Cushing's Syndrome & Disease PDF - 2013 Update

P AT I E N T I N F O R M AT I O N CUSHING’S SYNDROME AND CUSHING’S DISEASE YOUR QUESTIONS ANSWERED 2013 Update Contents What are Cushing’s syndrome and Cushing’s disease? What a...

P AT I E N T I N F O R M AT I O N CUSHING’S SYNDROME AND CUSHING’S DISEASE YOUR QUESTIONS ANSWERED 2013 Update Contents What are Cushing’s syndrome and Cushing’s disease? What are Cushing’s syndrome and Cushing’s disease? 1 Cushing’s syndrome is a rare condition that occurs when there What causes Cushing’s syndrome and Cushing’s disease? 2 is excess cortisol in the body. Cortisol is a hormone normally made by the adrenal glands and is necessary for life. It allows us What are the symptoms of Cushing’s syndrome? 2 to respond to stressful situations such as illness or injury, and How is Cushing’s syndrome diagnosed? 3 has effects on almost all body tissues. It is produced in varying amounts over the course of the day, most in the early morning, What tests are needed specifically to diagnose 4 with very little at night. Cushing’s disease? Cushing’s syndrome refers to the condition caused by excess cortisol in the body, regardless of the cause. When Cushing’s What can I do to help myself manage Cushing’s syndrome? 5 syndrome is caused by a pituitary tumor, it is called Cushing’s What are the treatment options for Cushing’s disease? 6 disease. Cushing’s syndrome is more often found in women than in How can I expect to feel after treatment for 8 men and often occurs between the ages of 20 and 40. Cushing’s disease? Cushing’s disease FAQs 9 For further information 12 Glossary Cushing’s syndrome is caused by the production of too much cortisol. Funding was provided by the Ipsen Group; Novo Nordisk, Inc; Pfizer; and Eli Lilly through unrestricted educational grants 1 PATIENT INFORMATION CUSHING’S SYNDROME AND CUSHING’S DISEASE What causes Cushing’s syndrome and Cushing’s disease? Table 1. Signs and symptoms of Cushing’s syndrome Cushing’s syndrome can be caused by cortisol-like medications (called COMMON FEATURES LESS COMMON FEATURES glucocorticoids) or by a tumor. Sometimes, there is a tumor of the adrenal Weight gain Insomnia gland(s) that makes too much cortisol. Cushing’s syndrome may also be caused Hypertension Recurrent infection by a tumor in the pituitary gland (a small gland under the brain that produces Poor short-term memory Thin skin and stretch marks hormones that in turn regulate the body’s other hormone glands). Some pituitary tumors produce a hormone called adrenocorticotropic hormone (ACTH), which Irritability Easy bruising stimulates the adrenal glands and causes them to make too much cortisol. This is Excess hair growth (women) Depression termed Cushing’s disease. ACTH-producing tumors can also originate elsewhere Red, ruddy face Weak bones in the body and these are referred to as ectopic tumors. See Figure 1 for an Extra fat around neck Acne illustration of the differences between these three situations. Round face Balding (women) It is important to note that pituitary tumors are almost never cancerous. Fatigue Hip and shoulder weakness Figure 1. The various causes of Cushing’s syndrome Poor concentration Swelling of feet/legs hypothalamus hypothalamus hypothalamus Menstrual irregularity Diabetes CRH CRH CRH How is Cushing’s syndrome diagnosed? pituitary gland ectopic pituitary gland pituitary gland Because not all people with Cushing’s syndrome have all signs and symptoms, tumor and because many of the features of Cushing’s syndrome, such as weight gain pituitary and high blood pressure, are common in the general population, it can be tumor difficult to make the diagnosis of Cushing’s syndrome based on the symptoms cortisol ACTH cortisol ACTH cortisol ACTH alone. As a result, doctors use laboratory tests to help diagnose Cushing’s syndrome and, if that diagnosis is made, go on to determine whether it is caused by Cushing’s disease (i.e., from a pituitary tumor). These first diagnostic adrenal glands adrenal glands adrenal tests determine if too much cortisol is being made spontaneously or if the tumor normal control of hormones isn’t working properly. In Cushing’s disease a pituitary In ectopic ACTH secretion, a In primary adrenal disease, tumor makes ACTH, which non-pituitary tumor makes the adrenal glands The most commonly used tests measure the amount of cortisol in the saliva or stimulates adrenal gland ACTH, which stimulates adrenal independently make too production of cortisol. High gland production of cortisol. much cortisol. High cortisol urine. It is also possible to check whether there is over-production of cortisol by cortisol levels inhibit CRH secretion and ACTH secretion High cortisol levels inhibit CRH secretion