Elevated levels of cortisol hormone are mainly responsible for the occurrence of Cushing syndrome. Cortisol is mainly produced by adrenal glands in the body. Cortisol performs important functions in the body like regulation of blood pressure and normal functioning of cardiovascular system. Cortisol is also helpful in responding to stress and metabolizing carbohydrates, proteins and fats in the usable energy. However, elevated levels of cortisol, disrupt these physiological processes and lead to development of Cushing syndrome. Cortisol levels in MV might increase due to high levels of stress, malnutrition, depression and high levels of emotional stress. Cortisol levels in a person can also increase due to athletic training, alcoholism and panic disorders. High doses of anti-inflammatory medications like corticosteroids might increase cortisol levels. Pituitary gland releases more adrenocorticotropic (ACTH) hormone in pituitary gland tumor. This increase in the adrenocorticotroic hormone is known as Cushing’s disease. Adrenal gland abnormality or tumor might cuase Cushing’s syndrome. Even though70 – 80 % cases of the Cushing's syndrome occur due to excessive secretion of ACTH from the pituitary adenomas, it is evident that only 10 – 15 % pituitary adenomas secret excessive ACTH. Even though approximately 10 % cases of the Cushing's syndrome occur due to excessive secretion of cortisol from the adrenal adenomas, it is evident that only 6 % adrenal adenomas secret excessive cortisol. However, exact aetiology of excessive secretion of ACTH from pituitary adenomas and cortisol secretion from adrenal adenomas has not been well established. Genetic studies established that mutation in the ubiquitin-specific protease 8 is responsible for Cushing's disease 1,2.
Difference between Cushing’s syndrome and Cushing’s disease:
Tumor in the adrenal gland produces more amount of cortisol. This leads to the development of Cushing’s syndrome. Cushing’s syndrome can also be developed due to tumor in the pituitary gland. Cushing’s syndrome is the group of symptoms in which cortisol levels remains elevated for the longer duration. Tumor in the pituitary gland produces more amount of ACTH. This ACTH stimulates more secretion of cortisol from the adrenal gland. This type of Cushing’s syndrome is called as Cushing’s disease. Tumors produced by ACTH can be produced anywhere in the body and these are termed as ectopic tumors. Long term steroid administration is one of the causes of Cushing’s syndrome. Cushing’s disease may occur due to the endogenous factors like self-overproduction of cortisol by the body. Endogenous over-production of cortisol may occur due to pituitary tumor (Cushing’s disease), adrenal tumor and ectopic tumors3.
Hypothalamus is the part of brain below which pituitary gland is present. Corticotropin-releasing hormone (CRH) is secreted by paraventricular nucleus (PVN) of the hypothalamus. CRH stimulates pituitary gland to secret ACTH. ACTH gets transported through blood and as result adrenal gland gets stimulated to secret cortisol. Zona fasciculata is the region of cortex of adrenal gland which is responsible for the secretion of cortisol. Corticosteroid hormones are under the control of hypothalamus-pituitary-adrenal axis. Corticosteroids exhibit most prominent metabolic activity during the postprandial period. During this period, these hormones behave as contra-insular hormones. Hence, it provides substrates for oxidative metabolism and stimulate lipolysis and proteolysis. This results in the release of fatty acids and amino acids which induce glucose production by stimulating gluconeogenesis and inhibiting glycogen synthesis. Elevated levels of cortisol are responsible for the negative feedback which is responsible for the reduced secretion of ACTH.
In all types of etiologies of Cushing syndrome, there are raised levels of cortisol. Cortisol secreting adenoma in the cortex of adrenal gland occurs in Cushing’s syndrome. This adenoma of cortex of adrenal gland might be of primary hypercortisolism or hypercorticism types. Cushing’s syndrome due to elevated levels of ACTH is known as ectopic Cushing syndrome. Patients with severe hypercortisolism are associated with the phenotypes like glucose intolerance, dyslipidaemia, metabolic bone disease, and abnormal weight gain. On the other hand patients with mild or moderate hypercortisolism are rarely associated with glucose intolerance, dyslipidaemia, metabolic bone disease, and abnormal weight gain. Hence, it would be difficult to differentiate these patients from other patients with metabolic syndrome. There is presentation of striae, supraclavicular fat pads, and proximal muscle weakness in patients with increased hypercortisolism6. Elevated levels of corticosteroids results in the augmented production of glucose at the level of liver and skeletal muscle. In liver corticosteroids increase levels of glucose by stimulating gluconeogenesis and inhibiting insulin sensitivity. Corticosteroids stimulate gluconeogenesis by acting on different genes responsible for glucose metabolism. Corticosteroids reduce insulin sensitivity by exerting antagonistic effect on metabolic action of insulin which is most important hormone required for suppression of glucose production7,8.
