Case Summary: A twenty-one year old female reserve field hockey athlete reported experiencing periods of fatigue and recent weight gain. She had a viral URI infection several weeks ago and although those signs and symptoms are gone she does not feel normal. She is not currently sexually active and has little desire in this area. She feels her face getting puffy, and her hands and feet feel cold from time to time. Some of her menstrual periods have been irregular and she took prednisone as a child for asthma. She is currently not taking any medications.

Signs of Cushing's Syndrome http://www.bmb.leeds.ac.uk/teaching/icu3/lecture/21/image82.gif

Evaluation: The evaluation in this case is critical for the athlete's diagnosis. It is essential to find out about the athlete's previous history with taking prednisone for her asthma and to see if any other glucocorticoids were taken in addition to this. Once her history of what medications were administered, how long they were taken, and if any side effects were experienced in the process is established, a better grasp on whether or not prednisone was the cause of the onset of her symptoms may be considered. There will not be any special tests administered because this is not a sport-related injury; however, testing the athlete's strength in all of her extremities should be considered to determine the degree of muscular weakness. Also if her symptoms become worse and she becomes weaker, a bone scan may be administered to determine if any bone loss is present. To begin the objective evaluation, the athlete's blood pressure should be taken because if it is high, it may be a result of Cushing's syndrome; which is indicative of excess plasma cortisol that could have been a side effect of taking prednisone. At high enough concentrations, cortisol exerts aldosterone-like actions on the kidney, resulting in salt and water retention, which contributes to hypertension.1 The athlete's blood sugar levels should also be measured for abnormalities. Once this test is complete, diabetes and other metabolic irregularities needs to be considered. This patient could present signs of diabetes even though she has Cushing's syndrome because the increased catabolism of bone, muscle, skin, and other organs that is common with Cushing's syndrome, may produce such a large quantity of precursors for hepatic gluconeogenesis that blood sugar increases to levels observed in diabetes.1 To diagnose Cushing's syndrome, the physician will ask about the athlete's medical history and perform a physical examination. The physician can usually determine from these exams whether corticosteroid medication is causing the condition or if the disease is caused by another underlying factor. If it is cause by the corticosteroid, other tests usually are not done and your health professional will consider changing your medication if any is being taken. If you are not taking steroid medication or the health professional believes something other than steroid medication is causing Cushing's syndrome, laboratory tests will be carried out to check the cortisol levels.3 These tests include: a cortisol test, which may be done on a sample of blood or on a sample of urine collected over a 24-hour period. A cortisol test is done to measure the level of the hormone cortisol in the blood, which may indicate problems with the adrenal glands or pituitary gland. Cortisol is produced by the adrenal glands and its levels increase when the pituitary gland releases another hormone called adrenocorticotropic hormone (ACTH). Normally, cortisol levels rise during the early morning hours and are highest in midmorning (about 7 a.m.). They drop very low in the evening and during the early phase of sleep. However, sleeping during the day and staying up at night may reverse this pattern.3 The absence of this daily variation (diurnal rhythm) in cortisol levels may be one of the first signs of overactive adrenal glands, especially Cushing's syndrome.4 Two blood samples may be taken: one in the morning and another in the afternoon in order to make general comparisons; this test can also be done on a sample of urine collected over 24 hours. An overnight dexamethasone suppression test using a low dose of steroid (often done to reconfirm a cortisol test) can be done in addition to the cortisol test. The overnight dexamethasone suppression test involves taking a dose of a corticosteroid medication called dexamethasone to see how it affects the level of a hormone called cortisol in the blood which screens for Cushing's syndrome.5 After taking a dose of dexamethasone, cortisol levels often remain abnormally high in people who have Cushing's syndrome. Occasionally other conditions (such as major depression, alcoholism, stress, obesity, kidney failure, pregnancy, or uncontrolled diabetes) can keep cortisol levels from decreasing after taking a dose of dexamethasone.3

Patient's facial appearance six weeks after start of itraconazole treatment, for a fungal infection, bronchopulmonary aspergillosis (an allergic lung disorder).7 http://www.bmj.com

