CSRF Questions & Answers

Question: The surgical incision to remove my pituitary tumor was done along the upper gum line. How long will it take to regain my sense of smell and taste and how long will it take for the swelling to go down?
Answer: The time it takes for recovering the sense of smell and taste after transsphenoidal surgery depends on whether nerves have been cut while gaining access to the pituitary gland. In some cases the loss of smell and taste may last for many months or never return. Swelling of the upper lip and gum should disappear within a few days or weeks after the surgery.

Question: Does age have anything to do with the time required to recover from Cushing's?
Answer: Age has a significant effect on the recovery from the effects of Cushing's disease. Younger people are more likely to heal faster and to recover more quickly from the catabolic effects of cortisol than patients in the older age group. Also, people who have had Cushing's for a long time may take longer to recover.

Question: I have Cushing's and have this incredible desire to eat all the time. Is there a medical explanation as to why we want to eat so much? Will this resolve once my Cushing's is cured?
Answer: Excessive cortisol levels do stimulate appetite and account for the rapid weight gain that occurs with Cushing's syndrome. The best way to deal with it is to bring the cortisol levels back to normal. This should occur if Cushing's syndrome is cured. There are several possible mechanisms by which patients with Cushing's have increased appetite. Insulin resistance associated with high insulin levels may be a cause since insulin plays a regulatory role on hunger and satiety. Also, some of the adipokines (leptin, resistin, adiponectin), fat cell chemicals that affect energy regulation are affected by cortisol and may disrupt the physiological control of energy metabolism and cause increased hunger.
Krsek M, et al. Adipokine levels in Cushing's syndrome; elevated resistin levels in female patients with Cushing's syndrome. Clinical Endocrinology 60:350; 2004
Ghizzoni et al. Leptin, cortisol and GH secretion interactions in short normal prepubertal children, J Clin Endocrinol Metab 86:3729; 2001
Gavrila et al. Diurnal and ultradian dynamics of serum adiponectin in healthy men: comparison with leptin, circulating soluble leptin receptor, and cortisol patterns. J Clin Endocrinol Metab 88:2838; 2003

Question: Does one require less hydrocortisone replacement after menopause?
Answer: Female hormones (estrogens) do affect cortisol metabolism by increasing the binding of cortisol to carrier plasma proteins. When the estrogen levels decrease after menopause cortisol binding also decreases. In people with intact pituitary-adrenal function, cortisol secretion decreases and levels adjust automatically. However, if a person depends on exogenous hydrocortisone to maintain normal levels, the amount required to achieve this level may decrease slightly.

Editor's Note: Dr. Schteingart is an endocrinologist at the University of Michigan, Ann Arbor, MI. He has been involved with the treatment of Cushing's for many years.

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Question: I am completely hypopituitary and had a bilateral adrenalectomy to control my Cushing’s. I now have Nelson’s Syndrome and am on 30mg/day of hydrocortisone replacement. I still have uncontrollable diabetes, muscle weakness and look and feel like I still have Cushing’s. Is this normal for Nelsons or could my replacement dose be too high? Answer: Patients who have had a bilateral adrenalectomy for treatment of Cushing’s disease and are on adequate hydrocortisone replacement should not have any persistent symptoms of Cushing’s syndrome. Nelson syndrome which occurs when there is an ACTH-secreting pituitary tumor is associated with increased pigmentation of the skin and if the tumor has enlarged, symptoms of tumor growth affecting vision. The problem that may arise on hydrocortisone is that the dose may be excessive for the patient’s optimal replacement and this hydrocortisone then causes symptoms of Cushing’s. Patients with hypopituitarism frequently have decreased clearance of cortisol and require a lower dose for maintenance. A good way of determining the right replacement dose of hydrocortisone is to measure urine free cortisol while taking the dose of hydrocortisone in question. Values should be in the middle of the normal reference range. Occasionally patients with hypopituitarism who need hydrocortisone replacement require only small doses of hydrocortisone, from 10 to 15 mg daily.

Question: Is it possible for someone with Cyclic Cushing’s to have too little cortisol at times?
Answer: Patients with cyclic Cushing’s syndrome may not return to normal levels during the off period. Levels may indeed be low or there may be a reversal of the normal circadian rhythm such that low levels are seen in the morning and high levels in the evening.

Question: Does strenuous exercise effect cortisol levels? If so, should I avoid exercise during a 24 hr urine test and/or for how long before starting the test?
Answer: Strenuous exercise may be stressful enough to increase cortisol levels transiently. If one wishes to obtain a perfect baseline cortisol level it would be best to avoid exercising during the 24 hour period of urine collection. Avoiding strenous exercise at least overnight before the beginning of the collection should be sufficient. Editor’s Note: Dr. Schteingart is an endocrinologist at the University of Michigan, Ann Arbor, MI. He has been involved with the treatment of Cushing’s for many years.

Editor’s Note: Dr. Schteingart is an endocrinologist at the University of Michigan, Ann Arbor, MI. He has been involved with the treatment of Cushing’s for many years.

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Question: I have been under constant, extreme stress for the past year and am now being tested for Cushing's. Can chronic stress cause elevated cortisol levels in the 24 hr urine test, the low dose dexamethazone test and the night-time salivary cortisol test? Also, can extreme stress cause Cushing's symptoms?
Answer: Stress may certainly increase cortisol secretion. Many types of stress have actually been studied and, in most cases, the increase in cortisol is within a physiologic range. However, chronic stress leading to significant depression may result in abnormal laboratory studies including urine free cortisol, abnormal dexamethasone suppression, and probably elevated late-night salivary cortisols. There is also data that supports the concept that stress-related increases in cortisol may be associated with some of the known physiological abnormalities seen in Cushing's syndrome such as hypertension, insulin resistance with impaired gluose tolerance, and dyslipidemia. Question: I am in the middle of testing for Cushing's and just realized that I am 8 weeks pregnant! Are there risks associated with a high cortisol and the baby? Can Cushing's be diagnosed during a pregnancy? Is it safe to take the dexamethasone suppresion tests during pregnancy? Will the baby need any special attention after delivery? Answer: Cushing's syndrome during pregnancy is rare and, quite frankly, I have never had the opportunity to manage a pregnant woman with Cushing's syndrome. Nonetheless, the literature does show significant risk to the mother and child if it is not properly treated. Dexamethasone suppression testing will not be helpful and I would strongly recommend that you see an endocrinologist with extensive experience in the diagnosis and management of patients with Cushing's syndrome.

Question: I am in the middle of testing for Cushing's and just realized that I am 8 weeks pregnant! Are there risks associated with a high cortisol and the baby? Can Cushing's be diagnosed during a pregnancy? Is it safe to take the dexamethasone suppresion tests during pregnancy? Will the baby need any special attention after delivery?
Answer: Cushing’s syndrome during pregnancy is rare and, quite frankly, I have never had the opportunity to manage a pregnant woman with Cushing’s syndrome. Nonetheless, the literature does show significant risk to the mother and child if it is not properly treated. Dexamethasone suppression testing will not be helpful and I would strongly recommend that you see an endocrinologist with extensive experience in the diagnosis and management of patients with Cushing’s syndrome.

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Question: My doctor talks about the hypothalamic-pituitary-adrenal-system. What is this and what does it have to do with Cushing's?
Answer: The hypothalamic - pituitary -adrenal system is the body's normal system for producing cortisol. The hypothalamus, a part of the brain, produces a hormone called CRH. CRH travels to the pituitary gland, located just below, where it stimulates the production of ACTH. ACTH in turn stimulates the adrenal to produce cortisol. When circulating cortisol levels are high, both the hypothalamus and pituitary decrease their hormonal output. This normally causes a decrease in ACTH production, which decreases the amount of cortisol produced by the adrenal. With Cushing's, regardless of the cause, this system does not function properly, and cortisol levels rise.

