Cushing’s Syndrome: A Tale of Frequent Misdiagnosis


What is it?

Cushing’s syndrome is a condition you probably have never heard of, but for those who have it, the symptoms can be quite scary.  Worse still, getting it diagnosed can take a while.  Cushing’s syndrome occurs when the tissues of the body are exposed to high levels of cortisol for an extended amount of time. Cortisol is the hormone the body produces to help you in times of stress. It is good to have cortisol at normal levels, but when those levels get too high it causes health problems.  Although cortisol is related to stress, there is no evidence that Cushing’s syndrome is directly or indirectly caused by stress.

Cushing’s syndrome is considered rare, but that may be because it is under-reported. As a result, we don’t have good estimates for how many people have it, which is why the estimates for the actual number of cases vary so much–from 5 to 28 million people.[1] The most common age group that Cushing’s affects are those 20 to 50 years old.  It is thought that obesity, type 2 diabetes, and high blood pressure may increase your risk of developing this syndrome.[2]

What causes Cushing’s Syndrome?

Cushing’s syndrome is caused by high cortisol levels. Cushing’s disease is a specific form of Cushing’s syndrome. People with Cushing’s disease have high levels of cortisol because they have a non-cancerous (benign) tumor in the pituitary gland.  The tumor releases adrenocorticotropin hormone (ACTH), which causes the adrenal glands to produce excessive cortisol.

Cushing’s syndrome that is not Cushing’s disease can be also caused by high cortisol levels that result from tumors in other parts of the body.  One of the causes is “ectopic ACTH syndrome.” This means that the hormone-releasing tumor is growing in an abnormal place, such as the lungs or elsewhere.  The tumors can be benign, but most frequently they are cancerous. Other causes of Cushing’s syndrome are benign tumors on the adrenal gland (adrenal adenomas) and less commonly, cancerous adrenal tumors (adrenocortical carcinomas). Both secrete cortisol, causing cortisol levels to get too high.

In some cases, a person can develop Cushing’s syndrome from taking steroid medications, such as prednisone. These drugs, known as corticosteroids, mimic the cortisol produced by the body. People who have Cushing’s syndrome from steroid medications do not develop a tumor.[3]

What are the signs and symptoms of Cushing’s Syndrome?

The appearance of people with Cushing’s syndrome starts to change as cortisol levels build up. Regardless of what kind of tumor they have or where the tumor is located, people tend to put on weight in the upper body and abdomen, with their arms and legs remaining thin; their face grows rounder (“moon face”); they develop fat around the neck; and purple or pink stretch marks appear on the abdomen, thighs, buttocks or arms. Individuals with the syndrome usually experience one or more of the following symptoms: fatigue, muscle weakness, high glucose levels, anxiety, depression, and high blood pressure. Women are more likely than men to develop Cushing’s syndrome, and when they do they may have excess hair growth, irregular or absent periods, and decreased fertility.[4]

Why is Cushing’s Syndrome so frequently misdiagnosed?

These symptoms seem distinctive, yet it is often difficult for those with Cushing’s syndrome to get an accurate diagnosis.  Why?  While Cushing’s is relatively rare, the signs and symptoms are common to many other diseases. For instance, females with excess hair growth, irregular or absent periods, decreased fertility, and high glucose levels could have polycystic ovarian syndrome, a disease that affects many more women than Cushing’s.   Also, people with metabolism problems (metabolic syndrome), who are at higher than average risk for diabetes and heart disease, also tend to have abdominal fat, high glucose levels and high blood pressure.[5]

Problems in testing for Cushing’s

When Cushing’s syndrome is suspected, a test is given to measure cortisol in the urine. This test measures the amount of free or unbound cortisol filtered by the kidneys and then released over a 24 hour period through the urine. Since the amount of urinary free cortisol (UFC) can vary a lot from one test to another—even in people who don’t have Cushing’s—experts recommend that the test be repeated 3 times. A diagnosis of Cushing’s is given when a person’s UFC level is 4 times the upper limit of normal.  One study found this test to be highly accurate, with a sensitivity of 95% (meaning that 95% of people who have the disease will be correctly diagnosed by this test) and a specificity of 98% (meaning that 98% of  people who do not have the disease will have a test score confirming that).[6] However, a more recent study estimated the sensitivity as only between 45%-71%, but with 100% specificity.[7]  This means that the test is very accurate at telling people who don’t have Cushing’s that they don’t have it, but not so good at identifying the people who really do have Cushing’s.  The authors that have analyzed these studies advise that patients use the UFC test together with other tests to confirm the diagnosis, but not as the initial screening test.[8]  

