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group_5_presentation_1_-_glucocorticoid_hyperfunction_cushing_s_syndrome [2018/01/25 15:18] (current) |
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| {{youtube>J6-KRmqimIQ?medium}} | {{youtube>J6-KRmqimIQ?medium}} | ||
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| + | ==== Adrenal Glucocorticoid Hyperfunction: Cushing's Syndrome PowerPoint ==== | ||
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| + | {{:cushing_s_presentation.pptx|}} | ||
| ===== Introduction ===== | ===== Introduction ===== | ||
| - | <box 34% round left | > {{ :hpa_.jpg?nolink&400 |}} </box| Figure 1: The HPA (stress response) Axis > | + | <box 32% round right | > {{ ::screen_shot_2017-10-01_at_12.42.47_pm.png?345 |}} </box| Figure 1: The HPA (stress response) Axis > |
| - | Cushing’s syndrome results from excessive, long-term exposure to endogenous or exogenous forms of glucocorticoids (Orth, 1995). Glucocorticoids are a class of steroids, with cortisol being the most important. Glucocorticoids are particularly important in mediating the stress response of the body, and they are also involved in anti-inflammatory actions (Marshall, Bangert & Lapsley, 2012). Normally, the hypothalamic-pituitary-adrenal axis (HPA Axis) releases cortisol from the adrenal glands in response to a stressor (Figure 1). The hypothalamus releases corticotropin-releasing hormone (CRH), stimulating the pituitary gland to release adrenocorticotropic hormone (ACTH), which acts on the adrenal glands to release cortisol. | + | Cushing’s syndrome results from excessive, long-term exposure to endogenous or exogenous forms of glucocorticoids (Orth, 1995). Glucocorticoids are a class of steroids, with cortisol being the most important. Glucocorticoids are particularly important in mediating the stress response of the body, and they are also involved in anti-inflammatory actions (Marshall, Bangert & Lapsley, 2012). Normally, the hypothalamic-pituitary-adrenal axis (HPA Axis) releases cortisol from the adrenal glands in response to a stressor (Figure 1). Activation of the HPA axis initiates a cortisol cascade. Various stressors will result in the secretion of corticotropin-releasing hormone (CRH) from the hypothalamus, which then stimulates the pituitary gland to release adrenocorticotropic hormone (ACTH). Circulating ACTH acts on the adrenal cortex to release cortisol and exert negative feedback control to restore homeostasis. |
| - | However, in Cushing's Disease (the most prevalent endogenous subtype of this syndrome), a tumour in the pituitary causes excessive release of ACTH, therefore acting on the adrenal glands to produce abnormally high levels of cortisol(Orth, 1995). Other endogenous causes of Cushing’s syndrome include an adrenal adenoma over-secreting glucocorticoids, or an ectopic non-pituitary ACTH-producing tumour. Potential sources of an ectopic tumour include the lungs, pancreas, or thymus (Marshall, Bangert & Lapsley, 2012). | + | However, in Cushing's Disease (the most prevalent endogenous subtype of this syndrome), a tumour in the pituitary causes excessive release of ACTH, therefore acting on the adrenal cortex to produce abnormally high levels of cortisol (Orth, 1995). The excess release of glucocorticoids present life-threatening conditions and a host of clinical manifestations. Other endogenous causes of Cushing’s syndrome include a tumour of the adrenal cortex over-secreting cortisol, an ectopic non-pituitary ACTH-secreting tumour, or a tumour of the hypothalamus secreting excessive CRH leading to activation of the cortisol cascade. Potential sources of an ectopic tumour include the lungs, pancreas, or thymus (Marshall, Bangert & Lapsley, 2012). |
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| - | A general diagnosis of Cushing’s Syndrome can be categorized into one of three classes: | + | A general diagnosis of Cushing’s Syndrome can be categorized into one of four classes: |
| * Primary (a tumour of the adrenal cortex) | * Primary (a tumour of the adrenal cortex) | ||
