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What is Cushing’s? Cushing’s Support & Research Foundation Cushing’s Syndrome is a relatively rare endocrine system disorder caused by the body’s exposure to excessive amounts of the hormone cortisol. Cushing’s Syndrome has many symptoms, including weight gain and a change in appearance and may go undiagnosed for many years. Recent studies show that 3-5% of poorly controlled diabetics may have Cushing’s. The most common cause of Cushing’s is the prolonged use of cortisone containing drugs, such as prednisone, which are commonly used to treat severe asthma or arthritis. Approximately 10-15 people per million per year are affected with Cushing’s due to the over-production of cortisol by the body’s adrenal glands. Cushing’s can be fatal if not correctly diagnosed and treated. Cushing’s was first reported by the American neurosurgeon, Dr. Harvey Cushing in 1932. Courtesy of www.CSRF.com

What is Cushing’s? Cushing’s Support & Research Foundation Normally, the pituitary gland, located at the base of the brain, releases ACTH (adrenocortiocotopin hormone) that stimulates the adrenal gland (located above the kidney) to release the exact amount of cortisol needed by the body. There are several situations that can cause over-production of cortisol by the body’s adrenal glands: A pituitary tumor can secrete excess ACTH. The excess ACTH causes over-production of cortisol by the adrenal glands. Cushing’s due to a pituitary tumor is called Cushing’s Disease and all other causes are termed Cushing’s Syndrome. A benign or malignant tumor on the lung or other organ can also secrete excessive amounts of ACTH, which again, stimulates over-production of cortisol by the adrenal glands. Tumors of the adrenal gland can secrete too much cortisol by themselves. With Cushings Normal Appearance Courtesy of www.CSRF.com

What are the Symptoms? Cushing’s Support & Research Foundation Cortisol affects almost every bodily function, thus the symptoms are multiple and often non-specific. Cushing’s cannot be diagnosed based on symptoms alone and symptoms vary widely from one patient to another. Not all patients experience every symptom and symptoms do not seem to appear in any particular order. Some patients report rapid changes, while others experience a slow onset. Cushing’s has many symptoms, but if the disorder progresses, most patients will report: weight gain a redistribution of fat to the face (moon face), the upper back (buffalo hump) and in the neck above the clavicle thinning extremities due to muscle weakness Some physicians consider purple striae (stretch marks) more specific to Cushing’s. Courtesy of www.CSRF.com

What are the Symptoms? Cushing’s Support & Research Foundation Cortisol affects almost every bodily function, thus the symptoms are multiple and often non-specific. Cushing’s cannot be diagnosed based on symptoms alone and symptoms vary widely from one patient to another. Not all patients experience every symptom and symptoms do not seem to appear in any particular order. Some patients report rapid changes, while others experience a slow onset. Cushing’s has many symptoms, but if the disorder progresses, most patients will report: weight gain a redistribution of fat to the face (moon face), the upper back (buffalo hump) and in the neck above the clavicle thinning extremities due to muscle weakness Some physicians consider purple striae (stretch marks) more specific to Cushing’s. Courtesy of www.CSRF.com

Cushing’s Support & Research Foundation Easy bruising Thinning skin Poor wound healing Acne Purple striae Hirsutism Female balding Menstrual irregularity Sleep disorders Excessive hunger Excessive thirst Frequent urination Sweating Anxiety Confusion Concentration loss Memory loss Depression Suicidal thoughts Panic attacks Symptoms Vary And may include any number of these: Abdominal weight gain Red, round ‘moon’ face Thinning extremities ‘Buffalo hump’ High blood pressure High blood sugar Muscle weakness Osteoporosis/Fractures Infections Blood clots Visual field defects Illustration from Mayo Clinic Family Health Book, 2d. ed, 1996 Courtesy of www.CSRF.com

Origins of Cushing’s Cushing’s Support & Research Foundation Pituitary Adenomas Pituitary Adenomas are small, usually non-cancerous, tumors which cause hormonal imbalances. There are two types of Pituitary tumors. Non-secretory tumors can cause problems because of their large size, or they prevent normal hormone production. Secretory tumors produce too much of a particular type of hormone. There are several disorders caused by secretory tumors depending on the type of hormone the tumor secretes. Pituitary Adenomas causing Cushing’s account for approximately 80% of all Cushing’s cases. They are 5x more frequent in women. Most adenomas causing Cushing’s are small, less than 10mm. Pituitary adenomas can cause headaches. Large pituitary adenomas can affect the optic nerve and invade adjacent structures such as the cavernous sinus. Courtesy of www.CSRF.com