Corticosteroids decrease expression and phosphorylation of insulin receptor substrate (IRS)-1, phosphatidylinositol-3kinase (PI3K) and protein kinase B (PKB/AKT). As a result, there is decrease in migration of glucose transporter GLUT4 to the cell surface which results in the reduction of glucose uptake. It also leads to decrease of glycogen synthase kinase (GSK)-3 phosphorylation and results in the decrease of glycogen synthesis. In skeletal muscles, corticosteroids increase insulin resistance which results in the decreased glucose uptake and prevention of glycogen synthesis. Corticosteroids exhibit effect on insulin resistance by directly acting on the insulin receptor or alteration in the insulin function by altering lipid and protein metabolism9,10.
Corticosteroids also play prominent role in the regulating adipose tissue differentiation, distribution and metabolism. Corticosteroids can stimulate differentiation of pre-adipocytes in adipocytes. Increased adipocytes are associated with raised body fat mass. Corticosteroid specifically act on visceral fat and not on the peripheral fat. Hence, corticosteroids are associated with central obesity in Cushing’s syndrome. Corticosteroids also play role in the release of hormone like adipokine which is responsible for the development of insulin resistance. Co-occurrence of insulin resistance and increased visceral fat can lead to the development of metabolic syndrome which is associated with impairment in the glucose metabolism. Metabolic syndrome comprises of visceral obesity, diabetes mellitus, and dyslipidemia. Effect of corticosteroids on the pancreatic beta cells result in the decreased insulin secretion. Corticosteroids exhibit effect on insulin secretion in dose dependent and time dependent manner. Corticosteroid exhibit effect on different steps of insulin secretion like glucose uptake, glucose utilization and calcium fluxes and exocytosis of granules containing insulin. Glucose transporter GLUT2 and glucokinase expression gets reduced due to corticosteroids11,12.
Corticosteroids can change AMP-activated protein kinase (AMPK) activity in tissue specific manner. Suppression of AMPK is proportional to hypercortisolism. Due to tissue specific activities, AMPK increases appetite, visceral obesity and dyslipidemia. Upon activation, AMPK plays key role in glycolysis and fatty acid synthesis which produces ATP. Due to hormone-sensitive lipase (HSL), there is increased level of lipids form adipose tissue which lead to development of adipocytes. 11 ?- hydroxysteroid dehydrogenase type 1 (11 ?H SD1) is responsible for the activation of cortisol from the inactive cortisone. 11 ?H SD1 overexpressed in mature adipocytes in conditions like hepatic steatosis and there is increased levels of cholesterol and triglycerides. 11 ?H SD1 is also associated with insulin resistance.
Cardiovascular complications associated with corticosteroids include systemic arterial hypertension, atherosclerosis, and thromboembolism. It has been established that elevated levels of corticosteroid can lead to the increase in renin-angiotensin system, stimulated sympathetic nervous system and endothelin system. It also leads to reduced nitric oxide (NO) synthesis and kallikrein-kinin system. Patients of Cushing’s syndrome are associated with irreversible arterial stiffness. Endothelin, homocysteine, vascular endothelial factor, adrenomedulin, and cell adhesion molecules are the markers of endothelial dysfunction and are responsible for vascular endothelial and smooth muscle proliferation and fibrosis around vessels and consequently development of atherosclerosis plaques. In subclinical Cushing’s syndrome both systolic and diastolic hypertension can occur. Blood pressure can elevate in patients with Cushing’s syndrome due to ACTH stimulated cortisol level15,16. Corticosteroids also produces immunosuppression and neuropsychiatric complications. Ectopic ACTH production lead to Cushing’s syndrome and neurocognitive impairment. Neuropsychiatric disorders associated with Cushing’s syndrome are major depression, mania, anxiety, and cognitive impairment17. Bone complications associated with corticosteroids include osteoporosis and osteoarthritis. Osteoporosis may occur in patients with Cushing’s syndrome due to increased bone reabsorption, decreased bone formation, reduced intestinal calcium absorption and increased urinary calcium excretion18.
Adrenocortical carcinomas are associated with clinical hypercortisolism and androgen overproduction. Elevated levels of urinary metabolites of androgens or glucocorticoid precursors are evident in the adrenocortical carcinomas. It reflects reduced activity of steroidogenic enzymes. Bilateral macronodular adrenal hyperplasia (BMAH) is seldom connected with MEN1, familial adenomatous polyposis, and fumarate hydratase gene mutations. Bilateral adrenal hyperplasias are presented as in the form of nodule diameter greater than 1 cm (macronodular) or less than 1 cm (micronodular). Patients with Cushing’s syndrome possesses ARMC5 gene mutations and associated with subclinical BMAH. In addition to the ARMC5 gene mutation, there is occurrence of mutations in histone H3 lysine 79 methyltransferase gene (DOTL1), in a histone deacetylase gene (HDAC9), or in a prune homologue 2 gene (PRUNE2) in BMAH19,20.