| * Secondary (a tumour of the pituitary) | * Secondary (a tumour of the pituitary) | ||
| * Tertiary (a tumour of the hypothalamus) | * Tertiary (a tumour of the hypothalamus) | ||
| - | * Ectopic (an ACTH secreting tumour) | + | * Ectopic (a non-pituitary ACTH secreting tumour) |
| - | Regardless of the class of diagnosis, patients with Cushing’s disease exhibit a multitude of similar symptoms with some sex specific. | + | Regardless of the class of diagnosis, patients with Cushing’s exhibit a multitude of similar symptoms with some sex specific. |
| Most Common Symptoms: | Most Common Symptoms: | ||
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| * Moon Face (Fat deposits around the face) | * Moon Face (Fat deposits around the face) | ||
| * Irregular Menstruation Cycle (Women) | * Irregular Menstruation Cycle (Women) | ||
| - | * Excessive Body Hair Growth (Women) | + | |
| Least Common Symptoms: | Least Common Symptoms: | ||
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| * Edema of the Exteremities | * Edema of the Exteremities | ||
| * Erectile Dysfunction (Men) | * Erectile Dysfunction (Men) | ||
| + | * Excessive Body Hair Growth (Women) | ||
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| Regulation of the HPA axis is critical, otherwise disorders of the adrenal cortex can arise and present life-threatening conditions. In Cushing's Syndrome, there is overproduction of glucocorticoids. The various causes of Cushing's Syndrome, illustrated in figure 5 below, include a pituitary adenoma over-secreting ACTH, ectopic ACTH secretion, an adrenal adenoma over-secreting glucocorticoids, or an exogenous supply of glucocorticoids (Marshall, Bangert & Lapsley, 2012). The most common endogenous cause is a pituitary adenoma which accounts for 60-70% of diagnosis (Marshall, Bangert & Lapsley, 2012). | Regulation of the HPA axis is critical, otherwise disorders of the adrenal cortex can arise and present life-threatening conditions. In Cushing's Syndrome, there is overproduction of glucocorticoids. The various causes of Cushing's Syndrome, illustrated in figure 5 below, include a pituitary adenoma over-secreting ACTH, ectopic ACTH secretion, an adrenal adenoma over-secreting glucocorticoids, or an exogenous supply of glucocorticoids (Marshall, Bangert & Lapsley, 2012). The most common endogenous cause is a pituitary adenoma which accounts for 60-70% of diagnosis (Marshall, Bangert & Lapsley, 2012). | ||
| - | {{:causes.png?450|}} | + | {{::screen_shot_2017-09-30_at_5.27.00_pm.png?600|}} |
| **Figure 5:** The possible causes of Cushing's Syndrome (Marshall, Bangert & Lapsley, 2012) | **Figure 5:** The possible causes of Cushing's Syndrome (Marshall, Bangert & Lapsley, 2012) | ||
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| * Eosinophils and Lymphocytes | * Eosinophils and Lymphocytes | ||
| - | - Eosinophils and lymphocytes are decreased because excess cortisol weakens the immune system. T-cells respond to cytokine molecules (called interleukins)via a signalling pathway. Cortisol blocks the proliferation of T-cells by preventing them from recognizing interleukin signals. | + | - Eosinophils and lymphocytes are decreased because excess cortisol weakens the immune system. T-cells respond to cytokine molecules (called interleukins)via a signalling pathway. Cortisol blocks the proliferation of T-cells by preventing them from recognizing interleukin signals. More specifically some individuals with Cushings' may also be needed to be treated for severe parasitic infections, since eosinophils are responsible for clearing parasitic infections, declined levels leave affected individuals more susceptible to parasites. |
| - | + | ===== Diagnosis of Adrenal Hyperfunction: Glucocorticoids ===== | |
| - | ===== Diagnosis of Adrenal Hyperfunction ===== | + | |