Cushing’s Support & Research Foundation Adrenal Tumors Adrenal tumors release excessive amounts of cortisol independently of ACTH production by the pituitary Most adrenal tumors are non-cancerous adrenal adenomas and are located only on one adrenal gland. Carcinomas (cancerous tumors) may also cause high hormone levels and rapid development of Cushing’s symptoms. Over all, adrenal tumors are rare, causing about 15% of all cases of Cushing’s syndrome. With Cushings Normal Appearance Courtesy of www.CSRF.com

Cushing’s Support & Research Foundation Adrenal Macronodular Hyperplasia Another very rare cause of Cushing’s is termed macronodular adrenal hyperplasia. The adrenal glands are enlarged and appear to have multiple nodules, which may be pigmented or non-pigmented. Macronodular hyperplasia usually affects both adrenal glands rather than just one. Some macronodular hyperplasias respond to hormones such as gastric peptides, adrenalin, and vasopressin. An increase in that hormone can cause a rise in cortisol. Patients affected with macronodular adrenal hyperplasia should be studied extensively to determine responses to hormones other than ACTH. Some conditions can be treated by medications. It is becoming apparent that some bilateral macronodular hyperplasias can be inherited. Courtesy of www.CSRF.com

Cushing’s Support & Research Foundation Ectopic Cushing’s Syndrome Is caused by other ACTH-secreting tumors in the body. Small tumors of the lung, tumors of the thymus gland, tumors of the pancreas and carcinoma of the thyroid can secrete ACTH. These types of tumors can cause a slight differentiation in symptoms – higher blood pressure, lower potassium and possible weight loss due to underlying cancer. With Cushings Normal Appearance Courtesy of www.CSRF.com

Cushing’s Support & Research Foundation Steroid Usage - Exogenous Exogenous Cushing’s is caused by a patient’s use of corticoid steroids in the treatment of other diagnosed conditions like severe asthma, rheumatoid arthritis or serious skin conditions. Also called Iatrogenic Cushing’s syndrome, some sources consider this the most likely cause of Cushing’s syndrome. The number of patients being treated with immunosuppressive medication out numbers the cases caused by tumors. This type of Cushing’s may be relieved by dosage adjustments or a change to another type of medication. Patients must not stop medications without consulting a medical professional. With Cushings Normal Appearance Courtesy of www.CSRF.com

Cushing’s Support & Research Foundation Diagnosis Is it Cushing’s? Many Cushing’s patients have long histories of misdiagnoses since symptoms vary, are common in the general population, may be subtle and often develop slowly. Many of the tests used to diagnose Cushing’s depend on the body’s “feedback” system that maintains cortisol levels in a normal range. The hypothalamus secretes a hormone called CRH that stimulates the pituitary to release ACTH. ACTH then stimulates the adrenals to make more cortisol. As cortisol levels rise, a “negative feedback” mechanism lets the hypothalamus and pituitary gland know that there is enough cortisol, thus as cortisol levels rise, they normally decrease their production of CRH or ACTH. This does not occur in a patient with Cushing’s. The Hypothalamic-Pituitary-Adrenal Axis From Endocrinology, Hadley, M.C. 1988, Prentiss Hall, N.J. Courtesy of www.CSRF.com

Cushing’s Support & Research Foundation Diagnosis of Cushing’s The first step in diagnosing Cushing’s is to determine whether the patient has high levels of cortisol. Cortisol levels vary throughout the day, making testing more difficult. The normal “diurnal rhythm” for cortisol secretion is that cortisol and ACTH levels are the highest in the morning and the lowest at 11PM to midnight. Mild or cyclical cases of Cushing’s can be very difficult to diagnose and repeated testing is very often required. Cyclic Cushing’s will only show abnormal test results when the tumor is active. The second step in the diagnosis of Cushing’s is to determine whether the cortisol production is dependent on ACTH (pituitary or ectopic sources) or ACTH independent (adrenal tumors). This is termed the “differential diagnosis”. Courtesy of www.CSRF.com

Cushing’s Support & Research Foundation Screening Tests for Cushing’s Courtesy of www.CSRF.com