and ACTH secretion levels inhibit CRH secretion and ACTH secretion from giving a medication called dexamethasone that mimics cortisol. This is called a from normal pituitary cells. from normal pituitary cells. normal pituitary cells. dexamethasone suppression test. If the body is regulating cortisol correctly, the KEY cortisol levels will decrease, but this will not happen in someone with Cushing’s Excess levels of hormone production syndrome. Sub-normal levels of hormone production These tests are not always able to definitively diagnose Cushing’s syndrome because other illnesses or problems can cause excess cortisol or abnormal control of cortisol production. These conditions that mimic Cushing’s What are the symptoms of Cushing’s syndrome? syndrome are called ‘pseudo-Cushing’s states’ and include the conditions shown The main signs and symptoms are shown in Table 1. Not all people with in Table 2. Because of the overlap in symptoms and laboratory test results the condition have all these signs and symptoms. Some people have few or between Cushing’s syndrome and pseudo-Cushing’s states, doctors may have to mild symptoms – perhaps just weight gain and irregular menstrual periods. do a number of tests and may treat pseudo-Cushing’s states – such as depression Other people with a more severe form of the disease may have nearly all the – to see if the high cortisol levels become normal during treatment. If they do symptoms. The most common symptoms in adults are weight gain (especially not, and especially if the physical features get worse, it is more likely that the in the trunk, and often not accompanied by weight gain in the arms and person has true Cushing’s syndrome. legs), high blood pressure (hypertension), and changes in memory, mood and concentration. Additional problems such as muscle weakness arise because of loss of protein in body tissues. 2 3 PATIENT INFORMATION CUSHING’S SYNDROME AND CUSHING’S DISEASE Table 2. Pseudo-Cushing’s states Figure 2. Use of Magnetic Resonance Imaging (MRI) to Visualize the Pituitary Gland Strenuous exercise Sleep apnea Psychiatric disorders Pregnancy Pain Stress Uncontrolled diabetes Alcoholism Extreme obesity What tests are needed specifically to diagnose Cushing’s disease? Patients with adrenal causes of Cushing’s syndrome have low blood ACTH levels and patients with the other causes of Cushing’s syndrome have normal or high levels. A doctor can measure the level of ACTH in the blood; measuring the ACTH levels helps to determine if the tumor is in the adrenal gland(s) or elsewhere in the body. The best test to distinguish an ACTH-producing tumor in the pituitary from one in another part of the body is a procedure called inferior petrosal sinus sampling, or IPSS. This test involves inserting small plastic tubes into both the If this test shows a definite tumor and the CRH and dexamethasone test results right- and left-sided veins in the groin (or neck) and threading them up to the are compatible with Cushing’s disease, IPSS may not be needed. However, up veins near the pituitary gland. Blood is then taken from these locations and also to 10% of healthy people have an abnormal area on their pituitary consistent from a vein not close to the pituitary gland. with a tumor. Therefore, the presence of an abnormality alone is not diagnostic During the procedure, a medication that increases ACTH levels from the of Cushing’s disease. Also, in about 50% of patients with Cushing’s disease, the pituitary is injected. By comparing the levels of ACTH produced close to tumor is too small to be seen. Thus the absence of a tumor on a MRI scan does the pituitary gland in response to the medication with those produced by not necessarily exclude Cushing’s disease. other parts of the body, the presence or absence of a pituitary tumor can be determined. What can I do to help myself manage Cushing’s syndrome? There are other tests used for the diagnosis of Cushing’s disease, such as the Look after your general health, eat well, and exercise regularly. However, because dexamethasone suppression and corticotropin-releasing hormone (CRH) bones may weaken, avoid high impact exercise or sports that involve falls, to stimulation tests. However, these are not as reliable as IPSS to distinguish reduce the chance of a broken bone. between the causes. A doctor may want to do multiple tests to confirm the Ask your doctor if you are getting enough calcium and vitamin D in your diet. results. These may help strengthen the bones. It is also possible to visualize the pituitary gland using a process called magnetic Give up smoking. This decreases the chance of having problems with surgery. resonance imaging (MRI). This involves an injection of a contrast agent that Don’t drink too much alcohol. will help the tumor to show up on the MRI scan (Figure 2). Make sure you take the full course of any medicines that your doctor may give you. Do go back and see your doctor if any of your symptoms worsen. The tests involved to make the diagnosis are unfamiliar and may seem complicated. Make sure you understand how to do and time the tests (swabs for salivary cortisol, urine collections, and medications for suppression testing). If you have questions, ASK! A doctor can diagnose whether too much After pituitary surgery, if you feel sick or suffer flu-like symptoms, do contact your doctor. ACTH is causing Cushing’s syndrome by measuring its level in the blood. 