| One of the goals of diagnosis is to distinguish Cushing’s disease from Cushing’s syndrome, as the disease is a variation of Cushing's syndrome. Secondary adrenal hyperfunction results from a pituitary tumour leading to excessive production of ACTH. Elevated ACTH stimulates the adrenal cortex to produce high levels of cortisol giving rise to the disease state. Testing for Cushing's is outlined below and random plasma cortisol levels are unacceptable due to the variations of cortisol levels throughout the day. | One of the goals of diagnosis is to distinguish Cushing’s disease from Cushing’s syndrome, as the disease is a variation of Cushing's syndrome. Secondary adrenal hyperfunction results from a pituitary tumour leading to excessive production of ACTH. Elevated ACTH stimulates the adrenal cortex to produce high levels of cortisol giving rise to the disease state. Testing for Cushing's is outlined below and random plasma cortisol levels are unacceptable due to the variations of cortisol levels throughout the day. | ||
| - | {{::screen_shot_2017-09-25_at_12.28.25_pm.png?650|}} | + | {{::screen_shot_2017-09-30_at_5.03.43_pm.png?675}} |
| **Figure 2:** Suspected Cushing's syndrome algorithm to determine the origin of excess glucocorticoids in the blood (Marshall, Bangert & Lapsley, 2012) | **Figure 2:** Suspected Cushing's syndrome algorithm to determine the origin of excess glucocorticoids in the blood (Marshall, Bangert & Lapsley, 2012) | ||
| - | === 24-Hour Urinary Cortisol Excretion === | + | === 24 Hour Urine Free Cortisol Excretion === |
| The best screening test for Cushing's is 24 hour urinary free cortisol, as urine cortisol levels are representative of blood cortisol levels. A 24 hour urine collection test is done to collect urine over a full daily cycle of the patient. 24 hour urinary cortisol excretion have normal levels of less than 300 nmol/24 hours (Marshall, Bangert & Lapsley, 2012). Values exceeding the normal range are characteristic of Cushing's. | The best screening test for Cushing's is 24 hour urinary free cortisol, as urine cortisol levels are representative of blood cortisol levels. A 24 hour urine collection test is done to collect urine over a full daily cycle of the patient. 24 hour urinary cortisol excretion have normal levels of less than 300 nmol/24 hours (Marshall, Bangert & Lapsley, 2012). Values exceeding the normal range are characteristic of Cushing's. | ||
| - | === Low-Dose Dexamethansone Suppression Test === | + | === Low Dose Dexamethasone Suppression Test === |
| Dexamethasone is a synthetic glucocorticoid that binds to cortisol receptors in the pituitary and suppresses ACTH release. This ultimately suppresses the secretion of cortisol by the adrenal gland in normal, healthy individuals (Marshall, Bangert & Lapsley, 2012). A 1mg dosage is given at night and blood is drawn for measurement of cortisol the next morning. In healthy individuals this level should be less than 50 nmol/L. (Marshall, Bangert & Lapsley, 2012). Failure to suppress ACTH levels are suggestive of Cushing’s. | Dexamethasone is a synthetic glucocorticoid that binds to cortisol receptors in the pituitary and suppresses ACTH release. This ultimately suppresses the secretion of cortisol by the adrenal gland in normal, healthy individuals (Marshall, Bangert & Lapsley, 2012). A 1mg dosage is given at night and blood is drawn for measurement of cortisol the next morning. In healthy individuals this level should be less than 50 nmol/L. (Marshall, Bangert & Lapsley, 2012). Failure to suppress ACTH levels are suggestive of Cushing’s. | ||
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| ====Ketoconazole==== | ====Ketoconazole==== | ||
| - | <box 30% round right| > {{ :drugs.jpg?325 |}} </box| Figure 10. Various drugs for Cushing's disease and their area of effect (Fleseriu, 2014)> Ketoconazole is a drug that inhibits the process of steroidogenesis in the adrenal glands. This limits the production of steroids such as cholesterol. A study done with 200 patients with Cushing’s disease were treated with ketoconazole. At the last follow-up for the experiment, 49.3% of the patients showed normalized UFC levels and 25.6% had at least a 50% decrease (Castinetti et al, 2014). However, this drug is shown to have some adverse side effects among patients that take it. Gastrointestinal issues, such as diarrhea and nausea, seem to be most common. One major concern for the drug, although rare, is that it can increase liver enzyme levels and cause hepatotoxicity. (Fleseriu, 2014) | + | <box 30% round right| > {{ :drugs.jpg?325 |}} </box| Figure 10. Various drugs for Cushing's disease and their area of effect (Fleseriu, 2014)> |