Molecular genetic abnormalities are helpful in the identifying causes of the Cushing’s syndrome. Glucocorticoid receptor gene mutation, dysfunction of proteins related to glucocorticoid-receptor function (Brg1 and HDAC2), and TP53-inactivating defects are responsible for the occurrence of Cushing’s syndrome. Overexpression of testicular orphan receptor 4 (TR4),30 a nuclear receptor with unknown ligand, the pituitary transforming gene (PTTG),31 and epidermal growth factor receptor are responsible for occurrence of Cushing’s syndrome. Overexpression of these genes are useful in identifying causal relationship and establishing therapeutic roles. Somatic mutations in the ubiquitin speci?c peptidase 8 gene (USP8) established role of epidermal growth factor receptor in Cushing’s syndrome. USP8 inactivation produces augmented epidermal growth factor receptor deubiquitination which leads to impairment in its down regulation and increased growth factor signalling and pro-opiomelanocortin (POMC) and ACTH synthesis. Mutations in the cAMP-dependent or ?-catenin signalling pathways are expresses in the adrenal adenomas. Mutations of GNAS (encoding Gs?, which activates adenylate cyclase) are reported in cortisol secreting adenomas and ?-catenin (CTNNB1) mutations in cortisol-secreting adenomas. Protein kinase A (PRKACA) mutations are reported in adenomas of Cushing’s syndrome. Phosphodiesterase 11A (PDE11A) or phosphodiesterase 8B (PDE8B) genetic variants are responsible for adrenal adenomas21.
Most of the clinical features of Cushing’s syndrome like body weight gain and blood pressure are common. Hence, it would be difficult to make exact diagnosis of Cushing’s syndrome. Hence, laboratory tests need to be performed for the diagnosis of Cushing’s syndrome. These tests would also be helpful in identifying Cushing disease which mainly occurs due to tumor of pituitary gland. Dexamethasone suppression test and 24-hour urinary and salivary measurement for cortisol are useful for the confirmation of Cushing’s syndrome. Dexamethasone suppression test involves frequent administration of dexamethasone and continuous monitoring of cortisol and ACTH levels. In this test, if body is monitoring cortisol, there would be decrease in the cortisol level. However, in cases of Cushing’s syndrome, there would be increase in the cortisol level. This test is not always useful because other illness or condition may produce high level of cortisol. This condition is called as pseudo-Cushing’s states. Doctors need to treat pseudo-Cushing’s states like depression. Post treatment, if there is no reduction in cortisol along with other physical worsening, Cushing’s syndrome would be confirmed.
ACTH measurement in the blood can be useful in differentiating Cushing’s syndrome and Cushing’s disease. Blood ACTH levels would be less in cases of Cushing’s syndrome, however it would be normal or higher in cases of Cushing’s disease. This is because, blood ACTH levels would be less in patients with adrenal origin Cushing’s syndrome as compared to the other origin of Cushing’s syndrome. ACTH producing tumor from the pituitary origin can be differentiated from the other parts of origin by using inferior petrosal sinus sampling, or IPSS. In this test, small plastic tube need to be inserted in the right and left veins in the groin and attach them to the veins near the pituitary gland. Blood should be collected form these veins and other locations far from the pituitary. During this procedure, medications which increase ACTH levels from the pituitary need to be injected. ACTH levels produced near pituitary and far from the pituitary need to be measured to assess tumors produced by pituitary origin. Inferior petrosal sinus sampling (IPSS) is more reliable as compared to the dexamethasone suppression test. Magnetic resonance imaging (MRI) can also be used as a diagnostic tool for Cushing’s syndrome. In this test, contrast is useful for showing up tumor in the MRI scan. Identification of the definitive tumor along with positive dexamethasone suppression test would be useful in diagnosis of Cushing’s disease. In such cases, there is no requirement of IPSS test. In few healthy people, there may be abnormal area on the pituitary, which might resemble tumor in MRI, hence abnormality doesn’t reflect occurrence of Cushing’s disease. In few cases, tumor may be too small to detect using MRI. Hence, absence of tumor should not exclude Cushing’s syndrome. Sodium and potassium levels can be increased in patients with Cushing’s syndrome, hence assessment of electrolyte balance can be used as a diagnostic tool23.