4 5 PATIENT INFORMATION CUSHING’S SYNDROME AND CUSHING’S DISEASE What are the treatment options for Cushing’s disease? pituitary surgery is not completely successful. One important side effect of radiation therapy is that it can damage the pituitary gland and affect other The best way to cure the tumor is by surgically removing it, but there are other pituitary cells that make other hormones. As a result, up to 50% of patients ways to control the tumor and effects of excess cortisol. In addition, there who undergo radiation therapy will need to take other hormone replacement are other complementary approaches that may be used to treat some of the within 10 years of the treatment. Radiation therapy and radiosurgery can symptoms. For example, diabetes, depression and high blood pressure will be take up to 10 years to have full effect. In the meantime patients take medicine treated with the usual medicines used for these conditions. Also, doctors may to reduce adrenal gland production of cortisol. These medications include prescribe calcium or vitamin D supplements, or other medicine to prevent ketoconazole, metyrapone and/or occasionally mitotane. Gastrointestinal thinning of the bone. complaints such as nausea, lack of interest in eating, and diarrhea can occur Removal of the pituitary tumor by surgery is recommended for those who have with each of these. Ketoconazole can damage the liver, so blood tests are done a tumor that is not extending into areas outside of the pituitary gland, and who to monitor liver function. Metyrapone can cause excess hair growth in women are well enough to have anesthesia. This approach, known as transsphenoidal and high blood pressure in both men and women. At high doses, mitotane surgery, is usually carried out by going through the nose or underneath the can cause problems with coordination and thinking and it also can cause birth upper lip and then through the sphenoid sinus to reach the tumor (Figure 3). defects or abortion. Neither ketoconazole nor mitotane should be given to a This route is less traumatic for the patient than having to get to the pituitary woman who would like to have children in the near future. through the upper skull and allows quicker recovery. Removal of both adrenal glands eliminates the ability of the body to produce Figure 3. Transsphenoidal Surgical Approach cortisol, and so the effects of excess cortisol resolve. Since adrenal hormones are necessary for life, patients must then take a cortisol-like hormone and the hormone fludrocortisone, which controls salt and water balance, every day for the rest of their life. Since removing the adrenal glands does not treat the underlying pituitary tumor, the pituitary needs to be monitored with periodic MRI scans to observe for possible tumor enlargement. There are now new medications that can be used to treat Cushing’s syndrome. One of these, pasireotide, may act to both stop tumor growth and lower ACTH production. Since it does not kill the tumor, it has to be given indefinitely. One of the important side effects of pasireotide is that it can raise blood sugar levels; therefore, blood sugar levels must be carefully monitored. Pasireotide is FDA- approved for the treatment of Cushing’s disease. It is given by injection twice daily and normalizes urine cortisol levels in about 20% of patients. Cabergoline, another medical treatment, is given by mouth about twice a week, Removing only the tumor leaves the rest of the pituitary gland intact so that and normalizes urine cortisol levels in about 40% of patients. Its main side it will eventually function normally. This is successful for 70–90% of people effect is fatigue. when performed by the best pituitary surgeons. The success rates reflect the Another recently introduced medication, mifepristone, does not affect the experience of the surgeon performing the operation. However, the tumor tumor itself but blocks the effects of cortisol in the entire body, and improves can return in up to 15% of patients, probably because