Other common tests that may be used to diagnose Cushing’s syndrome are: 1) the midnight plasma cortisol and late-night salivary cortisol measurements, and 2) the low-dose dexamethasone suppression test (LDDST).  The first test measures the amount of cortisol levels in the blood and saliva at night.  For most people, their cortisol levels drop at night, but people with Cushing’s syndrome have cortisol levels that remain high all night. In the LDDST, dexamethasone is given to stop the production of ACTH.  Since ACTH produces cortisol, people who don’t have Cushing’s syndrome will get lower cortisol levels in the blood and urine. If after giving dexamethasone, the person’s cortisol levels remain high, then they are diagnosed with Cushing’s.[9]

Even when these tests, alone or in combination, are used to diagnose Cushing’s, they don’t explain the cause. They also don’t distinguish between Cushing’s syndrome, and something called pseudo-Cushing state.

Pseudo-Cushing state

Some people have an abnormal amount of cortisol that is caused by something unrelated to Cushing’s syndrome such as polycystic ovarian syndrome, depression, pregnancy, and obesity. This is called pseudo-Cushing state.  Their high levels of cortisol and resulting Cushing-like symptoms can be reversed by treating whatever disease is causing the abnormal cortisol levels. In their study, Dr. Giacomo Tirabassi and colleagues recommend using the desmopressin (DDAVP) test to differentiate between pseudo-Cushing state and Cushing’s.  The DDAVP test is especially helpful in people who, after being given dexamethasone to stop cortisol production, continue to have moderate levels of urinary free cortisol (UFC) and midnight serum cortisol.[10]

An additional test that is often used to determine if one has pseudo-Cushing state or Cushing’s syndrome is the dexamethasone-corticotropin-releasing hormone (CRH) test. Patients are injected with a hormone that causes cortisol to be produced while also being given another hormone to stop cortisol from being produced. This combination of hormones should make the patient have low cortisol levels, and this is what happens in people with pseudo-Cushing state.  People with Cushing’s syndrome, however, will still have high levels of cortisol after being given this combination of hormones.[11]

How can Cushing’s be treated?

Perhaps because Cushing’s is rare or under-diagnosed, few treatments are available. There are several medications that are typically the first line of treatment.  None of the medications can cure  Cushing’s, so they are usually taken until other treatments are given to cure Cushing’s, and only after that if the other treatment fails.

The most common treatment for Cushing’s disease is transsphenoidal surgery, which requires the surgeon to reach the pituitary gland through the nostril or upper lip and remove the tumor.  Radiation may also be used instead of surgery to shrink the tumor.  In patients whose Cushing’s is caused by ectopic ACTH syndrome, all cancerous cells need to be wiped out through surgery, chemotherapy, radiation or a variety of other methods, depending on the location of the tumor. Surgery is also recommended for adrenal tumors.  If Cushing’s syndrome is being caused by corticosteroid (steroid medications) usage, the treatment is to stop or lower your dosage.[12]

Medications to control Cushing’s (before treatment or if treatment fails)

According to a 2014 study in the Journal of Clinical Endocrinology and Metabolism, almost no new treatment options have been introduced in the last decade. Researchers and doctors have focused most of their efforts on improving existing treatments aimed at curing Cushing’s. Unfortunately, medications used to control Cushing’s prior to treatment and when treatment fails are not very effective.

Many of the medications approved by the FDA for Cushing’s syndrome and Cushing’s disease, such as pasireotide, metyrapone, and mitotane, have not been extensively studied.  The research presented to the FDA by the makers of these three drugs did not even make clear what an optimal dose was.[13] In another 2014 study, published in Clinical Epidemiology, researchers examined these three same drugs, along with ten others, and found that only pasireotide had moderate evidence to support its approval.  The other drugs, many of which are not FDA approved for Cushing’s patients, had little or no available evidence to show that they work.[14] They can be sold, however, because the FDA has approved them for other diseases.  Unfortunately, that means that neither the FDA nor anyone else has proven the drugs are safe or effective for Cushing patients.

Pasireotide, the one medication with moderate evidence supporting its approval, caused hyperglycemia (high blood sugar) in 75% of patients who participated in the main study for the medication’s approval for Cushing’s.  As a result of developing hyperglycemia, almost half (46%) of the participants had to go on blood-sugar lowering medications. The drug was approved by the FDA for Cushing’s anyway because of the lack of other effective treatments.

Other treatments used for Cushing’s have other risks.  Ketoconazole, believed to be the most commonly prescribed medications for Cushing’s syndrome, has a black box warning due to its effect on the liver that can lead to a liver transplant or death.  Other side effects include: headache, nausea, irregular periods, impotence, and decreased libido. Metyrapone can cause acne, hirsutism, and hypertension. Mitotane can cause neurological and gastrointestinal symptoms such as dizziness, nausea, and diarrhea and can cause an abortion in pregnant women.[15]

So, what should you do if you suspect you have Cushing’s Syndrome?