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| + | Ketoconazole is a drug that inhibits the process of steroidogenesis in the adrenal glands. This limits the production of steroids such as cholesterol. A study done with 200 patients with Cushing’s disease were treated with ketoconazole. At the last follow-up for the experiment, 49.3% of the patients showed normalized urinary free cortisol (UFC) levels and 25.6% had at least a 50% decrease (Castinetti et al, 2014). However, this drug is shown to have some adverse side effects among patients that take it. Gastrointestinal issues, such as diarrhea and nausea, seem to be most common. One major concern for the drug, although rare, is that it can increase liver enzyme levels and cause hepatotoxicity(Fleseriu, 2014). | ||
| ====Pasireotide (Signifor)==== | ====Pasireotide (Signifor)==== | ||
| - | Pasireotide acts as an analog to somatostatin, which is known as a growth hormone-inhibiting hormone. The drug inhibits corticotropin secretion from the hypothalamus, a hormone that leads to the secretion of ACTH and eventually the secretion of cortisol (McKeage, 2013). | + | Pasireotide acts as an analog to somatostatin, which is known as a growth hormone-inhibiting hormone. The drug inhibits adrenocorticotropin (ACTH) secretion from the pituitary gland, a hormone that eventually leads to the secretion of cortisol (McKeage, 2013). |
| A study done by researchers looked at patients with Cushing’s disease and prescribed them with pasireotide for 6 months. At the end of the trials, 25% of all patients have normalized UFC levels and a significant decrease in the mean UFC levels of all patients. Patients that saw a reduction in their UFC levels also saw improvements in clinical symptoms as well, such as blood pressure and body weight. The drug, however, has shown to cause hyperglycemia in patients and is still under further testing (McKeage, 2013). | A study done by researchers looked at patients with Cushing’s disease and prescribed them with pasireotide for 6 months. At the end of the trials, 25% of all patients have normalized UFC levels and a significant decrease in the mean UFC levels of all patients. Patients that saw a reduction in their UFC levels also saw improvements in clinical symptoms as well, such as blood pressure and body weight. The drug, however, has shown to cause hyperglycemia in patients and is still under further testing (McKeage, 2013). | ||
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| ====Cabergoline==== | ====Cabergoline==== | ||
| - | Cabergoline is a dopamine receptor agonist and initially just used to inhibit the production of prolactin in patients that had hyperprolactinemia. However, studies have shown that Cabergoline might have some potential as a treatment for Cushing’s disease. A study looked at 30 patients with Cushing disease and treated them with Cabergoline at varying doses. Around 40% of the patients treated with a maximum dose of 6 mg/week achieved normalized UFC levels in little over 4 months. Around 30% of the patients that were prescribed long-term treatments at doses of 2.1 mg/week for 37 months achieved normalized UFC levels. (Godbout, 2010) | + | Cabergoline is a dopamine receptor agonist and initially just used to inhibit the production of prolactin in patients that had hyperprolactinemia. However, studies have shown that Cabergoline might have some potential as a treatment for Cushing’s disease. A study looked at 30 patients with Cushing's disease and treated them with Cabergoline at varying doses. Around 40% of the patients treated with a maximum dose of 6 mg/week achieved normalized UFC levels in little over 4 months. Around 30% of the patients that were prescribed long-term treatments at doses of 2.1 mg/week for 37 months achieved normalized UFC levels (Godbout, 2010). |
