Cushings Syndrome and Addisons Disease - Essay Example

Assignment 1: Discuss the Cortisol-ACTH axis BIO3215 Clinical Biochemistry 2 Name Institutional Affiliation Date Abstract The cortisol-adrenocorticotropic hormone (ACTH) axis represents the body’s endocrinal negative feedback response to stress. Abnormal secretion of cortisol and/or ACTH, and failure to restore homeostasis through the axis’ feedback mechanism can result in endocrinal-related disorders. The aim of this paper is to discuss Cushing’s syndrome and Addison’s disease caused by hyper cortisol and hypo cortisol production respectively. Evidence to support the discussion was collected using PubMed database where a review of relevant studies was conducted. Studies that were published between 2009 and 2015 were selected. 15 articles that were best suited to contribute to the discussion content were used. The synthesis of the evidence shows excessive cortisol production result from adrenal or pituitary tumors leading to Cushing’s syndrome. Damage to adrenal glands inhibits cortisol production leading to Addison’s disease. The underlying physiology shows that the hypothalamus acts on the pituitary by releasing the corticotrophin-releasing hormone which stimulates ACTH production. Increase in ACTH levels triggers the release of cortisol from the adrenal cortex. Cortisol responds to stress and acts on the pituitary to inhibit ACTH production and subsequently its own production. Finally, the evidence provided show how the endocrine secretion disorders Cushing’s syndrome and Addison’s disease are tested, diagnosed and treated. Introduction Cortisol and ACTH (adrenocorticotropic hormone) are part of the HPA (hypothalamic-pituitary-adrenal) axis. The axis denotes the signaling relationship between the hypothalamus and the pituitary and adrenal glands responsible for feedback mechanisms that result in hormonal homeostasis (Hershel, Sharma & Nieman 2014). The axis is the body’s stress response system. Inadequate or excessive activation of the axis may contribute to the development of pathologies (Hershel, Sharma & Nieman 2014). This research focuses on disorders related with hypersecretion and/or hyposecretion of cortisol and adrenocorticotrophic hormone (ACTH). Cushing’s syndrome is characterized by cortisol hypersecretion, while Addison’s disease is characterized by cortisol hyposecretion (Hershel 2009; Yoon et al. 2013). Their history and name significance, symptoms, underlying physiology, diagnostic tests, further tests recommended and treatment are discussed. a. History and name significance of related disorders Cushing’s syndrome is named after the neurosurgeon, Harvey Cushing who first described the disorder in 1932 (Kooistra & Galac 2012). Cushing’s syndrome results when there is hypersecretion of cortisol, also referred to as hypercortisolism (Kooistra & Galac 2012). Cushing’s syndrome can be caused by a tumor in adrenal cortex or pituitary gland (Biller et al. 2010). When there is hyposecretion of cortisol, the condition is referred to as adrenal insufficiency, which can be primary or secondary (Neary & Nieman 2010). This is known as hypocortisolism or Addison’s disease, named after Thomas Addison, who first described the condition in 1849 (Neary & Nieman 2010). Primary adrenal insufficiency occurs when there is damage to the adrenal glands resulting in reduced cortisol secretion (Baruah 2012). Hence, ACTH production cannot be inhibited by the negative feedback mechanism and its levels are elevated (Hershel, Sharma & Nieman 2014). Secondary or hypopituitary adrenal insufficiency occurs due to a tumor or abnormality in the pituitary that suppresses ACTH production. b. Symptoms Cushing’s syndrome manifests various symptoms including rapid weight gain, accumulation of fat in the abdominal area but with thinner limbs, fat lump between shoulders and a moon face, where the face appears round and pale. Other symptoms are hypercalcemia and hyperhydrosis with weak bones, weak muscles, pinkish stretch marks, acne and fragile skin that heals poorly (Fallo et al. 2011). Chronic fatigue and headaches are also common. Female patients may have more hair and amenorrhea due to hormonal imbalance. Psychological symptoms include mood instability, lethargy, depression and anxiety. Hypercortisolism is a common characteristic type of central obesity (Fallo et al. 2011). It also results in insulin resistance leading to type 2 diabetes mellitus, hypertension, and excessive bone resorption leading to osteoporosis (Fallo et al. 2011). Addison’s disease symptoms manifest gradually. They include weight loss and poor appetite, salt cravings, hyperpigmentation, low blood pressure, muscle weakness and fatigue, lightheadedness when standing up, loss of consciousness, muscle or joint pains, hypoglycemia, nausea, vomiting and diarrhea (Oboni et al. 2013). Women may experience body hair loss and sexual dysfunction. Psychological and behavioral symptoms include mood and personality changes (Oboni et al. 2013). Addison’s disease is associated