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Table of Contents
Glucocorticoid Hyperfunction: Cushing's Syndrome
Introduction
![](/LIFESCI_4M03/_media/hpa_.jpg?w=400&tok=7074f9)
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.
However, in Cushing's Disease (the most prevalent endogenous subtype of this syndrome), a tumor 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, or an ectopic non-pituitary ACTH-producing tumor. The sources of an ectopic tumor include the lungs, pancreas, or thymus (Marshall, Bangert & lapsley, 2012).
History
The history of Cushing’s disease dates back to 1912 (Medvei, 1991). Harvey Cushing was an American neurosurgeon born in Cleveland, Ohio. He received his education at Yale and Harvard Medical School. Cushing was a professor of surgery at Harvard Medical School, and he was the surgeon-in-chief at the Peter Brent Brigham Hospital (Medvei, 1991). In 1931, he published “The basophilic adenomas of the pituitary body and their clinical manifestations”. In this paper, he mentioned a patient with the name of Minnie. Minnie’s symptoms included amenorrhea, abnormal periods, and abnormal hair growth. He claimed that her symptoms resembled the symptoms seen with adrenal tumors due to dysfunction of the pituitary glands (Medvei, 1991). Cushing hypothesized that if acidophil hyperpituitarism (excess acidophil cells) caused acromegaly, then excess basophil cells would be involved with a pituitary disorder that involves sexual function (amenorrhea in women, impotence in men) (Medvei, 1991). In 1932, Cushing published “A Case of Basophil Adenoma of the Anterior Lobe of the Pituitary: Cushing’s Syndrome”, which led to the introduction of the disease (Medvei, 1991).
Epidemiology
Signs and Symptoms
A general diagnosis of Cushing’s Syndrome can be categorized into one of three classes:
- Primary (damage to the adrenal cortex itself)
- Secondary (damage to the pituitary)
- Tertiary (damage to the hypothalamus itself)
Regardless of the class of diagnosis, patients with Cushing’s disease exhibit a multitude of similar symptoms with some sex specific.
Most Common Symptoms:
- High-Blood Pressure
- Weight Gain
- Fatigue
- Poor-Short Term Memory
- Irritability
- Poor Concentration
- Muscle Weakness
- Sore Joints
- Bone Weakness
- Weakened Skin
- Poor Wound Healing
- Moon Face (Fat deposits around the face)
- Irregular Menstruation Cycle (Women)
- Excessive Body Hair Growth (Women)
Least Common Symptoms:
- Insomnia
- Recurrent Infections
- Acne
- Edema of the Exteremities
- Erectile Dysfunction (Men)
Diagnosis
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 is unacceptable due to the variations of cortisol levels throughout the day.
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
Testing for Cushing’s involves screening for cortisol levels. The sample of interest in this screening process is almost always urine (although saliva can be an alternative), as urine cortisol levels are representative of blood cortisol. A 24-hour urine collection test is done to collect urine over a full daily cycle of the patient. 24-Urinary cortisol excretion have normal levels of under 300 nmol/24 hours. (Marshall, W. J., Bangert, S. K., Lapsley, M. (2012)). A positive result from this test indicates Cushing's Syndrome.
Low-Dose Dexamethansone Suppression Test
Dexmethasone is a synthetic glucocorticoid that binds to cortisol receptors in the pituitary and suppresses ACTH release which ultimately suppresses the secretion of cortisol by the adrenals in normal healthy individuals without Cushing’s. 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, W. J., Bangert, S. K., Lapsley, M. (2012)) Failure of suppression is characteristic of Cushing’s.
Once increased cortisol has been established, the measurement of plasma ACTH has is used to determine the cause of increased cortisol levels in the blood. Low levels of ACTH, a key regulator of glucocorticoid activity in the blood, suggests an adrenal tumour over-secreting cortisol. On the other hand, very high levels of ACTH suggest ectopic secretion of ACTH which could be from a pituitary tumour or an ectopic ACTH secreting tumor (Marshall, Bangert & Lapsley, 2012). In order to distinguish between the two, a high dose dexamethasone test is needed.