Cushing’s Support & Research Foundation Late Night Salivary This is the latest diagnostic test for Cushing’s. Elevated cortisol levels between 11PM and midnight are the earliest indications of the disease. This is an easy test for patients to perform and provides 93-100% accuracy for the diagnosis of Cushing’s. Normal levels of cortisol at this time of day virtually eliminates a diagnosis of Cushing’s. 24-hour Urinary Free Cortisol This test is considered the gold standard diagnostic test. However, additional testing is always needed. There are conditions not related to Cushing’s that provide the same results. Many Cushing’s patients will have a normal 24 hour urine free result from time to time, thus a normal result does not exclude the diagnosis of Cushing’s. With Cushings Dex-CRH Stimulation In patients with equivocal results, combination of dexamethasone suppression with a stimulation test using the hypothalmic hormone CRH can be useful in making the diagnosis of Cushing’s syndrome. This study should only be performed in a setting by endocrinologists who have had experience with the test to ensure it is performed properly. Normal Appearance Courtesy of www.CSRF.com

Cushing’s Support & Research Foundation Dexamethasone Suppression This test has been used for 40 years. It is still widely used and useful when combined with other tests. Patients take 1 mg of dexamethasone, a synthetic steroid, at 11 pm and cortisol and ACTH are measured at 8 the next day. Normal persons will show low ACTH and low cortisol due to proper functioning of the feedback system. Cushing’s patients “do not suppress” thus the cortisol levels remain elevated. When performed accurately this test provides a 95-97% efficiency in the diagnosis of Cushing’s. Petrosal Sinus Sampling This test is useful in differentiating pituitary and ectopic sources of ACTH. PSS uses catheters inserted through the large veins in the groin to sample ACTH levels as they drain from the pituitary veins. This test is most useful when combined with CRH stimulation and can in some cases localize the pituitary tumor to one side of the pituitary gland. This particular study needs to be performed by a skilled interventional radiologist with extensive experience. It has a diagnostic accuracy rate is between 95-98%. Courtesy of www.CSRF.com

Cushing’s Support & Research Foundation Direct Visual – MRI & CT Scan If ACTH levels are increased, the next step in the diagnosis is to determine the location of the ACTH producing tumor. Hopefully direct visual imaging associated with MRI of the pituitary gland will show the tumor. If a tumor greater than 5mm is clearly identified, further testing may not be needed, however care needs to be exercised as approximately 10% of the population have small non-functioning pituitary tumors. In about 50% of cases, the pituitary tumor is so small that it can not be seen with conventional imaging techniques. If ACTH is elevated, and the pituitary MRI is “normal”, further testing is required to differentiate between unseen pituitary sources and an ectopic tumor located elsewhere in the body. If ACTH levels are low or not detectable, a CT or MRI of the adrenal glands almost always identifies the tumor or tumors. With Cushings Normal Appearance Courtesy of www.CSRF.com

Cushing’s Support & Research Foundation Differential Diagnosis Once it is established that cortisol levels are elevated, several tests are used to determine the cause of Cushing’s: Measurement of serum ACTH – ACTH will be elevated in patients with pituitary tumors and ectopic tumors. ACTH will be low or not detectable in patients with adrenal tumors. High Dose Dexamethasone Suppression Test Endocrinologists may perform high-dose dexamethasone suppression testing to help distinguish a pituitary from a non-pituitary ACTH-secreting tumor. Whole Body Imaging If the source of ACTH secretion is thought to be ectopic, often whole body images are performed. Some larger tumors may be identified using CT or MRI scans PET scans can also be useful in identifying ectopic tumors Ectopic tumors are successfully located in the majority of cases, however small tumors can remain unseen or “occult”. Courtesy of www.CSRF.com

Cushing’s in Children Cushing’s Support & Research Foundation Most of the symptoms of Cushing’s in children are similar to that of adults. An added concern however, is the symptom of growth failure or a deceleration of growth accompanied by weight gain. It is vital that children be evaluated by Pediatric Endocrinologists who are experienced with adjusting test requirements for their size. The best diagnostic for children is the Urinary Free Cortisol test. The most common cause of Cushing’s in infants and toddlers is an adrenal tumor. The most common cause of endogenous Cushing’s in older children is an ACTH secreting pituitary tumor. With Cushings With Cushings Normal Appearance Normal Appearance Courtesy of www.CSRF.com