with the development of other autoimmune diseases including type I diabetes, Hashimoto’s thyroiditis, and vitiligo (Baruah 2012). c. Underlying physiology including diagrams if appropriate The secretion of cortisol and ACTH is regulated by the HPA axis where the hormones regulate their own secretion through a negative feedback inhibition mechanism (Balbo, Leproult & Cauter 2010). The significance of the negative feedback inhibition mechanism is establishing hormonal homeostasis. When the body is expressed to stress the paraventricular nucleus of the hypothalamus releases CRH (corticotrophin-releasing hormone) (Balbo, Leproult & Cauter 2010). CRH stimulates the anterior lobe of the pituitary gland to release ACTH. ACTH stimulates the adrenal cortex in the zona fasciculate which results in the release of cortisol (Balbo, Leproult & Cauter 2010). Once homeostasis is achieved, cortisol inhibits the secretion of its tropic hormone CRH, leading to inhibition of ACTH and hence inhibiting the cortisol production (Balbo, Leproult & Cauter 2010). Figure 1: The negative feedback loop of the HPA axis In Cushing’s disease caused by pituitary tumor, more CRH is secreted triggering higher ACTH secretion and subsequent higher cortisol release (Hershel, Sharma & Nieman 2014). In Cushing syndrome caused by adrenal tumor, cortisol production is higher leading to suppression of the tropic CRH and subsequent low ACTH release (Hershel, Sharma & Nieman 2014). In case one adrenal gland is damaged in adrenal insufficiency or Addison’s disease, there will be decreased cortisol production (Hershel, Sharma & Nieman 2014); hence, a decrease in the degree of the negative feedback inhibition. Reduced cortisol production means that there will be reduced stimulation on the hypothalamus from the adrenal. Thus, the CRH will not be inhibited by cortisol resulting in more ACTH secretion (Hershel 2009). Increased non-inhibited ACTH will stimulate the healthy adrenal glands to grow and secrete more cortisol. The cortisol levels will thus be brought back to normal and retain the usual negative feedback inhibition. In hypopituitary adrenal insufficiency, low ACTH secretion results in low cortisol secretion (Neary & Nieman 2010). Figure 2: Negative feedback inhibition in hypocortisolism d. Diagnostic tests including normal reference ranges Tests to diagnose Cushing syndromes include a physical examination to look for the symptoms. Suggestive features include a moon face, a lump of fatty tissue between the shoulder and neck, and skin that appears thin with bruises and stretch marks. Dexamethasone suppression test is done to confirm the diagnosis (Sakihara et al. 2014). Dexamethasone is administered and the patient’s blood or urine analyzed. If urine is used, the sample should be collected over a 24 hour period (Findling, Raff & Aron 2014). Dexamethasone is a glucocorticoid that mimics the effects of cortisol including the negative feedback against the ACTH (Finding, Raff & Aron 2014). Cortisol levels above 1.81µg.dl indicate Cushing’s syndrome (Sakihara et al. 2014). An above-normal level is indicative of an exogeneous source of cortisol or ACTH, usually an adrenal or pituitary tumor exists, as it was not inhibited by the dexamethasone (Sakihara et al. 2014). Another approach is to use a saliva sample collected late at night (Hershel 2009). Cortisol levels usually rise and fall throughout the day and in healthy people, the cortisol level drops significantly in the evening (Hershel 2009). An elevated cortisol level in late-night salivary samples is indicative of Cushing’s syndrome (Hershel 2009). If Addison’s disease is suspected, a blood test is done to measure the levels of ACTH, cortisol, sodium, and potassium (Neary & Nieman 2010). Laboratory tests may reveal various features suggesting Addison’s disease. These include hypoglycemia, hyponatremia, hypercalcemia, easinophilia and lymphocytosis, and metabolic acidosis (Oboni et al 2013). ACTH stimulation test is used to diagnose Addison’s disease. Tetracosactide, a synthetic pituitary ACTH is used (Neary & Nieman 2010). Two tests are performed. One test is short and compares blood cortisol levels before and after administration of 250µg of tetracosactide intramuscularly or intravenously (Oboni et al. 2013). If after an hour, the cortisol level exceeds 170nmol/l and has risen by at least 330nmol/l to at least 690nmol/l, adrenal insufficiency is excluded (Oboni et al. 2013). If the short test result is abnormal, the long test is used to determine whether it is primary or secondary adrenal insufficiency. The long test uses 1 mg tetracosactide administered intramuscularly. Blood is taken after 1 hour, 4 hrs, 8 hrs and 24 hrs (Neary & Nieman 2010). Normal cortisol levels should reach 1000nmol/l by the 4th hour. In primary Addison’s disease, the cortisol level is reduced at all intervals, whereas in secondary adrenal insufficiency, a delayed but normal response is observed (Neary & Nieman 2010). e. Recommended further testing if any If Cushing’s disease is suspected