Diagnosis: The athlete clearly presents with characteristics involved with Cushing's syndrome. However, lab tests need to be thoroughly completed before the final diagnosis and all other hormonal/endocrine issues need to be ruled out. She is currently not believed to be taking medications therefore it can be assumed that prednisone or any other glucocorticoid is presently not the cause. However, her previous history of taking the medication for asthma may have contributed to the onset of these symptoms due to the side effects of the drug. Some of the side effects of taking prednisone that are present with this athlete include: irregular periods, mood changes, abnormal fat distribution from the extremities and with redistribution of the fat in the trunk, face and back of the neck (moon face), weight gain, muscle weakness, and fatigue.3,6 Combined with an increased appetite, often triggered by high concentrations of cortisol, this results in obesity and a characteristic facial appearance in many patients.1

Differential Diagnosis: Cushing's syndrome can be difficult to diagnose because a variety of factors-from the time of day to a temporary illness-can lead to a higher-than-average cortisol level in people who do not have Cushing's syndrome.3 It also can be difficult to pinpoint the cause of Cushing's syndrome, which is important, because treatment depends upon this. Visiting an endocrinologist, a doctor who specializes in hormone disorders, may be necessary to diagnose or treat Cushing's syndrome and rule out the following illnesses/problems: hormonal imbalances metabolic issues diabetes hypothyroidism chronic fatigue syndrome alcoholism chronic renal failure

Key Current Literature: In Cushing's syndrome, there is excess plama cortisol concentration even in the nonstressed individual (it can also known as hypercortisolism). Normally, cortisol levels increase through a chain reaction of hormones. The brain's hypothalamus produces corticotropin-releasing hormone (CRH), which stimulates the pituitary gland to make adrenocorticotropic hormone (ACTH). Then, ACTH stimulates the adrenal glands to produce cortisol.3 The cause of Cushing's syndrome may be a primary defect (i.e. a cortisol-secreting tumor of the adrenal gland) or may be secondary (usually due to an Adrenocorticotropic Hormone (ACTH)-secreting tumor of the pituitary gland).1 With the secondary case, the condition is known as Cushing's disease, which accounts for most cases of Cushing's Syndrome. Cortisol affects almost every area of the body and is particularly important in regulating blood pressure and metabolism.3 As previously stated, the increased blood levels of cortisol also tend to promote uncontrolled catabolism of bone, muscle, skin, and other organs. Therefore, bone strength diminishes and can even lead to osteoporosis, muscle weakness, and the skin becomes thinned and easily bruised.1 A further problem associated with Cushing's Syndrome is the possibility of developing hypertension. This is not due to increased aldosterone production, but instead to the pharmacological effects of cortisol, including cortisol's ability to trigger the pressor effects of epinephrine and norepinephrine.1

Hypothalamic-pituitary-adrenal axis. (CRH = corticotropin-releasing hormone; ACTH = adrenocorticotropin hormone) http://www.aafp.org/afp/20000901/1119.html

Facial appearance six months after patient stopped taking traconazole for bronchiectasis and asthma.7

Prednisone, a corticosteroid, is similar to a natural hormone produced by your adrenal glands. It often is used to replace this chemical when your body does not make enough of it.8 It relieves inflammation (swelling, heat, redness, and pain) and is used to treat certain forms of arthritis; skin, blood, kidney, eye, thyroid, and intestinal disorders (e.g., colitis); severe allergies; and asthma.2,4,8 The following serious si de effects of taking prednisone may result in: an allergic reaction, difficulty breathing, closing of the throat, swollen lips, tongue, or face, developing hives, increased blood pressure, severe headache, blurred vision, or sudden weight gain (more than 5 pounds in a day or two).2,4,8 Some less severe side effects consist of: insomnia; nausea, vomiting, upset stomach, fatigue, dizziness, muscle weakness, joint pain, problems with diabetes control, or increased hunger or thirst. Other side effects that occur only rarely, usually with high doses of prednisone, include: irregular periods, acne, increased hair growth, thinning of skin, cataracts, glaucoma, osteoporosis, roundness of the face, and changes in behavior.2,3 Some of the latter of the side effects were presented in this females' case, which may be a chronic or long term side effect of taking the prednisone for her asthma as a child.3