of incomplete tumor the complications associated with excess cortisol. It is approved for the removal at the first surgery. treatment of high blood sugar caused by Cushing’s syndrome. Because there Other options for treatment include radiation therapy to the entire pituitary is no anti-tumor effect, the tumor itself has to be carefully followed, and there gland or targeted radiation therapy (called radiosurgery), when the tumor is are other important side effects of the treatment as well. These drugs are best seen on MRI. This may be used as the only treatment or it may be given if administered by a pituitary or neuro-endocrinologist skilled in their use. 6 7 PATIENT INFORMATION CUSHING’S SYNDROME AND CUSHING’S DISEASE How can I expect to feel after treatment for Cushing’s disease? take extra glucocorticoid during illness as described above, and wear a MedicAlert bracelet. Most people will start to feel gradually better after surgery and the hospital stay may be quite short if there are no complications. It can take some time It is important to note that, if you are taking replacement cortisol, there to feel completely back to normal, to lose weight, to regain strength, and to may be a number of occasions when you need additional replacement. This recover from depression or loss of memory. It is important to remember that can include stressful situations, such as surgical procedures – whether or not the high cortisol levels physically change the body and brain, and that these related to Cushing’s syndrome – dental procedures, and so on. You should changes may reverse quite slowly. This is a normal feature of the recovery discuss your specific condition with your endocrinologist and ensure you period and patience is definitely a virtue here. know what situations to look out for and what action to take. After successful pituitary surgery, cortisol levels are very low. This can continue for 3–18 months after surgery. These low levels of cortisol can cause nausea, vomiting, diarrhea, aches and pains, and a flu-like feeling. Cushing’s disease FAQs These feelings are common in the first days and weeks after surgery as the 1. I have been told I might have Cushing’s syndrome and have been referred to an body adjusts to the lower cortisol levels. Doctors give people a cortisol-like endocrinologist. Why is this? medicine (glucocorticoid) until recovery of the pituitary and adrenal glands is An endocrinologist is a physician who specializes in hormone disorders. either well under way or complete, and this medication may be required for Cushing’s syndrome and disease are fairly rare, the diagnostic procedure is months. Hydrocortisone or prednisone is usually used for this purpose. complex, and the best results can be expected when these are treated by a Doctors monitor the recovery of the pituitary and adrenal glands by specialist endocrinologist, often together with a neurosurgeon. measuring morning cortisol values, or by testing the ability of the adrenal glands to secrete cortisol in response to an injected medication similar to 2. I have been told I need pituitary surgery. What does this involve? ACTH. The most common way to remove pituitary tumors is through the Until the pituitary and adrenal glands recover, the body does not respond transsphenoidal approach. This involves entering the pituitary gland by going normally to stress – such as illness – by increasing cortisol production. As through the nose or underneath the upper lip, and approaching the pituitary a result people who suffer with ‘flu’, fever or nausea may have to double gland through the sphenoid sinus. Using a microscope or endoscope, the surgeon the oral dose of the glucocorticoid when they are sick. However, this will explore the pituitary gland, hopefully find the tumor, and remove it. increased dosage should only be used for 1–3 days. On occasion, people can suffer vomiting or severe diarrhea that prevents them from absorbing the glucocorticoids taken by mouth. In this situation, it may be necessary 3. What are the risks of this surgery? to receive injections of dexamethasone or another glucocorticoid, and seek emergency medical care. For this reason, patients should wear a MedicAlert Since these tumors are very small, it can be difficult to find them, and the bracelet until glucocorticoid replacement is stopped. normal pituitary gland can be damaged during the procedure. If this happens (about 10–20% of the time), other hormone function can be lost. Since the If it is necessary to have a prolonged increase in hydrocortisone or other pituitary gland controls the production of thyroid hormone, estrogen in glucocorticoid, a doctor should evaluate this need, and a ‘tapering’ regimen women and testosterone