Treatment and management:
Main aim of the treatment of Cushing’s syndrome should be reduction in the level of cortisol. Treatment of Cushing’s syndrome may vary based on the cause of the disease. Corticosteroid medication use should be reduced. Dose of the corticosteroid should be reduced. However, reduced dose of corticosteroid should be useful in the management of chronic inflammatory disease. Non-corticosteroids drugs can be administered along with corticosteroids to reduce dose of corticosteroids. Use of corticosteroids should not be stopped abruptly because it may lead to decrease in cortisol levels. In patients with existence of tumor, surgery should be performed to remove tumor. Pituitary tumors can be removed by performing surgery through nose and neurosurgeon can perform this surgery. Adrenal gland tumors can be removed by standard surgical procedure and using minimally invasive surgical technique. After the completion of the surgery, cortisol replacement medications should be provided to the patients to maintain normal levels of cortisol. Cortisol replacement medications usually takes long duration to maintain normal level of cortisol. Radiation therapy should be provided to the patients, in whom surgeon can’t remove tumor completely. Hence, in such cases radiation therapy should be used as an adjuvant therapy along with surgery. Radiation therapy should be used in patients in whom surgery can not be performed. Radiation should be given in little doses for a duration of 6 weeks. Stereotactic radiosurgery, which is also called as Gamma Knife surgery can also be used, in which large single dose of radiation should be given to tumor part with minimal exposure to the surrounding area. Medications to control cortisol levels should be administered to patients, whom are very sick and surgery can not be performed in such patients24.
Ketoconazole, mitotane and metyrapone can be used to reduce excessive production of cortisol from the adrenal gland. It is evident that, Ketoconazole can reduce plasma cortisone, however it can not reduce plasma ACTH. Metyrapone exhibits its action by inhibiting 11?-hydroxylase. Due to use of metyrapone, there may be increase in ACTH levels relative to the decrease in the cortisol levels. This may result in the stimulation of the adrenal androgen and increased mineralocorticoid production. Mifepristone is useful in the Cushing’s syndrome patients with diabetes and glucose intolerance. Mitotane exhibits its action by inhibiting 11?-hydroxylase, 18-hydroxylase, 3?-hydroxy-lase, hydroxysteroid dehydrogenase, and several cholesterol side chain cleavage enzymes. Mitotane exhibits adrenolytic action by binding its metabolite to the macromolecules in adrenal cortical cell mitochondria. This results in the cell destruction and cellular necrosis. Mifepristone does not reduce cortisol level; however it blocks action of cortisol on tissues. Pasireotide is useful in the Cushing’s disease because it reduces the ACTH secretion from pituitary tumor. This medication should be administered twice daily, if surgery can not be performed or in cases of unsuccessful surgery. If none of the treatment works, bilateral adrenalectomy should be performed. In bilateral adrenalectomy, there would be surgical removal of adrenal gland. This surgical intervention is useful in reducing excess levels of cortisol, however such patients require life-long cortisol replacement medications.
Newer compounds like CDK2/cyclin inhibitor R-roscovitin (targeting PTTG overexpression) or ge?tinib, the epidermal growth factor receptor-tyrosine kinase inhibitor are responsible for the inhibition of corticotroph tumour growth. Hence, these compounds are helpful in the alleviate clinical and biochemical features of Cushing’s syndrome. Ge?tinib exhibits effect in Cushing’s syndrome by decreasing ACTH secretion in USP8-mutated human corticotroph cells26.
Patients with Cushing’s syndrome should take care of their general health. They should take healthy diet and exercise on regular basis. High impact or heavy weight exercise should be avoided by patients with Cushing’s syndrome because bones might weaken in these patients. More amount of calcium and vitamin D should be administered to strengthen the bones. Patient’s with Cushing’s syndrome should quit smoking and avoid consumption of large quantity alcohol. Nurse should advise MV to follow-up regular basis. MV should inform doctor about adverse effects of medications. Nurse should advise MV to keep adequate supply of corticosteroids to avoid shortage. MV and her family members should be aware of evaluating and measuring blood pressure, blood glucose and body weight. Safe environment should be provided to MV because there is possibility of fall due to weak bones. Fall prevention strategies should be provided to MV. MV should wear identification mark for Cushing’s syndrome, hence other doctors can identify her as patient. Nurse should encourage MV to verbalize feelings and concerns. MV and family members should adapt to the emotional instability and should cope with mood swings, irritability, and depression. Assurance should be given to MV that, physical changes occurred due to Cushing’s syndrome can be disappeared if cause of the disease treated. Weight gain and edema can be managed by consuming low carbohydrate and low sodium diet.
Excessive exposure to glucorticoids results in mortality and morbidity due to Cushing's syndrome. Genetic and molecular studies established that primary adrenal lesions and ACTH secretion are responsible for the excessive secretion of cortisol. Biochemical and imaging diagnostic studies proved useful in differentiating Cushing's syndrome from Cushing's disease. Radiotherapy, drug therapy and surgical treatment improved management of patients with Cushing's syndrome. Management goals for the patients with Cushing's syndrome should be normal functioning of the hypothalamic-pituitary-adrenal axis, normal functioning of the pituitary gland, and evading of tumour recurrence.
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