Question: What is the difference between Cushing's Syndrome and Cushing's disease?
Answer: Cushing's syndrome refers to the physical and emotional changes that occur when there is excess cortisol in the body. A very common cause is steroid medication that is prescribed for many diseases such as asthma and arthritis. Endogenous Cushing's refers to disorders in which the body itself is overproducing cortisol. This can be due to a pituitary tumor which is termed Cushing's Disease and accounts for 70% of endogenous Cushing's. Other causes of endogenous Cushing's include adrenal tumors, adrenal hyperplasia, and ectopic tumors (tumors, such as in the lung, that can produce hormones similar to a pituitary gland.) It is absolutely essential that the correct cause of Cushing's be determined prior to treatment.

Question: I have Cushing's Disease and my doctor insists that I travel to a major medical center to have surgery. Why is it so important to have an expert pituitary neurosurgeon?
Answer: The success in curing a patient of Cushing's Disease is directly related to the experience of the neurosurgeon. In other words, it is essential to be operated on by a neurosurgeon who has done many hundreds of pituitary tumor removals. This is critical to providing the highest chance of cure, as well as the lowest chance of any damage to the normal pituitary gland. There are several medical centers in the United States and elsewhere, where there are expert pituitary neurosurgeons.

Question: Why does a patient who has been overproducing steroids due to Cushing's need to take steroids following curative surgery?
Answer: When a patient has been cured of Cushing's, their normal hypothalamic-
pituitary-adrenal system is not producing any cortisol because the high circulating levels prior to cure have suppressed the normal system. The normal hypothalamic- pituitary - adrenal system usually recovers, but this may take up to a year or two. In the interim, it is absolutely essential to life that the patient take replacement steroid medication.

Question: Why do so many patients have pain, fatigue and mood swings months after successful surgery for Cushing's?
Answer: Following successful cure of Cushing's, patients may experience physical and emotional difficulty for many months. Part of this is related to the withdrawal of the high blood levels of steroids to which the patient's body had become accustomed. This is best treated by working closely with the endocrinologist to determine the best steroid taper rate. Research shows the vast majority of patients who have had emotional and psychiatric difficulty in association with high cortisol levels experience complete recovery following cure. However, a small number of patients may actually have an exacerbation of psychiatric problems several months following surgery. This does appear to resolve with time.

Question: Since I had successful surgery for Cushing's, I cannot lose weight and the weight is on my face and abdomen, just like when I was ill. Is the steroid replacement therapy responsible for this weight?
Answer: It should be possible to lose weight following cure, once the steroid replacement doses are below the levels experienced during Cushing's. Once the patient has been tapered down to physiologic replacement (levels equivalent to what is normally produced by the adrenal, approximately 5mg prednisone or 30 mg hydrocortisone daily), there should be no greater difficulty losing weight than there would be for a person of the same weight without Cushing's. The best way to achieve weight loss following surgery for Cushing's is to use a sensible diet and exercise program and to be supervised closely by an endocrinologist in order to have the steroid replacement tapered as rapidly as possible without producing steroid withdrawal symptoms.

Question: I have symptoms of Cushing's but my 24-hour urinary cortisol measurement is normal. Is it possible to have a normal test and still have Cushing's?
Answer: The 24h urine free cortisol test is an extremely sensitive and specific test for the presence of Cushing's. When the level is high, it is likely that the patient has Cushing's. There are a few other conditions that can cause high cortisol, including depression and alcoholism. When a 24h urine free cortisol is normal, the chance of the patient having Cushing's syndrome is less than 1%. This generally occurs only in: 1) a very early stage of Cushing's before the urine cortisol is consistently high, or 2) a rare condition called "periodic hormonogenesis" or cyclic Cushing's, in which a patient has periodic excess secretion of cortisol, but is normal between these episodes. These conditions are best diagnosed by having the patient collect multiple samples over time. In the vast majority of patients, however, a normal 24h urine free cortisol excludes the diagnosis of Cushing's.

Question: What is an ACTH Stimulation Test and what is it used for?
Answer: An ACTH stimulation test is most commonly used in patients with Cushing's Syndrome many months after surgery to determine whether their hypothalamic-pituitary-adrenal axis is recovering and whether it is therefore safe to discontinue their steroid medications. It is a 1 hour test in which an injection of synthetic ACTH is administered and cortisol levels are measured at the start of the test, and at 30 and 60 minutes. If the cortisolrises to 18 or higher, the patient is making enough cortisol on their own to discontinue steroid medication. There are other uses of this test in other adrenal disorders.

Question: What is Nelson's syndrome?
Answer: Up to 10% of patients who have had a bilateral adrenalectomy for the cure of pituitary Cushing's can develop Nelson's syndrome. This syndrome refers to the enlargement of the pituitary tumor after removal of both adrenal glands. Bilateral adrenalectomy was the primary treatment for pituitary Cushing's prior to the 1970's. However, since that time, transsphenoidal surgery is able to cure 80-90% of patients with Cushing's disease if the surgery is performed by an experienced pituitary neurosurgeon. For this reason, bilateral adrenalectomy is not often necessary, meaning that the incidence of Nelson's syndrome is now fairly low.

Question: What percentage of patients with Cushing's syndrome resulting from an adrenal tumor recover full use of their atrophied adrenal after a unilateral adrenalectomy? How long does this process take?
Answer: The majority of patients who have undergone a unilateral adrenalectomy recover adrenal function within 1 to 2 years following surgery.

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Question: I have osteoporosis due to Cushing's. Will this improve over time?
Answer: A recent study has shown substantial improvements in bone density within several years after the successful cure of patients with pituitary Cushing's. Bones have the best possible chance for recovery when the replacement steroid dosage is as low as possible. If you are on replacement therapy following surgery, you should be working with your doctor to taper the steroid dose at a rapid , but tolerable rate.

Bones can also benefit from a healthy diet and intake of at least 1 gram of calcium per day. Exercise has also been shown to be beneficial, but is best started under the supervision of a physician. Most patients with osteoporosis can undertake exercise such as walking or swimming without risk of injury. Exercise that is weight bearing, such as weight lifting, or exercise that involves a risk of falling, such as skiing, would not be advisable unless under the direction of a physician or physical therapist.

Question: How often do additional pituitary tumors develop in Cushing's patients who have had a pituitary tumor successfully removed? Is there a time frame during which this occurs?
Answer: "New" pituitary tumors very rarely occur in patients who have had a pituitary tumor removed. However, a recurrence (regrowth of a tumor in the same area of the pituitary) is seen in approximately 5 % of cases. This is most likely due to incomplete removal of perhaps a few cells of the previous tumor. Most recurrences are observed within the first five years after surgery.

Question: Like others, it took me a long time to obtain a correct diagnosis of Cushing's. Why does it take so long before a doctor thinks of Cushing's and is there anything that we can do so we are taken more seriously?
Answer: There are several factors that contribute to the difficulty of a Cushing's diagnosis. First, Cushing's is a rare disorder with an incidence rate of 5 cases per million. In contrast, diabetes is a very common disorder. Many physicians in private practice will never encounter a patient with Cushing's, whereas most will see a number of diabetic patients. Thus, doctors are inclined to diagnose the most common disorder and in most cases, that diagnosis will be correct. The second reason for the difficulty in diagnosis is the minimal amount of training on Cushing's that MD's receive during medical school and their internships. This relates to the fact that Cushing's is a rare disorder. Patient groups, such as yourselves, can be instrumental in increasing the awareness of Cushing's in medical schools and teaching hospitals by sponsoring physician speakers who are experts in Cushing's. A third reason for the difficulty in diagnosis has to do with non-specific symptoms. In other words, the symptoms associated with Cushing's are symptoms that are also associated with more common disorders such as diabetes, high blood pressure, depression and obesity. There are other rare illnesses that are easier to diagnose simply because the symptoms are more specific.