Cushing’s syndrome is a serious disease that needs to be treated, but there are treatment options available for you if you are diagnosed with the disease. If the symptoms in this article sound familiar, it’s time for you to go see your doctor. Make an appointment with your general practitioner, and explain your symptoms to him or her.  You will most likely be referred to an endocrinologist, who will be able to better understand your symptoms and recommend an appropriate course of action.

 

All articles are reviewed and approved by Dr. Diana Zuckerman and other senior staff.

  1. Nieman, Lynette K. Epidemiology and clinical manifestations of Cushing’s syndrome, 2014. UpToDate: Wolters Kluwer Health
  2. Cushing’s syndrome/ disease, 2013. American Association of Neurological Surgeons. http://www.aans.org/Patient%20Information/Conditions%20and%20Treatments/Cushings%20Disease.aspx
  3. Cushing’s syndrome, 2012. National Endocrine and Metabolic Diseases: National Institutes of Health. http://endocrine.niddk.nih.gov/pubs/cushings/cushings.aspx#treatment
  4. Cushing’s syndrome, 2012. National Endocrine and Metabolic Diseases: National Institutes of Health. http://endocrine.niddk.nih.gov/pubs/cushings/cushings.aspx#treatment
  5. Cushing’s syndrome, 2012. National Endocrine and Metabolic Diseases: National Institutes of Health. http://endocrine.niddk.nih.gov/pubs/cushings/cushings.aspx#treatment
  6. Newell-Price, John, Peter Trainer, Michael Besser and Ashley Grossman. The diagnosis and differential diagnosis of Cushing’s syndrome and pseudo-Cushing’s states, 1998. Endocrine Reviews: Endocrine Society
  7. Carroll, TB and JW Findling. The diagnosis of Cushing’s syndrome, 2010. Reviews in Endocrinology and Metabolic Disorders: Springer
  8. Ifedayo, AO and AF Olufemi. Urinary free cortisol in the diagnosis of Cushing’s syndrome: How useful?, 2013. Nigerian Journal of Clinical Practice: Medknow.
  9. Cushing’s syndrome, 2012. National Endocrine and Metabolic Diseases: National Institutes of Health. http://endocrine.niddk.nih.gov/pubs/cushings/cushings.aspx#treatment
  10. Tirabassi, Giacomo, Emanuela Faloia, Roberta Papa, Giorgio Furlani, Marco Boscaro, and Giorgio Arnaldi. Use of the Desmopressin test in the differential diagnosis of pseudo-Cushing state from Cushing’s disease, 2013. The Journal of Clinical Endocrinology & Metabolism: Endocrine Society.
  11. Cushing’s syndrome, 2012. National Endocrine and Metabolic Diseases: National Institutes of Health. http://endocrine.niddk.nih.gov/pubs/cushings/cushings.aspx#treatment
  12. Cushing’s syndrome, 2012. National Endocrine and Metabolic Diseases: National Institutes of Health. http://endocrine.niddk.nih.gov/pubs/cushings/cushings.aspx#treatment
  13. Tirabassi, Giacomo, Emanuela Faloia, Roberta Papa, Giorgio Furlani, Marco Boscaro, and Giorgio Arnaldi. Use of the Desmopressin test in the differential diagnosis of pseudo-Cushing state from Cushing’s disease, 2013. The Journal of Clinical Endocrinology & Metabolism: Endocrine Society.
  14. Galdelha, Monica R. and Leonardo Vieira Neto. Efficacy of medical treatment in Cushing’s disease: a systematic review, 2014. Clinical Endocrinology: John Wiley & Sons.
  15. Adler, Gail. Cushing syndrome treatment & management, 2014. MedScape: WebMD.

Adapted from https://www.center4research.org/cushings-syndrome-frequent-misdiagnosis/

Interview with Deborah March 30, 2016

Deborah has many symptoms but is not yet diagnosed.

interview

Deborah will be our guest in an interview on BlogTalk Radio  Wednesday, March 30 at 6:00 PM eastern.  The Call-In number for questions or comments is (845) 241-9850.