from the demaxathone suppression test, imaging tests can be done to determine the source of the excessive cortisol (Schteingart 2009). These include CT (computed tomography) scanning of the adrenal gland and magnetic resonance imaging (MRI) of the pituitary gland. ACTH levels can also be determined occasionally through venous catheterization of various veins in the body including petrosal sinus sampling (Grant, Dworakowska & Carroll 2012). For Addison’s disease, a further blood test can be done to measure antibodies that are associated with the autoimmune Addison’s disease (Neary & Nieman 2010). An MRI scan of the pituitary gland can be ordered if the initial tests indicate that the patient may have secondary adrenal insufficiency. CT scan of the abdomen can be performed to check the size of the adrenal glands and other abnormalities that may be the cause of primary adrenal insufficiency (Yoon et al. 2013). f. Treatment Treatment for Cushing’s syndrome is designed to lower the level of cortisol in the body (Biller et al. 2010). The treatment option depends on the cause of hypercortisolism. If the hypercortisolism is caused by long-term use of corticosteroid medication, for example in managing arthritis or asthma, the corticosteroid should be reduced (Schteingart 2009). The physician can prescribe non-corticosteroid medication which will allow the patient to eliminate or reduce the dosage of the corticosteroid (Schteingart 2009). For patients with established Cushing syndrome, there are medications that can be prescribed to control the excessive cortisol production. These include ketoconazole, mitotane, and metyrapone (Schteingart 2009).Surgery can also be recommended if the hypercortisolism is caused by an adrenal or pituitary tumor (Biller et al. 2010). The patient is then prescribed cortisol replacement medication to enable the body correct its amount of cortisol (Dalmazi et al. 2014). Radiation therapy can also be used either in combination with surgery or alone for patients who are not suitable candidates for surgery (Yoon et al. 2013). Radiation therapy works by shrinking the tumor. It can be given in small doses over a six-week period or by stereotactic surgery which is administered as a single treatment with a large dose targeted to the tumor (Biller et al. 2010). Treatment of Addison’s disease entails hormone replacement therapy to correct the levels of steroid hormones that the body has ceased producing (Grossman et al. 2013). The treatment includes oral corticosteroids such as hydrocortisone, prednisone or cortisone acetate which replaces cortisol and fludrocortisones which replaces aldosterone (Grossman et al. 2013). Corticosteroid injections can be used instead of oral therapy of the patient is vomiting and cannot retain oral medications (Schteingart 2009). Androgen replacement therapy such as dehydroepiandrosterone can be prescribed to women to treat androgen deficiency (Grossman et al. 2013). Conclusion The cortisol-ACTH axis is responsible for stress response through negative feedback inhibition. On stress exposure, the hypothalamus releases the tropic hormone CRH which signals the pituitary gland to release ACTH. ACTH stimulates cortisol release. Cortisol enables the body to cope with the stress, and when required levels are reached, cortisol inhibits CRH production, thus lowering ACTH production, and subsequently its own production. Pituitary and adrenal tumors can result in hypercortisolism or Cushing syndrome. Damage of adrenal glands or pituitary abnormalities can inhibit cortisol and ACTH production resulting in adrenal insufficiency or Addison’s disease. Primary adrenal insufficiency occurs when adrenal glands are damaged. Secondary adrenal insufficiency occurs when an abnormality in the pituitary gland inhibits ACTH production. Cushing’s disease symptoms include moon face, hypertension, abdominal fat and fat lump between shoulders. Addison’s disease symptoms include weight loss, hyperpigmentation and hypotension. Body fluid tests including blood, urine and saliva, and imaging tests can be used to diagnose the disease and its underlying cause. Oral therapy, injections, surgery and radiation are some of the treatment options for the secretion disorders. Treatment for Cushing disease is to regulate excessive cortisol production while for Addison’s disease is to replace hormones that are no longer produced. References: Balbo, M, Leproult, R, & Cauter, E 2010, ‘Impact of sleep and its disturbances on hypothalamo-pituitary-adrenal axis activity’, International Journal of Endocrinology, http://dx.doi.org/10.1155/2010/759234 Baruah, M 2012, ‘Sub-clinical addison’s disease’, Indian Journal of Endocrinology and Metabolism, vol. 16, no. 2, S176-S177. Biller, B, Colao, A, Petersenn, S, Bonert, V, & Marco, B 2010, ‘Prolactinomas, Cushing’s disease and acromegaly: Debating the role of medical therapy for secretory pituitary adenomas’, BMC Endocrine Disorders, vol. 10, no. 10, doi:10.1186/1472-6823-10-10. 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