As far as being taken more seriously prior to a diagnosis, I would highly recommend showing old pictures of yourself to your physician. A photo from several years before can illustrate a rapid change in appearance. Relatively rapid changes in appearance, without dramatic changes in lifestyle, usually indicate medical problems that warrant further evaluation.

Question: I know a woman whose husband died of Cushing's Syndrome and her daughter subsequently developed it. Is Cushing's Syndrome hereditary?
Answer: As a rule, Cushing's is not hereditary. However, there is an extremely rare condition called "multiple endocrine neoplasia type 1" which can run in families. This disorder involves a combination of benign endocrine tumors of the parathyroid, pancreatic and pituitary glands. It is theoretically possible that two people in a family with this disorder could have Cushing's syndrome.

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Question: What are the differences between hydrocortisone, cortisone acetate, prednisone, and dexamethasone? Are there any guidelines as to when one is used versus another?
Answer: These compounds are all adrenal steroid analogs; specifically, they are called glucocorticoids. Glucocorticoids affect carbohydrate, protein, and fat metabolism, bone metabolism, and immune and inflammatory functions. In contrast, the mineralocorticoid aldosterone, also secreted by the adrenal, regulates sodium and potassium metabolism and fluid balance. The glucocorticoid that is produced by the body is cortisol, also known as hydrocortisone. Cortisone acetate is the glucocorticoid cortisone with an ester group attached that makes it soluble in water. Cortisone is biologically inactive and is rapidly converted to cortisol by the liver so that it can exert its effects. Hydrocortisone and cortisone acetate are both short-acting glucocorticoids. They are given once daily, in the early morning, to patients who are recovering from Cushing's syndrome or are being tapered off pharmacological dosages of glucocorticoids to allow their hypothalamic -pituitary-adrenal axis to recover. These are the only circumstances in which I prescribe hydrocortisone, and I do not use cortisone acetate.

Prednisone and dexamethasone are also synthetic glucocorticoids. Prednisone is 4 to 5 times more potent than hydrocortisone and has a longer duration of action, perhaps 12 hours or more. Dexamethasone is 40 to 50 times more potent than hydrocortisone and even longer-acting, 18 to 24 hours. Both of these glucocorticoids are given when a prolonged action is desired. This includes replacing cortisol in patients with permanent adrenal insufficiency (Addison's disease) or suppressing ACTH secretion in patients with congenital adrenal hyperplasia. In such cases, the medication is taken at bedtime, thus the patient awakens with appropriate levels of steroid. Very rarely, these medications cause insomnia if taken at night. These longer acting glucocorticoids are also used to suppress inflammation or immune rejection, and both are less expensive than hydrocortisone.

If a patient with permanent adrenal insufficiency is doing well on hydrocortisone replacement, usually split between two or three doses, the largest taken in the morning, I usually do not change the medication. However, if the patient is not doing well, I will change the medication to dexamethasone or prednisone. Some of my patients have reported remarkable improvements in their quality of life on these longer acting medications. The longer acting glucocorticoids have been reported to have greater catabolic activity on bone, but there is no evidence that they act differently than cortisol. Rather, it is probably because they are used in inappropriately high dosage.

The usual replacement dosages of these glucocorticoids are : hydrocortisone about 25 mg/day, cortisone acetate about 37.5 mg/day, prednisone about 5 mg/day, and dexamethasone about 0.5 mg/day. Glucocorticoid replacement in any patient must be carefully monitored and individualized.

Question: What medication is given following surgery for Cushing's syndrome and is there a proper procedure for weaning a patient from replacement medication?
Answer: During and immediately following surgery, the patient is usually placed on high doses of hydrocortisone, 200 to 300 mg/day. Beginning the day after surgery, I normally decrease the dose by half each day, (e.g., 200 mg, 100 mg, 50 mg, then 25 mg). Most patients are taking a replacement dosage within one week of surgery. Exceptions to this are found in cases of surgical complications or infection, in which case the dosage is tapered over a somewhat longer period of time. When the patient leaves the hospital, however, he or she should be taking no more than a replacement dosage of hydrocortisone. Longer-acting glucocorticoids should not be taken if hypothalamic-pituitary- adrenal axis recovery is the anticipated result.

Before release from the hospital, the patient is instructed to wear a Medical Alert bracelet or necklace, is prescribed three or four preloaded 1-mL (4 mg) dexamethasone syringes which should be close by at all times (one on his or her person, one at home, one in the car, one at work, etc.). The patient is instructed when and how to inject the dexamethasone for emergencies, and how to adjust the glucocorticoid dosage for minor illnesses or major stresses.

I advise my patients that they may experience symptoms of glucocorticoid deficiency or dependency. These symptoms are flu-like: malaise, weakness, easy fatigue, mild nausea, muscle and joint aches and pains. Most patients either don't have these, don't complain about them, or can tolerate them. In instances where the symptoms are severe, I explain to my patients that, in general, the quicker that they are able to work through this stage, the quicker their overall recovery will be. While I like to reach a true replacement dosage as quickly as possible, I will compromise within limits to make the patient more comfortable. However, too high a replacement dosage for too long a time period can jeopardize the patient's health. Withdrawal symptoms can be uncomfortable, but they are not dangerous. Patients should be aware of the more serious symptoms of acute adrenal insufficiency, which may include abdominal pain, nausea, vomiting, fever, and low blood pressure, which may cause lightheadedness and fainting when standing up from a lying or sitting position.

The patient is left on the physiological replacement dose only for as long as is necessary to recover from surgery and hospitalization, no longer than six or eight weeks. Recovery of normal hypothalamic-pituitary-adrenal function requires that the patient be weaned from the replacement medication. The steps I take are as follows:

1. If the patient has been taking prednisone or dexamethasone, it should be changed to hydrocortisone.

2. The hydrocortisone should be tapered as quickly as tolerated to 10 mg each morning soon after awaking. Patients who have been taking prednisone or dexamethasone may feel bad in late afternoon. They can take 5 mg of hydrocortisone at 2 or 3 in the afternoon initially, but this should be discontinued as quickly as possible.

3. At some point, usually after a few weeks to a month on the single morning 10 mg hydrocortisone dose, an early morning (i.e., 8 a.m.) plasma cortisol level is obtained. That day's hydrocortisone tablet is delayed until after the blood is drawn, because the test cannot distinguish between hydrocortisone secreted by the adrenal and that taken by mouth. When the morning plasma cortisol reaches 10 mcg/dL, the daily hydrocortisone medicationcan be discontinued. However, supplementation for minor illnesses and major stresses is still required.
4. After a few more weeks, a standard Cortrosyn (synthetic corticotropin, or ACTH) stimulation test is performed and is repeated every month or so until it becomes normal (i.e., when the plasma cortisol is equal to or greater than 20 mcg/dL at any time during the test). When the test becomes normal, the function of the hypothalamic-pituitary-adrenal axis is also normal. The bracelet and dexamethasone syringe can be discarded and no further treatment for stress or illness is required.