| ====Mitotane==== | ====Mitotane==== | ||
| - | Mitotane can be used to as a treatment of adrenocortical carcinoma, but it can also be used to limit cortisol production by inhibiting cholesterol side-chain cleavage and 11 β-hydroxylase, which is used in the final phase of cortisol synthesis as a catalyst. It has shown some prospect in managing hypercortisolemia, however, there are better options such as ketoconazole and metyrapone as they are easier on the body of patients. Some of the common side effects of this drug are diarrhea, nausea, and anorexia. (Trainer, 2013) | + | Mitotane can be used to as a treatment of adrenocortical carcinoma, but it can also be used to limit cortisol production by inhibiting cholesterol side-chain cleavage and 11 β-hydroxylase, which is used in the final phase of cortisol synthesis as a catalyst. It has shown some prospect in managing hypercortisolemia, however, there are better options such as ketoconazole and metyrapone as they are easier on the body of patients. Some of the common side effects of this drug are diarrhea, nausea, and anorexia (Trainer, 2013). |
| ====Metyrapone==== | ====Metyrapone==== | ||
| - | Metyrapone is an adrenal steroidogenesis inhibitor. Specifically, it inhibits the enzyme 11β-hydroxylase, which converts 11-deoxycortisol into cortisol. Metyrapone is used to treat adrenal insufficiencies, but also hypercortisolism in Cushing’s syndrome. Using this medication for the long-term results in side-effects, such as an increase in ACTH production, acne, hirsutism, hyperkalemia, and edema (Daniel, Aylwin, Mustafa, et al., 2015). Currently, it is used for short-term treatment before surgeries, but it shows some promise as a long-term treatment, especially when combined with other drugs (Daniel, Aylwin, Mustafa, et al., 2015). Metyrapone’s long-term use on its own is still in question as its depletion of cortisol levels does seem to affect memory formation and retrieval (Marin, Hupbach, Maheu, et al., 2011). Its long-term usage should not be ruled out but approached with caution. | + | Metyrapone is an adrenal steroidogenesis inhibitor. Specifically, it inhibits the enzyme 11β-hydroxylase, which converts 11-deoxycortisol into cortisol. Metyrapone is used to treat adrenal insufficiencies, but also hypercortisolism in Cushing’s syndrome. Using this medication for the long-term results in side-effects, such as an increase in ACTH production, acne, hirsutism, hyperkalemia, and edema (Daniel, Aylwin, Mustafa, et al., 2015). Currently, it is used for short-term treatment before surgeries, but it shows some promise as a long-term treatment, especially when combined with other drugs (Daniel, Aylwin, Mustafa, et al., 2015). Metyrapone’s long-term use on its own is still in question as its depletion of cortisol levels seem to affect memory formation and retrieval (Marin, Hupbach, Maheu, et al., 2011). Its long-term usage, however, should not be ruled out, rather it should be approached with caution. |
| ====Mifepristone==== | ====Mifepristone==== | ||
| - | Mifepristone is a progesterone receptor antagonist, but at higher doses, it also acts as a glucocorticoid receptor antagonist (Fleseriu, Biller, Findling, et al. 2012). It is most known for its use in abortions, but it is also used to treat Cushing’s disease. As a glucocorticoid receptor antagonist, mifepristone blocks cortisol’s mechanism of action. Studies do show benefits in its use for people with Cushing’s disease, especially for those with more fat and abnormal glucose metabolism, but there are still side effects worth examining. A few studies of mifepristone used for Cushing’s disease have exhibited symptoms such as increased blood pressure due to lowered HDL, low potassium, alkalosis, vaginal bleeding, and uterine contractions (Castinetti, Conte-Devolx, Brue, et al., 2010; Fleseriu, Biller, Findling, et al. 2012). Mifepristone has its benefits, but more research has to be done on its