High Dose Dexamethasone Suppression Test
A 2mg dosage is given to patients every 6 hours for a total of 48 hours. Plasma cortisol levels are then measured again at 9am the next morning. Patients with Cushing's Disease would have their cortisol concentration levels drop by at least 50% of pre-treatment value. This indicates that the high cortisol concentrations due to a pituitary tumour over-secreting ACTH is because of a failure in the negative feedback mechanisms that needed a higher dose to counteract. On the other hand, failure to suppress ACTH levels is suggestive of an ectopic ACTH secreting tumour that will continue to stimulate the adrenal cortex to release cortisol irregardless of the negative feedback loops.
CRH Dynamic Testing
Dynamic testing on patients is normally not performed unless absolutely necessary as it puts strain on the patient. In Cushing's dynamic testing is used to distinguish pituitary adenomas from ectopic ACTH secreting tumours or adrenal secreting tumours. Corticotropin Releasing Hormone (CRH) which is released by the hypothalamus in response to stress stimulates the entire cortisol release cascade. Providing CRH and measuring the ACTH levels helps to further diagnose the form of Cushing's. An exaggerated elevated response of excessive ACTH levels suggest a pituitary tumour (secondary class diagnosis) while no response after the administration of CRH indicates a primary class disorder.
Figure 3: Typical results of Adrenal Hyperfunction tests in Cushing's syndrome (Marshall, Bangert & Lapsley, 2012)
Screening for Tumours
CT (Computed Tomography) or an MRI (Magnetic Resonance Imaging)of the pituitary helps to visualize the regions of the brain where a ACTH-secreating tumour is suspected to be localized. These visualization tests are often ordered when the patient has failed the low-dose dexamethansone test and has exhibited an exaggerated response ACTH response. This test is done to confirm the existence of a ectopic tumour.
Lab Abnormalities
Due to the actions of glucocorticoids and their mineralcorticoid activity, blood tests of patients with Cushing's Syndrome are quite distinct. Some abnormalities in the lab results are outlined below (Marshall, Bangert & Lapsley, 2012):
Increased
- Cortisol
- Glucose
- This is due to the increased hepatic gluconeogenesis that occurs with high amounts of glucose, causing the liver to produce glucose from proteins, lipids, and other metabolic sources such as lactate and pyruvate. A high concentration of plasma glucose may cause insulin resistance due to the pancreas' inability to keep up with insulin production.
- Bone turnover markers
- Cortisol is a catabolic hormone. It triggers bone resorption of amino acids in order to be used as an energy source in gluconeogenesis. This is achieved indirectly through cortisol by blocking calcium absorption in order to decrease bone growth.
Decreased
- Potassium
- Cortisol promotes sodium absorption in the small intestine, while at the same time acting to excrete potassium in the urine. This results in a state of hypokalemia, which occurs when the body experiences a decrease in the level of potassium.
- Eosinophils
- 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.
Hypothalamic-Pituitary Adrenal Axis
Several stimuli can perturb homeostatic mechanisms resulting in the secretion of glucocorticoids, mainly cortisol in humans, from the adrenal cortex. The most common stimulus, stress, is a potent activator of the HPA axis. Our body's stress system coordinates the adaptive responses of organisms to different types of stressors resulting in changes that improve our ability to adjust homeostasis and increase chances of survival (Tsigos & Chrousos, 2002). Cortisol is the end product of the activation of the hypothalamic-pituitary adrenal (HPA) axis. The HPA axis consists of excitatory signals and negative feedback loops to regulate its activity (Nicolaides, Kyratzi, Lamprokostopoulou, Chrousos, & Charmandari, 2015).
Physiology of Glucocorticoids: Cortisol
In response to a stressor, the hypothalamus secretes corticotrophin releasing hormone (CRH) which acts on the anterior pituitary gland to secrete adrenocorticotrophin hormone (ACTH). Circulating ACTH is a key regulator of cortisol secretion from the adrenal cortex. The release of glucocorticoid hormones help regulate homeostatic imbalances and mediate the body's response to stress (Tsigos & Chrousos, 2002).