Cushing’s Support & Research Foundation Treating Cushing’s Pituitary Adenomas The first choice in treating pituitary tumors is surgical removal. Transsphenoidal surgery is done through the nose and is performed by a neurosurgeon. It is important to find a surgeon who specializes in pituitary surgery. Long-term follow up is required after tumor removal. Hormone supplementation post-surgery needs to be monitored by an experienced endocrinologist. Provided that normal pituitary tissue remains, normal pituitary function returns gradually. If the tumor or part of it can not be removed surgically, radiation and medical treatments may be required. In some cases a small amount of tumor cells remain. These may grow and cause a recurrence. Radiating the pituitary gland may take as long as 3 years to be effective. In the mean time, medical treatments are needed to control the cortisol production and it’s complications such as high blood pressure, high blood sugar, osteoporosis, etc. Courtesy of www.CSRF.com

Cushing’s Support & Research Foundation Adrenal Tumors Small non-cancerous adrenal tumors (adenomas) can be removed with the less invasive laparoscopic surgery techniques. Larger cancerous tumors are removed using open surgical techniques. If a rare cancerous tumor is found, surgery may be followed by radiation or chemotherapy. In cases of bilateral adrenal hyperplasia, both glands may need to be removed. In this case, the patient will need hormone replacement for the rest of their life. With Cushings Normal Appearance Courtesy of www.CSRF.com

Cushing’s Support & Research Foundation Recovery Patients and their family should not expect immediate recovery following surgery. Just as each patient’s symptoms are unique, so is the recovery period. Some patients move steadily through the process. Others experience a process of small steps of improvement with multiple set backs along the way. The length of time the patient’s body was exposed to the excessive cortisol is an indication for the length of the recovery period. Patients who have had pituitary surgery or radiation should be periodically evaluated for deficiencies of other hormones such as thyroid and Growth Hormone. During the recovery process, it is not unusual to experience fatigue, muscle aches and pains, a lack of appetite and mild nausea. Courtesy of www.CSRF.com

Cushing’s Support & Research Foundation Recovery Patients must be informed about adrenal insufficiency “sick day rules”. Patients who are prescribed physiological replacement doses of cortef need to know that additional doses of cortef are required during acute illnesses to prevent serious problems such as low blood sugar level or a drop in blood pressure. Following curative surgery, cortisol levels drop to virtually zero. Cortisol is needed by the body, thus replacement medication is needed. For patients with pituitary or single adrenal tumors, the dose is gradually tapered down to physiological replacement levels, so that the patient’s own HPA axis recovers. This can take a substantial period of time. Most patients are able to stop replacement medication after 1 year. After physiological replacement levels are reached, most patients are tapered to lower levels using the short acting drug, hydrocortisone (Cortef). Follow up 24 hour urine for cortisol or MRI / CT scans may be necessary to evaluate recurrences of tumors. Courtesy of www.CSRF.com

Cushing’s Support & Research Foundation Recovery It is not uncommon for patients who are affected by a life threatening disease to experience depression. Some studies indicate that Cushing’s may have the highest occurrence at 90%. This is partly due to the effects of excessive cortisol on the brain. Continued evaluation of symptoms by your health care professionals is also necessary to help identify and treat the symptoms. Medications to treat the symptoms may need to be re-evaluated throughout the recovery process. In the End Normal Appearance A positive attitude is the best recourse. Continually focusing on the progress you have made is the only way to see through both the good and bad times. With Cushings Courtesy of www.CSRF.com

Cushing’s Support & Research Foundation Mission Provide information and support for Cushing’s Syndrome/Disease patients and their families. Increase awareness and educate the public. Be a resource of information and support for health care professionals. Raise and distribute funds for Cushing’s research. Organization The CSRF was incorporated in 1995 in the state of Massachusetts as a non-profit organization. We are an Associate Member of the National Organization for Rare Disorders(NORD) and The Endocrine Society Our Medical Advisory Board consists of world renowned Endocrinologists and Surgeons who specialize in Cushing’s Disorders. The CSRF is primarily funded by its membership and donations. Courtesy of www.CSRF.com

Aurora Borealis photos Copyright © 2003 Nordlyssenteret Cushing’s Support & Research Foundation www.CSRF.net Reviewed by: James Findling, MD, Endocrinology at St. Luke’s Medical Center in Milwaukee, WI and Meg Keil, MS, CNP, Director of Pediatric Programs at NICHD, NIH in Bethesda, MD It’s a long but worthwhile journey! And ‘NORDLYS’ www.northern-lights.no For the use of the Aurora Borealis photos Copyright © 2003 Nordlyssenteret Courtesy of www.CSRF.com