in men, and growth hormone – in addition to ACTH may be needed to reduce the dose back to the daily requirement. – replacement therapy for these other hormones might be required. Also, if the People who have had their adrenal glands removed will have to take a posterior part of the pituitary is damaged, anti-diuretic hormone can be lost. glucocorticoid (like cortisone) and a mineralocorticoid (like fludrocortisone) This hormone is responsible for water reabsorption by the kidneys, and without for the rest of their lives. There may be a concern that the pituitary tumor it patients urinate frequently and in large amounts (“diabetes insipidus”), will enlarge, so MRI imaging of the pituitary gland may be done after this leading to dehydration. This hormone can be replaced with a daily dose of a surgery. People whose adrenal glands have been removed may have initial nasal spray or pill. These hormone functions of the pituitary can be replaced symptoms that are similar to those after pituitary surgery, and they should with medication. 8 9 PATIENT INFORMATION CUSHING’S SYNDROME AND CUSHING’S DISEASE 4. Are there other risks associated with this surgery? 8. What if the treatment is not successful? Since the pituitary gland is bordered by the optic nerves and carotid arteries, There are a number of options if the initial transsphenoidal operation is there is a very small risk that these structures could be damaged (less than unsuccessful. Sometimes, a second operation is recommended if no tumor 1%). If this were to happen, the patient could suffer visual loss or a stroke. was found during the initial operation. Alternatively, radiation therapy of the The pituitary is separated from the spinal fluid by a thin membrane. If this pituitary gland can be considered. This is effective in about half the patients membrane is damaged during the surgery, a spinal fluid leak can result. If spinal within a few years, but medical control of cortisol levels is required while fluid leakage occurs and is undetected, a serious infection, meningitis, can awaiting the beneficial effects of radiation. Alternatively, the adrenal glands result. Most surgeons take a small piece of fat from the abdominal wall to use themselves can be removed. This stops the body from making any cortisol, and as a plug to prevent this leakage from occurring. The risk of this happening is so the symptoms of Cushing’s disease resolve, although the pituitary tumor about 1%. Since the pituitary gland is involved in water and sodium balance, itself remains untreated. Removal of the adrenals may lead to a more rapid this can be affected transiently by the surgery as well, and your endocrinologist growth of the remaining pituitary tumor, which will require careful monitoring will monitor your sodium levels for a few weeks after the surgery. All of these with MRI imaging. Finally, there are now new medical options to treat the risks are minimized in the hands of an experienced surgeon. disease. Administration of the drug cabergoline, initially used to treat prolactin- producing tumors, is effective in some cases of Cushing’s disease. Two new drugs, pasireotide and mifepristone, have recently been approved by the FDA. 5. How will I feel after the surgery? Pasireotide acts directly on the pituitary tumor to stop its growth and lower Direct effects of the surgery include nasal congestion and possibly headache. cortisol production. Mifepristone acts to block the peripheral effects of cortisol These symptoms will resolve after 1–2 weeks. If the operation is successful, and so improves the symptoms of the disease. Choosing between these options however, the cortisol levels will drop dramatically. Patients can experience requires a careful discussion between the patient, endocrinologist, and surgeon. symptoms of cortisol withdrawal, which can include profound fatigue, joint aches and mild nausea. This can sometimes last for weeks or months after the surgery. If the operation is successful, the patient will have to take cortisol 9. My surgery was unsuccessful and my endocrinologist has suggested treatment replacement until the remaining normal pituitary gland recovers. with cabergoline. What will this do? Cabergoline acts directly on the tumor to reduce ACTH production and tumor growth. It successfully normalizes urine cortisol for 12 months in about 40% 6. How will I know if my treatment has been successful? of patients. Some patients who have a response in the first one or two months Your endocrinologist will test your blood, urine, and/or salivary cortisol levels will “relapse”, meaning that the drug may not successfully control cortisol levels a few days after the surgery. Usually success can be determined within a few long-term. Because of this, the response should be monitored monthly. The weeks of the operation. overall effect on tumor size has not been well described, although some patients have had reduction in tumor size. 7. Will I feel better? Almost all of the symptoms of Cushing’s disease are reversible. When the cortisol levels drop, the obesity improves and appetite normalizes. Muscles and bones become stronger. These improvements occur slowly and may take months to achieve a normal state. Diabetes and hypertension improve, often very soon after surgery. The psychological effects can be very troublesome and can persist for months, even if cured. 