Question: Do the symptoms of fatigue and weakness improve even more after replacement medication is discontinued?
Answer: One can assume that true replacement medication does not cause fatigue and weakness, because it is merely replacing the normal amount of hormone secreted by the adrenal glands. However, there are usually other factors at work. First, it takes most patients a full year to recover from all of the effects of Cushing's syndrome. The fact that they are taking replacement glucocorticoid does not alter this prolonged recovery. Second, during some phase of their recovery, they are actually taking less than a full replacement dosage (i.e., 10 mg vs. 25 mg of hydrocortisone) and thus may have some symptoms of glucocorticoid deficiency. Third, there are many causes of fatigue and weakness, including mild depression. If these symptoms persist, their cause should be investigated and, when appropriate, treated.

Question: Does Cushing's syndrome have an effect on the thyroid gland? Are Cushing's patients more prone to thyroid problems?
Answer: There may be subtle changes in laboratory thyroid function test results. For example, serum thyroid-stimulating hormone (TSH) levels are often low. However these changes are not associated with clinical symptoms. Once the Cushing's syndrome is cured, the values return to normal. Cushing's patients are no more prone to thyroid disease than other individuals, but thyroid disease is more common in women during middle age, as is Cushing's.

Question: Is it possible to become pregnant and have a normal pregnancy after having had Cushing's syndrome?
Answer: Assuming that the treatment of the Cushing's syndrome has not interfered with reproductive function (e.g., that the neurosurgeon has not removed so much of the pituitary gland that it cannot secrete normal amounts of follicle-stimulating hormone (FSH) and luteinizing hormone (LH), which regulate ovarian function) the answer is an unequivocal "Yes". Cushing's syndrome, itself, has no lasting deleterious effect on reproductive ability, and Cushing's syndrome is, with extremely rare exceptions, not a familial or genetic condition. Even if the patient has had pituitary surgery or radiation that has inhibited or eliminated normal secretion of FSH and LH, it is often possible to become pregnant using hormone replacement methods frequently employed in infertility clinics. In cases of permanent adrenal insufficiency, some physicians will recommend a slight increase in the daily replacement glucocorticoid dose during pregnancy, although the need for this is debatable. Higher stress doses of hydrocortisone must be administered during labor and delivery, but the normal replacement dose can be resumed immediately thereafter.

Question: Are Cushing's patients prone to developing blood clots, particularly in the lungs? If so, what, if any, precautions should be taken?
Answer: There is some evidence that Cushing's syndrome patients have a greater tendency to form blood clots and that this may be due to increased levels of certain normal clotting factors in their blood. One does not usually form clots in the lungs; rather, the clots form in the deep veins of the legs. Once formed, they can break loose and travel through the major vein in the abdomen, (the inferior vena cava), through the right side of the heart, and out into the pulmonary artery through which the heart delivers blood to the lungs.There, the diameter of the blood vessels rapidly decreases, and the clot becomes lodged in the vessel, preventing blood flow to that part of the lung. This is called a pulmonary embolus.

Unless there is a preexisting history of blood clots (thrombophlebitis, phlebo-thrombosis, or pulmonary embolus), the main precaution is to exercise the legs. Clots tend to form when the blood runs very slowly. Muscle activity squeezes the blood up from the legs, past flap valves in the veins, and back to the heart. Patients should exercise for at least fifteen minutes three or four times a day, especially when they are in a hospital undergoing tests that keep them in bed much of the time. The best exercise is walking, but pushing the balls of the feet against the foot of the bed is also helpful. In addition, leg massage by a physical therapist can achieve a similar result.

Question: Can women on female hormone replacement therapy or birth control pills obtain meaningful results from an overnight dexamethasone suppression test?
Answer: It is well accepted that high levels of female hormones cause changes in the blood that can create a falsely high cortisol measurement. In cases of true hormone replacement therapy, the levels of hormones are usually low enough that false positive results are not a problem. In the case of birth control pills, the levels are sometimes high enough for false positive results to be obtained.

Cortisol is normally present in the blood both as free cortisol and bound to a protein called transcortin or cortisol-binding globulin (CBG). It is the increased free cortisol that causes the symptoms of Cushing's. High levels of female hormones cause the liver to increase production of CBG, which increases the total plasma cortisol level, the level measured in the usual laboratory tests. Because the normal output of cortisol is higher early in the morning, more cortisol is bound to circulating CBG at that time. This can create an artifactually high morning cortisol measurement. Since cortisol does not bind to CBG very tightly, plasma cortisol levels fall quite rapidly once cortisol secretion falls. Therefore, plasma cortisol levels at 8 a.m. after an overnight dexamethasone suppression test (dexamethasone taken at 11 p.m.) are usually within the expected range.

If the results are equivocal, measurement of bedtime plasma cortisol and the standard 2-day dexamethasone suppression test are the first alternatives I would consider. This allows cortisol sufficient time to dissociate from CBG and be cleared from the circulation. Since it is only the free cortisol that is excreted by the kidney, and since the free cortisol is essentially normal in patients on birth control pills, urine free cortisol is also usually a reliable index of dexamethasone suppression in the 2-day test. If the results are still equivocal, it many be necessary to discontinue the birth control pills for six to eight weeks and repeat the tests.

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Question: How is the proper dosage of maintenance medication determined?
Answer: Your endocrinologist begins with a "standard" dosage of steroid, which lies within a very narrow range. For an average adult, the usual daily dosage for glucocorticoid replacement would be .5 to .75 mg of dexamethasone taken as a single dose, 5 to 7.5 mg of prednisone taken as a single dose, 20 to 30 mg of hydrocortisone taken as multiple doses, and 30 to 45 mg of cortisone acetate taken as multiple doses. The "standard" replacement dosage of mineralcorticoid would be 0.1 to 0.2 mg of fludrocortisone taken as a single dose. Fludrocortisone may not be needed by individuals with remaining adrenal glands, but is almost always required when both adrenal glands are removed. The above "standard" dosages would be lowered appropriately for children or very small adults and might be increased for very large adults. The fludrocortisone dosage might be lowered in cases of essential hypertension or heart failure and may be increased during hot summer months or if your activities caused you to lose increased amounts of salt in sweat.

In addition to body weight, other factors influence the correct dosage for an individual patient. For example, different individuals tend to metabolize, that is, to inactivate, glucocorticoids at different rates. Thus, the same dosage of steroid my be excessive for someone who metabolizes it much more slowly than average and insufficient for someone who metabolizes it much more rapidly than average. Ideally, the endocrinologist would have some sort of a test to determine a "normal" level of steroid in plasma, or a reliable index of a "normal" level of glucocorticoid activity. While plasma cortisol can be measured, the results of such a test indicate only the level of cortisone present at that particular point in time and vary according to when the last dose was taken. 24 hour urinary cortisols measure

Consequently, your endocrinologist must rely upon signs and symptoms of glucocorticoid excess or deficiency to adjust your dosage. If, for example, you gain weight, develop insomnia, or start getting a ruddy complexion, or have any other symptoms that are consistent with early Cushing's syndrome, your endocrinologist will lower the dosage. Early Cushing's symptoms that are not caused by too high of a replacement dosage include excess hair growth, and in the case of prednisone and dexamethasone, high blood pressure. In addition, if you are going to be taking glucocorticoids for a long period of time, your endocrinologist will obtain a bone density test at the beginning of treatment and at intervals of about every year, because excessive glucocorticoid replacement can cause osteoporosis.