effects on blood pressure and deteriorative effects on the female reproductive system. | + | Mifepristone is a progesterone receptor antagonist, but at higher doses it also acts as a glucocorticoid receptor antagonist (Fleseriu, Biller, Findling, et al. 2012). It is most known for its use in abortions, but it is also used to treat Cushing’s disease. As a glucocorticoid receptor antagonist, mifepristone blocks cortisol’s mechanism of action. Studies do show benefits in its use for people with Cushing’s disease, especially for those with more fat and abnormal glucose metabolism, but there are still side effects worth examining. A few studies of mifepristone used for Cushing’s disease have exhibited symptoms such as increased blood pressure due to lowered high density lipoprotein (HDL), low potassium, alkalosis, vaginal bleeding, and uterine contractions (Castinetti, Conte-Devolx, Brue, et al., 2010; Fleseriu, Biller, Findling, et al. 2012). Mifepristone has its benefits, but more research has to be done on its effects on blood pressure and deteriorative effects on the female reproductive system. |
| ====Etomidate==== | ====Etomidate==== | ||
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| ====Future Research==== | ====Future Research==== | ||
| - | A study including 17 patients diagnosed with Cushing’s disease was given pasireotide as a treatment. After some time, five of those patients showed normalized UFC levels. The addition of cabergoline to the treatment normalized UFC levels in four further patients, furthermore the addition of ketoconazole normalized six more patients. At the end of the trials, only 2 out of 17 patients had elevated UFC levels. (Feelders and Hofland, 2013) | + | A study including 17 patients diagnosed with Cushing’s disease was given pasireotide as a treatment. After some time, five of those patients showed normalized UFC levels. The addition of cabergoline to the treatment normalized UFC levels in four further patients, and the addition of ketoconazole normalized six more patients. At the end of the trials, only 2 out of 17 patients had elevated UFC levels (Feelders and Hofland, 2013) |
| - | Another study looked at a combination of cabergoline and ketoconazole for treating Cushing’s disease. Initially, 12 patients were prescribed cabergoline for 6 months. Nine of these patients did not respond well to the treatment, however the addition of the ketoconazole to the treatment led to six of the nine patients having normalized UFC levels and the remaining patients showed a reduction in UFC levels of 44-52%. (Vilar et al, 2010) | + | Another study looked at a combination of cabergoline and ketoconazole for treating Cushing’s disease. Initially, 12 patients were prescribed cabergoline for 6 months. Nine of these patients did not respond well to the treatment, however the addition of the ketoconazole to the treatment led to six of the nine patients having normalized UFC levels and the remaining patients showed a reduction in UFC levels of 44-52% (Vilar et al, 2010) |
| Combination therapy is on the rise and has a lot of potential as it has shown to increase the effectiveness of different drugs while reducing their side effects. | Combination therapy is on the rise and has a lot of potential as it has shown to increase the effectiveness of different drugs while reducing their side effects. | ||
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| Vilar, L., Naves, L. A., Azevedo, M. F., Arruda, M. J., Arahata, C. M., Moura E Silva, L., … Canadas, V. (2010). Effectiveness of cabergoline in monotherapy and combined with ketoconazole in the management of Cushing’s disease. Pituitary, 13(2), 123–129. https://doi.org/10.1007/s11102-009-0209-8 | Vilar, L., Naves, L. A., Azevedo, M. F., Arruda, M. J., Arahata, C. M., Moura E Silva, L., … Canadas, V. (2010). Effectiveness of cabergoline in monotherapy and combined with ketoconazole in the management of Cushing’s disease. Pituitary, 13(2), 123–129. https://doi.org/10.1007/s11102-009-0209-8 | ||
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