The most important glucocorticoid hormone is cortisol. Glucocorticoids inhibit the immune response, have anti-inflammatory and catabolic effects, maintain blood pressure by sensitizing the arterioles to norepinephrine and increase glucose levels in the blood (Marshall, Bangert & Lapsley, 2012). Figure x shows cortisol exerting its negative feedback control on ACTH release through the inhibition of CRH as well as inhibiting CRH release itself (Marshall, Bangert & Lapsley, 2012).
Pathophysiology of Glucocorticoids: Excess Cortisol
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 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 cause is a pituitary adenoma which accounts for 60-70% of diagnosis (Marshall, Bangert & Lapsley, 2012).
Figure 5: The possible causes of Cushing's Syndrome (Marshall, Bangert & Lapsley, 2012)
Pathophysiology of Cushing's Disease
Cushing’s disease, a subtype of Cushing’s syndrome, is a disease caused due to the over secretion of adrenocorticotropic hormone (ACTH) by a pituitary adenoma. The pituitary tumors are usually microadenomas, which are 10 mm or less in diameter. These tumors are often discovered by doing tests for other reasons, since these microadenomas do not have mass effects. (Kirk and Jones, 2000). Cushing’s disease accounts for about two thirds of the cases of endogenous Cushing’s syndrome. It mainly affects women of reproductive age, but can also affect males and females in general (Kirk and Jones, 2000). In Cushing’s disease, ACTH secretion from the pituitary is increased because the pituitary becomes less sensitive to glucocorticoid effects. This means that excess cortisol will be required in order to suppress the release of ACTH from the pituitary though negative feedback. Therefore, as cortisol continues accumulating due to faulty negative feedback mechanisms, it begins causing negative effects throughout the body (Marshall, Bangert & Lapsley, 2012).
Presentation of clinical features
The clinical features of Cushing's Syndrome are primarily due to excess production of glucocorticoids. Taking into account the actions of glucocorticoids, high levels in the bloodstream will lead to easy bruising, poor wound healing, glucose intolerance, truncal obesity and purple stretc hmarks among other features. Interestingly, glucocorticoids also have mineralcorticoid activity. This means that cortisol can also act as aldosterone, an important mineralcorticoid, and present some of the clinical features characteristic of a patient with high levels of aldosterone in their bloodstream. This explains why patients present with high blood pressure (hypertension) due to the sodium retention, and metabolic alkalosis due to potassium wasting. Metabolic alkalosis is an increase in serum bicarbonate concentrations due to loss of hydrogen ions in the body, or a gain in bicarbonate ions. Since glucocorticoids have mineralocorticoid effects, an excess amount of aldosterone will increase the retention of sodium, and also dump hydrogen ions into the renal tubules. This loss of hydrogen ions creates a state of metabolic alkalosis.
Treatment
The main and primary treatment for patients with Cushing’s disease is pituitary surgery, which requires the surgical removal of the small pituitary adenoma. In most cases, it is done so through a transsphenoidal method. If the adenoma cannot be identified, then surgeons remove 50-90% of the pituitary gland. However, the problem with removing too much of the gland is that it reduces the effectiveness of the pituitary and causes problems with ovulation in women and sperm production in men. Cure rates from this approach are from 65-90% for microadenomas and much lower for macroadenomas. (Fleseriu and Petersenn, 2012)
Ketoconazole
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 has shown to have some adverse side effects among patients that take the drug. Gastrointestinal issue seems to be common such as nausea and diarrhea. One major concern for the drug, although rare, is that it can increase liver enzyme levels and cause hepatotoxicity. (Fleseriu, 2014)
Pasirotide (Signifor)
Pasirotide acts as an analogue to somatostatin, which is known as a growth hormone-inhibiting hormone. The drug inhibits corticotropin secretion from the pituitary gland. Corticotrophin is what leads to the secretion of ACTH, and ACTH is what 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 pasirotide 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 hyperglycaemia in patients and is still under further testing. (McKeage, 2013)
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)
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 hypercotisolemia, 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)
Conclusions and Future Implications
Maybe add a few sentences concluding Cushing's Syndrome and the disease.
Future Research
The future of treating Cushing’s syndrome may lie within a combination of different drug therapy rather than a single drug.
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)
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 have 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 effectiveness of different drugs while reducing their side effects.
References
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