If you develop symptoms of deficiency, which include muscle and joint aches and pains, generalized malaise, weakness, lack of energy, mild nausea, headaches, and easy fatigue, your endocrinologist may give you a trial for a week or two of increased glucocorticoid. These symptoms are not specific for glucocorticoid deficiency, but if they disappear, it is likely that they were caused by inadequate replacemnt. If they do not resolve at an increased dosage, they are problbly due to other causes, and your endocrinologist will lower the dosage back to where it was before and look for other possible causes so they can be treated. The aim is always to take the lowest dosage that is necessary to avoid symptoms of glucocorticoid deficiency.

For mineralocorticoids, the problem is much simpler. Your endocrinologist will measure your blood pressure supine and standing. If it's too high, you may be taking too much fludocortisone. If your pressure falls when you stand, you may be taking too little. Your endocrinologist will also look for signs of fluid retention, such as ankle swelling, and measure serum sodium and potassium. If your dose is inadequate, the sodium tends be low, and the potassium high. The opposite is true if the dosage is too low. Plasma renin (an enzyme released from the kidney in response to low blood pressure) activity can also be measured. If the replacement dose is too high, renin levels will be low, and if the dosage is too low, renin levels will be elevated.

Question: What changes should be made to replacement medications during illness.
Answer: For minor febrile illnesses, like the flu or other viral illness, use the "three for three" rule. This can be done without notifying your endocrinologist. Increase your dosage to three times the maintenance dosage for three days, while doing all the other things you should do during such an illness (plenty of fluids, rest, and medications such as ibuprofen or aspirin to make you more comfortable). If your illness continues to worsen during those three days, or if you do not feel well enough to return to the maintenance dosage on the fourth day, call your physician. You would do the same thing if you were not taking glucocorticoid replacement. Your physician can decide if you should be seen in the office or if you can wait for another day or two and continue to take the extra steroid. Your physician may be aware that the current "bug" going around might last six or seven days.

For major illnesses, such as broken bones, automobile injury, or loss of major amounts of blood, or if you are vomiting and cannot take your oral medication, you should inject yourself with 4 mg of dexamethasone anywhere on your body, using a 1-cc preloaded syringe that you have with you at all times. In case you are unconscious or cannot inject yourself, you should always have 1) a MedicAlert bracelet that indicates you have adrenal insufficieny, 2) a Medical Information Card in your wallet or purse that indicates what medications you are taking and what physician to call in an emergency, and 3) a preloaded dexamethasone syringe on your person or in your purse that a paramedic or passerby can inject. You cannot harm yourself by injecting the dexamethasone. If you think you need to inject it, do so, and then get to a physician ass soon as possible.

Finally, for major surgery, notify the surgeon that you have adrenal insufficiency so that supplemental glucocorticoid can be administered on the day of the procedure. Some surgeries, such as having all your wisdom teeth removed at the same time, fall into a grey area as to whether additional glucocorticoids are needed. If in doubt, it is safer to get steroid, than not. You should be back at your usual maintenance dosage with a day or two, and it will have caused no harm.

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Question: Three years ago, I had an adrenal gland removed due to an adrenal adenoma that was causing Cushing's. Now, I am told that I have another tumor on my right adrenal gland. Is this possible, and what is the best way to tell if it is secreting cortisol?
Answer: Removal of a solitary adrenal gland is often followed by a compensatory enlargement of the other (and presumably normal) adrenal gland. This phenomenon occurs in a normal fashion and is poorly understood and not often well appreciated. Occasionally, this enlargement can appear to represent an adrenal tumor. Assuming that you had a cortisol producing adrenal adenoma removed three years ago, it is very unlikely (and to my knowledge unheard of) that you would develop a similar tumor in the right adrenal gland. I have had a patient who developed a cortisol producing adrenal tumor several years after the other adrenal gland had been removed during surgery for kidney cancer. The best way to determine if your "tumor" in the right adrenal is secreting cortisol is to measure plasma ACTH levels and annual assessment of urinary free cortisol. If the plasma ACTH level is below normal or the 24 hour urine free cortisol is above normal, additional treatment may be necessary.

Question: Following surgery for Cushing's, I have had a lot of swelling in my hands, feet and face. Is there anything that can be done to help this problem and is it anything to be concerned about?
Answer: Swelling, or edema, may often accompany Cushing's syndrome. Following surgical treatment of Cushing's, some patients will continue to experience edema for some time following the surgery. This may be related to the frequent need for steroid therapy following curative surgery. This is really nothing serious, but can be uncomfortable. I usually treat patients with a water pill or decrease the dose of steroids.

Question: I had two unsuccessful transsphenoidal surgeries followed by radiation. Since my ACTH levels were still extremely elevated, I had a bilateral adrenalectomy. My physical appearance (weight and fat distribution) has not changed as much as my doctor expected. Would growth hormone therapy be useful in my case?
Answer: The lack of change in your physical appearance may be related to excessive hydrocortisone replacement. Over the past few years, it has become increasingly evident that many patients with adrenal insufficiency (no adrenal function) do not require as much hydrocortisone therapy as previously thought. In the past, many patients were treated with as much as 25-30 mg of hydrocortisone daily in divided doses; however, some patients really need no more than 10-15 mg daily. Patients without adrenal function should also be treated with Florinef. Your hydrocortisone replacement dose should be titrated down to as low a level as you can tolerate.

Growth hormone is now available for treatment of adult patients with hypopituitarism. Growth hormone therapy has been shown to decrease body fat as well as increase lean muscle mass in adult patients with hypopituitarism. Patients treated with growth hormone have also reported increased energy level and a better sense of well being; however, long term studies with growth hormone in adult patients have not been performed and some endocrinologists have questions about its possible side effects when taken for several years. In addition, growth hormone is very expensive and persuading insurance companies or HMO's to pay for this may be difficult.

Question: I have had two transsphenoidal surgeries, followed by removal of my adrenal glands, and now have Nelson's. What would be the treatment of choice, complete removal of my pituitary gland, radiation, or both?
Answer: Nelson's syndrome represents the enlargement of an ACTH secreting pituitary tumor following removal of both adrenal glands. Initially described in 1958, this problem is now relatively unusual since therapy is usually directed at the pituitary gland. However, when pituitary surgery is unsuccessful a bilateral adrenalectomy may be necessary and regrowth of the pituitary tumor may occur. If you have significant enlargement of pituitary tumor visible on MRI and if the tumor is near the optic nerve, another pituitary operation followed by radiation therapy would be a very reasonable approach. On the other hand, if the pituitary tumor is relatively small and not invasive, it may be possible to take a more conservative approach with MRI studies at six month intervals to assess the rate of tumor growth. If the tumor is not growing and plasma ACTH levels remain relatively stable, no further surgical intervention may be necessary. At this point, some authorities would also offer treatment with either conventional radiation therapy or possibly the newer gamma knife radiation therapy. Personally, I am not an enthusiastic supporter of primary radiation in cases such as this without surgical removal of all radiologically evident pituitary tumor.