Evidence Based Course of Care: Treatment of Cushing's syndrome primarily depends on the cause of the disease. The following explains treatments for Cushing's syndrome caused by long-term corticosteroid medication use (which may be the case for this athlete).3 Initially, the patient must never stop taking corticosteroid medication on their own because it might lead to a life-threatening adrenal crisis. The discontinuation of steroid therapy can be a huge challenge.6,8 Three issues exist with regard to withdrawal from steroid therapy: the possibility of suppression of the hypothalamic-pituitary-adrenal (HPA) axis and resulting secondary adrenal insufficiency the possibility of worsening of the underlying disease for which steroid therapy was initiated a phenomenon, sometimes called the steroid withdrawal syndrome, in which some patients encounter difficulty, and even significant symptoms, discontinuing or decreasing steroid doses despite having demonstrably normal HPA axes.6 When steroids are taken, the adrenal glands stop making cortisol; therefore, if the medication is suddenly stopped, the adrenal glands may not be able to start making cortisol quickly enough. This can lead to an adrenal crisis and a severe drop in blood pressure. 3 If reducing the dosage does not make Cushing's syndrome go away, a physician will have to perform more tests to look for another cause of her condition. Home treatment for Cushing's syndrome consists of lifestyle changes to prevent weight gain, strengthen muscles and bones, and prevent complications; which can be achieved by: eating a low-calorie, nutritious diet high in protein and calcium. This can help prevent muscle and bone loss caused by the high cortisol levels in her body.5 The athlete can take calcium and vitamin D supplements to decrease bone loss, which may have beneficial results. She should ask her physician whether she needs medication to help slow bone loss. Limiting salt (sodium) in the diet is especially important if high blood pressure is present among other symptoms.3,4 Regular exercise to help maintain muscles and bone mass and prevent weight gain are also a valuable part of a home treatment plan. Another way to prevent weight gain, is trying aerobic exercise to increase the heart rate. To maintain muscle and bone mass she should try weight-bearing exercises such as push-ups, sit-ups, or lifting weights. Some examples of aerobic exercise include: fast walking, jogging, cycling, and swimming. Avoiding possible falls by removing loose rugs and other hazards from the home/apartment is essential due to the fact that falling may lead to broken bones and other injuries and cause secondary complications in addition to already existing problems.3,4 The patient must also pay close attention to all wounds because too much cortisol, which is a symptom of Cushing's syndrome, slows wound healing. Cleaning all wounds immediately with antibacterial soap and using antibiotic ointment and dressings to prevent infection is critical. Counseling must also be available to the patient if there is a need to help deal with personal issues about possible changes in her body image as a result of the disease.3 Regular eye exams to check for glaucoma and cataracts should also be considered. The athlete must continue to see the physician regularly to help diagnose and treat diabetes, high blood pressure, and other potential complications associated with Cushing's syndrome. The decision for the athlete's return to physical activity will be determined by the physician. The risk of injury due to bone loss, risk of infection, and other various reasons needs to be taken into consideration before her return to play.

References: 1. Widmaier EP, Raff H, Strang KT. Human Physiology: The mechanisms of Body Function 10th Edition 2006 pgs. 377-378 2.Cerner Multum, Inc. Version: Prescription Drug Information for Consumers & Professionals.4.02. Revision Date: 2/14/03 http://www.drugs.com/prednisone.html. Accessed April 13, 2006 3. A-Z Health Guide from WebMD: Health Topics. Cushing's Syndrome. http://www.webmd.com/hw/hormonal_disorders/hw71648.asp. Accessed April 13, 2006 4. Miller WL, Chrousos GP (2001). Cushing's syndrome section of The adrenal cortex. In P Felig, LA Frohman, eds., Endocrinology and Metabolism, 4th ed., pp. 476-511. New York: McGraw-Hill. 5. Stewart PM (2003). Adrenocortical diseases section of The adrenal cortex. In PR Larsen et al., eds., Williams Textbook of Endocrinology, 10th ed., pp. 508-525. Philadelphia: Saunders. 6. Hopkins RL, Leinung MC. Exogenous Cushing’s Syndrome and Glucocorticoid Withdrawl. J Clin Endocrinol Metab. 34(2005) 371-384. 7.Mantero F, Terzoro M, Arnaldi G, Osella G, Masini AM, Ali A (2000) A Survey on adrenal incidentaloma in Italy. J Clin Endocrinol Metab 85:637-644 8.Van Staa T, Leufkens H, Cooper C. Use of inhaled corticosteroids and risk of fractures. J Bone Miner Res 2001; 16:581-88