10 11 PATIENT INFORMATION CUSHING’S SYNDROME AND CUSHING’S DISEASE Glossary 10. My surgery was unsuccessful and my endocrinologist has suggested treatment ACTH Adrenocorticotropic hormone. This hormone is produced by the with pasireotide. What will this do? pituitary gland and flows through the blood to the adrenal glands to tell them to produce more cortisol. Pasireotide acts directly on the tumor to reduce ACTH production and tumor growth. It successfully normalizes urine cortisol for 12 months in about 20% Adrenal glands Glands situated just above each of the kidneys and which produce various essential hormones including cortisol and aldosterone. of patients, and may work best in patients whose urine cortisol levels are less than two-times normal when treatment is started. At the highest dose tested, Adrenalectomy Surgical removal of the adrenal glands. it is associated with a decrease in tumor size in some patients. A common side effect is the development of high blood sugar levels requiring treatment (or Cortisol One of the hormones produced by the adrenal glands. It is particularly important in times of stress and illness. additional treatment) for diabetes. CRH Corticotropin-releasing hormone normally made by the hypothalamus to stimulate ACTH production. In synthetic form, used to test for 11. My surgery was unsuccessful and my endocrinologist has suggested treatment pituitary-dependent Cushing’s disease. with mifepristone. What will this do? Cushing’s disease Cushing’s syndrome when caused by a tumor of the pituitary gland. Mifepristone is approved by the FDA for the treatment of high blood sugar Cushing’s syndrome Caused by overproduction of cortisol for any reason. levels caused by Cushing’s syndrome. It blocks cortisol action throughout the body. As a result, its effects cannot be judged by cortisol levels, which may not Ectopic ACTH Production of ACTH from a site other than the pituitary gland. change. Because it is used to lower blood sugar levels, those levels should be Endocrinologist A doctor who specializes in treating hormone illnesses. monitored and medications adjusted. Its ability to normalize other features of Cushing’s syndrome is not clear, and additional treatment may be needed to Florinef A medication, also known as fludrocortisone, that controls salt and fully treat the signs and symptoms of Cushing’s syndrome. water balance. Glucocorticoid A medicine that has effects similar to those of cortisol, for example, hydrocortisone, prednisone and dexamethasone. After successful surgery, cortisol levels are low and a glucocorticoid is given to replace cortisol until the pituitary and adrenal glands resume normal function (in the case of Cushing’s disease) or as life-long replacement (if the For further information adrenal glands are removed). The Pituitary Society, VA Medical Center, 423 East 23rd Street, Rm 16048aw, Hydrocortisone The drug name of cortisol when it is made into a tablet or injection. New York, NY 10010, USA. MRI scan Magnetic resonance imaging – a type of scan that uses a strong Tel: (212) 951 7035. Fax: (212) 951 7050. www.pituitarysociety.org magnetic field and radio waves (no X-rays) to produce a detailed view of the brain and pituitary. Pituitary gland A small gland that is situated under the brain and which controls hormone production in many other parts of the body. Radiosurgery Precisely targeted radiation aimed directly at the tumor, usually given in a single dose. Radiotherapy Radiation treatment, usually used after surgery, which prevents regrowth of the tumor. Radiotherapy has a long-acting effect and may cause reduction of some of the other pituitary hormones over time, thus requiring them to be replaced. Transsphenoidal Surgery that involves approaching the pituitary gland via the nose surgery or upper lip and the sphenoid sinus, thus avoiding the need to go through the upper skull. 12 Written by Lynnette Nieman, M.D. and Brooke Swearingen, M.D. on behalf of the Pituitary Society. Series Editor David L. Kleinberg, M.D. produced and published by CMM Global www.cmmglobal.com