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Question: What is a petrosal sinus sampling test, how is it done, and when is it used?
Answer: The majority of patients with Cushing's syndrome have an ACTH-secreting tumor (pituitary or nonpituitary) causing both adrenal glands to produce excessive amounts of cortisol. Although the majority of patients have pituitary tumors, approximately 10-15% of patients have nonpituitary tumors that can be located in many places - most commonly, the lung. Obviously, it is essential to accurately distinguish where the ACTH-secreting tumor is located so that appropriate surgery can be recommended. Pituitary imaging studies, particularly Magnetic Resonance Imaging (MRI) may be helpful in locating pituitary tumors; however, 50-60% of patients with ACTH-secreting pituitary tumors have a normal pituitary MRI. Petrosal sinus sampling for ACTH is the diagnostic test of choice to distinguish pituitary from nonpituitary ACTH-secreting tumors in patients without an obvious radiographic lesion. Petrosal sinuses are actually the veins that drain the pituitary gland. The procedure is done on an outpatient basis and should be performed by an experienced invasive radiologist. The radiologist inserts small catheters in each vein that drains the pituitary and ACTH is measured from blood samples from each vein obtained simultaneously and compared to ACTH measurements from a peripheral vein. When performed properly, this study yields 100% diagnostic accuracy and, in many cases, provides accurate localization of the small pituitary tumor within the gland. The procedure is not helpful inlocating nonpituitary tumors. Approximately 10-15% of patients with Cushing's syndrome do not have an ACTH-secreting tumor, but have a cortisol producing adrenal tumor. Petrosal sinus sampling is not necessary for the correct diagnosis of these patients.

Question: What effects does Cushing's have on the eyes?
Answer: Patients with Cushing's syndrome may rarely develop an eye condition called central serous chorioretinopathy. This condition represents the accumulation of fluid behind the retina of the eye and may cause detachment of the retina resulting in impaired vision. Men are apparently affected more commonly than women, but the condition is quite unusual, even in Cushing's patients where the prevalence is probably less than 5%. Since patients with Cushing's syndrome may have diabetes, abnormalities in the retina can occur from elevated blood sugar. Since steroid therapy is associated with increased risk for cataract formation, it seems likely that patients with Cushing's syndrome probably carry an increased risk for cataracts.

Question: Can Cushing's cause arthritis?
Answer: There is no increased risk of arthritis with Cushing's syndrome. In fact, due to the anti-inflammatory effect of cortisone, many patients with arthritis have substantial improvement when they develop spontaneous Cushing's syndrome. Conversely, patients with arthritis may have exacerbation of the problem when the Cushing's syndrome is treated and cortisol levels are decreased into the normal or subnormal range. Another condition, osteonecrosis, is due to bone deterioration resulting from lack of blood supply to the bone. This condition often mimics arthritis in terms of joint pain and can be differentiated on the basis of bone scans or x-rays.

Question: What effects does Cushing's have on the immune system and does the immune system recover after treatment of Cushing's?
Answer: Cushing's syndrome, with its elevated cortisol levels, certainly suppresses the immune system. Patients with Cushing's syndrome are at risk for many unique and unusual infectious diseases. Patients with severe hypercortisolism may develop many of the same infections seen in patients with AIDS, such as tuberculosis, pneumoncystis, and fungal infections. The effect of elevated cortisol on the immune system is completely reversible and immune system function should return to normal after treatment of Cushing's.

Question: What medications are available to lower steroid production, what are the side effects, and when are these drugs used?
Answer: There are several medications available to lower steroid production and these can be used to treat patients temporarily until more definitive surgical intervention is possible. Ketoconazole is the most widely used medication. It is usually well tolerated, but is often accompanied by some mild liver function abnormalities which may necessitate its discontinuation. Metyrapone, often used in combination with Ketoconazole, is another agent and it is usually well tolerated. Aminoglutethimide is a potent drug which blocks the production of all steroids from the adrenal gland. It is associated with somnolence and GI side effects. Mitotane is a drug that damages the adrenal gland decreasing steroid secretion. This drug is often used in patients with adrenal cancer. It is associated with a great deal of nausea and vomiting and therapeutic doses are poorly tolerated in many patients. RU-486 (the controversial abortion pill) can also be used to block the effects of cortisol and decrease the symptoms of Cushing's syndrome. Due to the political volatility of this drug, it may never be available for use in the United States. Although all of these medications may be helpful in selected patients, they should only be used by endocrinologists with experience in managing patients with Cushing's syndrome.

Question: What are the typical medications for a person who has had their entire pituitary gland removed?
Answer: Patients with hypopituitarism (no pituitary function) require hormone replacement with thyroid hormone, adrenal steroids (hydrocortisone), and gonadal steroids (estrogen, progesterone, and testosterone). If the posterior part of the pituitary gland has also been damaged, the patient may have a condition called diabetes insipidus with a deficiency of antidiuretic hormone. Such patients have large volumes of urine which can be corrected with a synthetic form of antidiuretic hormone called DDAVP. Recently, growth hormone therapy has become available for adult patients with hypopituitarism. This therapy is quite expensive and long term clinical studies documenting its safety are in progress.

Question: Following radiation for a pituitary tumor, is there a risk that the entire pituitary will be unable to function normally?
Answer: Many patients maintain normal pituitary function following radiation therapy to the pituitary for a few years; however, within ten years, a significant percentage of patients develop some type of pituitary hormone deficiency and may require hormone replacement. Patients who undergo pituitary radiation should have at least an annual evaluation by an endocrinologist in order to assess pituitary function.

Question: My Cushing's has been cured for about 3 years, but my muscle strength is still not like it used to be. I work out at a gym regularly, but is there anything else that I can do to try and recover my strength?
Answer: Deterioration of muscle function is a common consequence of Cushing's syndrome. The majority of patients recover full muscle strength and performance after cure of their Cushing's syndrome. Physical therapy and a high protein diet have both been shown to improve muscle strength in patients with steroid-induced muscle damage. After cure, most patients recover normal muscle strength within 1-2 years.

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Question: What is a dexamethasone suppression test and why is it used?
Answer: ACTH is the pituitary hormone which regulates cortisol, the glucocorticoid, that is produced by the adrenal glands. Normally, the pituitary gland decreases or suppresses its output of ACTH when cortisol levels are high; the suppresion of ACTH then results in a return of cortisol levels to normal. Dexamethasone is a potent synthetic glucocorticoid which does not interfere with the measurement of cortisol levels in plasma or in urine. Dexamethasone suppression tests are used to determine whether the increased production of cortisol is caused by Cushing's syndrome or is secondary to other causes such as stress. In addition, the tests can also be useful to distinguish between the different causes of Cushing's.

In pituitary ACTH secreting tumors, the ACTH production by the tumor (and by extension cortisol levels also) can be decreased in part by dexamethasone, but only at higher levels than the normal pituitary cells. In Cushing's syndromes secondary to excess production of ACTH by tumors arising in organs other than the pituitary (ectopic ACTH syndrome), the dexamethasone can usually not suppress the ACTH production by the tumors; however this is not always the case as the ACTH produced by some benign carcinoid tumors of the lung or pancreas can be suppressed by dexamethasone. In Cushing's syndrome secondary to excess cortisol production by adrenal tumors, the ACTH levels are already very low and cannot be suppressed further by dexamethasone; thus cortisol levels do not decrease following dexamethasone administration.

Different dexamethasone tests have been used over the years since their original description by Grant Liddle from Vanderbilt University (Nashville TN) in 1960. The classical test reported by Liddle, uses oral administration of dexamethasone following 2 days of baseline 24 hour urine collections. Dexamethasone is administered at the dose of 0.5 mg every six hours for 48 hours, followed by 2 mg of dexamethasone every 6 hours for a second 48 hour period. Normal individuals will suppress their production of cortisol, as measured by plasma cortisol and urinary levels of its metabolites or free urinary cortisol itself, with the low dose of 2 mg/day (0.5 mg every 6 hours) of dexamethasone. Individuals with Cushing's syndrome do not suppress normally during the low level dexamethasone test. The high dose test (2 mg every 6 hours) is used to distinguish between ACTH-dependent pituitary disease (partial cortisol suppression) and either ACTH-independent adrenal tumors or the secretion of ACTH by ectopic tumors located elsewhere in the body (no suppression).

