1932). "The basophil adenomas of the pituitary body and their clinical manifestations (pituitary basophilism)". Bulletin of the Johns Hopkins Hospital 50 (4): 137–95. PMC 2387613. PMID 19310569.
- "Dr. Cushing Dead; Brain Surgeon, 70. A Pioneer Who Won Fame as Founder of New School of Neuro-Surgery. Discovered Malady Affecting Pituitary Gland. Was Noted Teacher and Author". The New York Times. October 8, 1939. Retrieved 2010-03-21. "Dr. Harvey Williams Cushing, international authority on brain surgery and neurology, who for his ..."
- Kwasnik, A.I.; Gurkalova, I.P.; Zukow, W. (2009). "Trematoda". Pathology: Medical Student's Library. Radomska Szkola Wyžsza uk. Zubrzyckiego. p. 280. ISBN 978-83-61047-18-6. More than one of
- Wilkinson, Allan B. (1961). "Cushing's Syndrome". California Medicine 94 (6): 357–362. PMC 1574387. PMID 13785315.
- Belanoff et al., 2001, Corticosteroids and cognition, J Psychiatric Research, 35(3):127-145
- Yudofsky, Stuart C.; Robert E. Hales (2007). The American Psychiatric Publishing Textbook of Neuropsychiatry and Behavioral Neurosciences (5th ed.). American Psychiatric Pub, Inc. ISBN 1-58562-239-7.
- James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0.
- Siminoski, K; Goss, P; Drucker, DJ (1989). "The Cushing syndrome induced by medroxyprogesterone acetate". Annals of internal medicine 111 (9): 758–60. PMID 2552887.
- Merrin, PK; Alexander, WD (1990). "Cushing's syndrome induced by medroxyprogesterone". BMJ (Clinical research ed.) 301 (6747): 345. doi:10.1136/bmj.301.6747.345-a. PMC 1663616. PMID 2144198.
- Schteingart DE, Lloyd RV, Akil H, Chandler WF, Ibarra-Perez G, Rosen SG, Ogletree R. (1989). "Cushing's syndrome secondary to ectopic corticotropin-releasing hormone-adrenocorticotropin secretion.". J Clin Endocrinol Metab. 63 (3): 770–5. PMID 3525603.
- Voyadzis JM, Guttman-Bauman I, Santi M, Cogen P. (2004). "Hypothalamic hamartoma secreting corticotropin-releasing hormone. Case report.". J Neurosurg 100 (2 Suppl Pediatrics): 212–6. doi:10.3171/ped.2004.100.2.0212. PMID 14758953.
- C. W. Burke (1969). "The effect of oral contraceptives on cortisol metabolism". J Clin Pathol 3: 11–18. doi:10.1136/jcp.s1-3.1.11. PMC 1436049.
- Ezzat S, Asa SL, Couldwell WT, et al. (2004). "The prevalence of pituitary adenomas: a systematic review". Cancer 101 (3): 613–9. doi:10.1002/cncr.20412. PMID 15274075.
- Ectopic Cushing syndrome at A.D.A.M. Medical Encyclopedia, PubMedHealth, National Institute of Health
- Medvei, VC (1991). "The history of Cushing's disease: A controversial tale". Journal of the Royal Society of Medicine 84 (6): 363–366. PMC 1293286. PMID 2061905.
- Raff H, Findling JW (2003). "A physiologic approach to diagnosis of the Cushing syndrome". Ann. Intern. Med. 138 (12): 980–91. PMID 12809455.
- Jr, edited by Lewis S. Blevins (2002). Cushing's syndrome. Boston: Kluwer Academic. p. 115. ISBN 1-4020-7131-0.
- Belanoff et al., 2001, Rapid reversal of psychotic depression using mifepristone, J Clin Psychopharmacol, 21(5):516-521
- "FDA approves mifepristone (Korlym*) for patients with endogenous Cushing' s syndrome". February 18, 2012.
- Nelson DH, Meakin JW, Thorn GW (1960). "ACTH-producing pituitary tumors following adrenalectomy for Cushing syndrome". Ann. Intern. Med. 52: 560–9. PMID 14426442.
- The European Register on Cushing's Syndrome
- Patient information (PDF)
- Cushing's Support and Research Foundation
- Brochure for Primary Care Physicians, to increase awareness of Cushing's syndrome
- The Pituitary Foundation providing support to patients with Cushing's and other pituitary disorders