During the 1980's, more rapid dexamethasone tests were designed. In one commonly employed test, dexamethasone is used at the dose of 1 mg taken at 11 PM or 12 midnight followed by the determination of plasma cortisol on the following morning at 8 AM. Again, patients with Cushing's syndrome do not suppress normally during this low dose test. A short test that can discriminate between pituitary Cushing's disease and other causes of Cushing's syndrome utilizes a dexamethasone dose of 8 mg at 11 PM followed by a measurement of plasma cortisol the following morning. Patients with pituitary Cushing's disease suppress their plasma cortisol by 50% or more following the 8 mg of dexamethasone, whereas patients with other causes of Cushing's syndrome do not usually suppress their plasma cortisol.

More recently, other investigators have used an intravenous infusion of dexamethasone over a period of 4 to 7 hours. This modified test has the advantage of requiring only 24 hours to discriminate between normal individuals and those with Cushing's syndrome. This test is also capable of suggesting whether the cause is pituitary, adrenal, or ectopic in origin.

Dexamethasone suppression tests are not 100% percent precise, but do give good indications. In general, the dexamethasone suppression tests will correctly indicate the presence of Cushing's syndrome in 85-90 % of the cases, and effectively determine the cause (pituitary, adrenal, or ectopic) in 75-90 % of the cases.

Question: What is pseudo-Cushing's?
Answer: Pseudo-Cushing's refers to individuals who have biochemical abnormalities or physical manifestations which are similar to Cushing's syndrome; abnormal production rates of cortisol and abnormal feedback inhibition by glucocorticoids like dexamethasone are also present. There are several common causes of pseudo-Cushing's. One that has been clearly described occurs in patients with severe endogenous depression. These patients can have increased cortisol production rates as measured in 24 hr urines and abnormal suppression of cortisol and ACTH with a dexamethasone suppression test. The test results can be very similar to those in pituitary Cushing's disease; however, in most cases, these patients do not have the physical features of Cushing's syndrome.

The second most common situation which can lead to excess cortisol production is excessive alcohol consumption. This can reproduce the same biochemical abnormalities of excess cortisol production and is often accompanied by central obesity with supraclavicular fat pads, and a red, round face. Alcohol-induced elevation of cortisol can be distinguished from other causes by the fact that when alcohol consumption is ceased, the biochemical abnormalities usually return to normal within a few days.

Previously, differentiation between some types of pseudo-Cushing's and Cushing's syndrome could be difficult. Recently, the NIH group has described a new combined dexamethasone/CRH test which discriminates between endogenous Cushing's syndrome and pseudo-Cushing's syndrome with close to a 100 % accuracy. Dexamethasone is given at 0.5 mg every 6 hrs. for 48 hours and two hours after the last dose, CRH is administered at the dose of 1ug/kg of body weight, intravenously; plasma cortisol is measured 15 minutes later. In endogenous Cushing's syndrome cortisol levels are elevated at the 15 minute time point, whereas in pseudo-Cushing's syndrome, the levels of cortisol are below 1.4 mcg/dl at the 15 minute time point.

There are other conditions that tend to increase cortisol production. Some of them are eating disorders like anorexia nervosa, or chronic illness such as AIDS. These patients can fail to suppress with dexamethasone and in most cases do not display the physical manifestations of Cushing's syndrome.

Question: What is cyclic Cushing's?
Answer: Cyclic Cushing's syndrome relates to the fact that the tumors responsible for Cushing's syndrome, whether they are of pituitary, adrenal, or ectopic origin, produce their hormones in an irregular fashion. The secretion of ACTH or of cortisol is not always constant, but can rapidly fluctuate between high levels and low levels. This occurs over various time periods ranging from 24 hours to several days or even weeks. These fluctuations can occur with any cause of Cushing's syndrome and can complicate the interpretation of test results. To avoid errors in diagnosis, it is usually recommended to collect several 24 hr urine samples for measurement of urinary free cortisol. Some patients with clinical manifestations suggestive of Cushing's syndrome may have normal levels if they are measured only once or twice and they have cyclic Cushing's syndrome. Similarly, the suppression of cortisol during a dexamethasone suppression test could be falsely determined as normal if a patient with cyclic Cushing's is tested during a phase where the secretion rates were decreasing spontaneously.

Several cases of cyclic Cushing's have been reported in the medical literature. In these case reports, some of the variations in cortisol levels are quite dramatic, varying from completely normal levels on one day, to very high levels on other days. It has also been observed that if 24 urine samples are collected and measured over many days, many Cushing's patients will show quite a bit of day to day variation in cortisol levels. However, in most cases, the variations are not as dramatic as indicated in the individual case studies reported in the literature.

Question: I've heard that some types of adrenal Cushing's can be caused by food or other hormones. Is that true?
Answer: The mechanism by which adrenal tumors continue to secrete cortisol in the absence of ACTH (the normal regulator that is suppressed due to excess cortisol) have not been well understood until recently. Recent work by our group and other investigators have suggested that the cause of adrenal Cushing's syndrome in certain patients could be due to the abnormal presence and/or function of hormone receptors on the adrenal gland (ectopic receptors).

Receptors are proteins on the surface of and in the membranes of individual cells that hormones bind to, causing a response by the cell. For example, ACTH normally stimulates cortisol production by binding to the ACTH receptor present on the adrenal gland cells. The presence of abnormal receptors in the adrenal gland cortex cells, or tumor, can place the production of cortisol under the control of hormones other than ACTH. These other hormones are present in the body, but normally serve a totally different function and do not stimulate cortisol production in normal individuals.

One of the first demonstrations of this concept came from the observation that some patients with adrenal Cushing's syndrome had increased cortisol production following eating, while cortisol levels remained low during fasting. It was demonstrated that this was secondary to the abnormal presence of receptors for a gastrointestinal hormone, called GIP for gastric inhibitory polypeptide. GIP is normally secreted by intestinal cells every time we eat. GIP normally provides a signal to the pancreas that glucose is entering the circulation and that insulin production should be stimulated to normalize blood glucose levels. GIP receptors are not normally present in large quantity in the adrenal gland and do not normally regulate cortisol production. In certain patients with either a single adrenal tumor or with bilateral macronodular adrenal hyperplasia, the abnormal increased presence of adrenal GIP receptors creates a new mechanism for control of cortisol secretion.

This first demonstration led to an investigation of the potential presence of other abnormal hormone receptors in patients with adrenal Cushing's syndrome. Since then, it has been demonstrated that other patients have abnormal stimulation of cortisol production by other hormones, mediated by their receptors. The list now includes vasopressin, adrenalin, LH (luteinizing hormone which normally regulates ovarian or testicular function), and serotonin.

The identification of the abnormal receptor can lead to novel approaches in the treatment of these conditions. It has now been shown that the use of drugs to block specific receptors or to block the release of the hormones for those receptors, can bring normalization of the production of cortisol in some individuals without performing surgery. It should be kept in mind that this work is still experimental and preliminary results indicate that this phenomenon may be more frequent in cases of bilateral macronodular adrenal hyperplasia and less frequent in cases of a single adrenal tumor.

Question: I had a pituitary tumor removed and am no longer on replacement medication. It seems that even something minor, like a cold, causes havoc with my system, including aches and pains. Is this normal after having had Cushing's?
Answer: Following the removal of an ACTH secreting pituitary tumor (or an adrenal cortisol secreting tumor), it takes on average 1 year before the pituitary-adrenal axis begins producing normal levels of cortisol. This occurs because the long term overproduction of cortisol has put to rest the normal ACTH producing pituitary cells that were not part of the pituitary tumor. Patients absolutely need to take cortisone replacement during this time period. In addition supplemental cortisone replacement (up to 2-3 times the normal amount) needs to be taken in case of a serious stress or illness. The relative lack of cortisol can manifest itself with fatigue, diffuse muscular and joint pains, lack of appetite, abdominal pain, low blood pressure or shock.

Once this axis recovers its basal level production of cortisol (measured by the determination of morning plasma cortisol prior to taking the replacement dose), it is then necessary to determine whether the pituitary and adrenal glands can produce sufficient amounts of cortisol during stress, such as an illness. To verify this, the patient is tested with an intravenous injection of ACTH (a synthetic form called Cortrosyn) to determine whether the adrenal reserve to produce increased cortisol is back to normal. In specific circumstances, it may be indicated to test the pituitary reserve in ACTH by injecting insulin intravenously under carefully controled guidelines, to induce hypoglycemia, commonly called low blood sugar. The body perceives this as a stressful situation and should increase ACTH and cortisol production, as measured by plasma cortisol levels.

It is also possible that patients who have undergone pituitary surgery could have relative deficiencies of otherhormones, such as TSH (which normally regulates thyroid hormone levels), growth hormone, prolactin (regulates milk production), FSH and LH (which regulate ovarian and testicular function) or vasopressin (which regulates urine volume). These hormones can be assessed during pituitary reserve tests where in addition to insulin induced hypoglycemia, stimulation with TRH and LHRH is performed. These hormones should be replaced (with the exception of prolactin) if they are found to be deficient.

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Question: From past issues of this newsletter, it appears that Cushing's doesn't cause arthritis. If it's not arthritis, why in the world do I have all these aches and pains?
Answer: The feeling of fatigue and the aches and pains in the muscles and joints of patients with Cushing's during the postoperative period are common and result from the withdrawal of the body from the high cortisol levels of active disease and the gradual return of the biochemistry of the brain to normal. Also, some of the aches and pains during the postoperative period are probably related to decreased muscle strength. As muscle strength returns to normal, these aches and pains should dissipate. It may take over a year for the patient to fully return to normal.

Cushing's does not cause the most common form of arthritis which is associated with the loss of cartilage from the joints. Rheumatoid arthritis, a different form of arthritis, is an inflammatory disease which gets better with glucocorticoid therapy. It is very unusual for a patient with active Cushing's to also have rheumatoid arthritis, because the immune system of such a patient is suppressed. After correction of the hypercortisolism, however, patients with Cushing's are at increased risk for developing autoimmune inflammatory diseases, such as rheumatoid arthritis and primary thyroiditis, because the activity of their immune system rebounds to a higher than normal level. This effect usually lasts only 2 to 3 months and occurs even though these patients receive normal cortisol replacement. Patients with immune system disorders should discuss their replacement dosage with their endocrinologist.

Question: I have been cured from Cushing's for quite some time and my memory and quick recall for facts is back as good as ever, but I am still slower in doing things, make more mistakes than I used to, and have trouble "multi-tasking". Does anyone know what causes this and will it ever return to normal?
Answer: Thinking processes depend upon optimal brain biochemistry. We have evidence from studying patients with Cushing's after their cure, that several measurable biochemical parameters take time to fully normalize. During the recovery period, there are indications that the speed of the thinking process is impaired.

Question : I am recovered from Cushing's but have developed asthma. Is this related to Cushing's?
Answer: Asthma is an allergic, autoimmune state that like rheumatoid arthritis responds to treatment with glucocorticoids. Frequently, Cushing's patients with a personal or family history of allergy, and this includes asthma, hay fever and allergic dermatitis (eczema), get worse after correction of their hypercortisolism. This occurs because of the immune system rebound. These conditions may be treated with steroids and allergy antigens as determined appropriate by an allergist.

Question: Since my adrenal glands were removed, my testosterone and DHEA levels are low. Is there value in taking replacement doses of either one of these?
Answer: Although it is not part of the standard of care to treat women or men with primary adrenal insufficiency (and bilateral adrenalectomy is such a state) with adrenal androgens, it makes sense to mimic nature and provide such steroids at replacement amounts. Because DHEA is converted by the body to both testosterone and estrogen, taking DHEA would be like taking small amounts of each of these hormones. The first studies on this issue have just started to be published and the appropriate doses of DHEA are currently being defined, as are the potential benefits of such replacement. Adrenal androgens may be more important in women than in men because normally the adrenals produce about half of the daily androgen requirement of a young adult woman. Taken in excess, DHEA can cause undesirable side effects, thus if replacement proves beneficial, this should be managed by your physician.

Question: I am recovering from Cushing's and I feel like I have a cold, but don't seem to be running a fever. Does Cushing's have something to do with this?
Answer: After correction of the hypercortisolism and during the immune system rebound period, the body is in fact protected from viruses, such as those causing common cold. Frequently, the flu-like symptoms of postoperative patients with Cushing's are due to exacerbations of glucocorticoid withdrawal rather than a true viral or other infectious illness. The symptoms for either condition are quite similar and it is hard to distinguish between them.

Question: What kind of patients does the National Institute of Health (NIH) accept for diagnosis and treatment of Cushing's and how does one go about getting into NIH?
Answer: The National Institue of Health in Bethesda, MD is the medical research facility supported by the US government. At the present time, the NIH accepts all children and adolescents with Cushing's as well as adults with Cushing's and Pseudo-Cushing's states (Cushing's appearance with elevated cortisol, but no tumor) that fit into the active NIH protocols. There are also special studies for patients with Carney Complex and patients with periodic or cyclical Cushing's. The best way to know if a patient fits in any of the current protocols is to have a doctor's summary directed to the NIH investigators.

Question: When I had Cushing's I lost a number of my teeth due to what I was told was bone loss. Is that the same as osteoporosis and would any of the osteoporosis drugs help me from loosing more teeth as some are still loose?
Answer: Patients with Cushing's are at increased risk to develop periodontal disease and its sequelae of tooth loss for two reasons: first, cortisol inhibits white blood cells from migrating into the space between the gum and teeth where they can fight against local bacteria; second, cortisol inhibits new bone formation which contributes to the osteoporosis of the jaw bone. Things get better after cure of the hypercortisolism. At this time there is a study in progress for treating periodontal disease with osteoporosis drugs. The outcome of the study is not known as yet.

Question: From reading this newsletter, it seems that a number of us develop Cushing's following a pregnancy. Are Cushing's symptoms more likely to appear after a pregnancy and if so, why?
Answer: It may be pure coincidence; or it is possible that the corticotropin releasing hormone (CRH) secreted from the placenta during the second and third trimester, stimulates the growth of already present small pituitary tumors. These tumors then declare themselves clinically sometime in the postpartum period.

Question: I have been told that I either have Pseudo-Cushing's or a form of Cushing's that has not been detected by standard tests. It has been suggested that I take antidepressants for a while, specifically one of the serotonin reuptake inhibitors. Why should I do this?
Answer: First, antidepressant therapy usually works for both the depression of Cushing's and that of Pseudo-Cushing's states. Secondly, with Cushing's, the antidepressant does not influence cortisol hypersecretion. In cases of Pseudo-Cushing's, which are believed to result from a biochemical over stimulation of the stress axis, antidepressants can normalize hypersecretion. In that sense, a therapeutic trial with an antidepressant can be diagnostic of either condition. Both the serotonin reuptake inhibitors and the tricyclic antidepressants serve to increase serotonin and should work equally well in Cushing's and Pseudo-Cushing's