The archived interview will be available after 7:00 PM Eastern through iTunes Podcasts (Cushie Chats) or BlogTalkRadio.  While you’re waiting, there are currently 89 other past interviews to listen to!

~~~~~~

Deborah’s Bio:

Hello all,

I do not know where to begin. For many years I have been struggling with these symptoms. I have proximal weakness, intolerance to stress, blood pressure fluctuations, hyperpigmentation, reactive hypoglycemia, sweating, severe dehydration, very bad confusion, vision, memory problems, physical body changes (hump, bruises), carb intolerance, and inability to exercise.

My endocrinologist did a workup for Cushing’s disease and the midnight saliva test was high. She brushed it off as “stress”. I am seeing a doctor now that says I have POTS and Dysautonomia. My doctor says I have inappropriate adrenaline rushes.

My body is falling apart because I haven’t found a doctor who will take my symptoms and test results serious. I would like to talk to others who are having trouble getting diagnosed and also to those who have gotten diagnosed who have a good doctor.

God Bless and Thank You,
Deborah

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In Production: Quick and Cheap Bedside Test for Cortisol Uses Smartphone

An innovative method of measuring the stress hormone cortisol is being developed by researchers in Utah. Requiring just a simple kit and a smartphone to read results, this new approach should allow quick, affordable, and accurate testing of cortisol levels, enabling rapid diagnosis of adrenal diseases, the investigators say.

“A lab charges about $25 to $50 for a quantitative salivary cortisol test and has a turnaround time of days to a week,” said lead researcher Joel Ehrenkranz, MD, director of diabetes and endocrinology at Intermountain Medical Center, Murray, Utah. “This test, taken in a medical office or at home, will cost less than $5 and take less than 10 minutes,” he noted.

Dr. Ehrenkranz reported the details of the new test kit, developed at his institution, at ICE/ENDO 2014 week. He said he and his fellow researchers are now collating clinical data for a Food and Drug Administration (FDA) submission and hope to gain approval of the test as a class 2 medical device in the United States in 2015.

Chair of the session, Jeremy Tomlinson, MD, of University of Birmingham, United Kingdom, said the new approach employs “great technology and is an interesting innovation, but there are a few concerns. For example, how well will it perform against the state-of-the-art technique for measuring salivary cortisol, which is mass spectrometry — is it as sensitive?”

Also there is a possibility the immunoassay in the new test will cross react with another steroid hormone, prednisolone, that people might be taking for a whole range of inflammatory conditions, so “you would want to make sure it’s measuring what you want it to,” he noted.

And finally, there is the question of exactly how this would be used.

Cortisol levels are needed when conditions are suspected where too much or too little cortisol is produced, but the diagnosis for most of these doesn’t really need to be immediate, Dr. Tomlinson explained to Medscape Medical News. However, he conceded there might be a role for the assay in patients presenting to the emergency room or in developing nations.

No More Presumptive Treatment of Adrenal Insufficiency

At the meeting, Dr. Ehrenkranz said that adrenal diseases are commonly overlooked because current methods of measuring salivary cortisol require instrumentation and technical personnel and so are costly and unable to deliver timely results.

He noted also that a stint in the developing world convinced him that a simpler test was needed, so he and his colleagues set about developing an assay that would be inexpensive and easy to perform — they came up with disposable cortisol immunoassay strips containing a glass fiber element with colloidal gold-labeled murine anticortisol antibodies and a saliva collection pad.

The person being tested inserts a strawlike saliva collector under the tongue, which wicks the saliva to the immunoassay test strip housed in a cassette, which is then inserted into a reader in the device.

“The device…includes a case, a light pipe, and a lens and costs about a dollar to make. There is no battery power, and it’s unbreakable, passive, and reusable,” Dr Ehrenkranz said.

Because of the physical properties of the gold nanoparticles, a smartphone flash can illuminate and camera-image the color generated by the colloidal gold-labeled anticortisol antibodies, he explained.

The color subsequently generated is “read” by an app on the smartphone to give a cortisol reading, based on an algorithm derived from observed vs reference salivary cortisol values. The R value of this curve was 0.996 for salivary cortisol in the range of 0.012-3.0 µg/dL, Dr Ehrenkranz noted.

The new technology can therefore measure cortisol in a range sufficient to diagnose adrenal insufficiency and hypercortisolism and monitor physiologic variations in cortisol concentration, he said.

And the software is “operating-system agnostic,” he added, meaning the device can be used on all platforms, including iOS, Android, Windows, and BlackBerry, and it has a universal form factor that works with all smartphones.

“Measuring salivary cortisol at the point of care in 5 minutes using an inexpensive immunochromatographic assay, reader, and smartphone may obviate the need to presumptively treat patients for adrenal insufficiency and makes cortisol assays available to regions of the world that currently lack access to this diagnostic test,” he concluded.

Test of Use in Emergency Room, in Developing Countries

Dr. Tomlinson explained that diagnosis of Cushing’s syndrome — caused either by tumors of the pituitary gland producing too much ACTH or tumors of the adrenal gland producing too much cortisol — or alternatively, diagnosis of conditions where it’s thought too little cortisol is being secreted, such as Addison’s disease — an autoimmune process whereby the adrenal gland is destroyed — are not conditions “you necessarily have to diagnose in a few minutes by the bedside,” and therefore it is better to use the “gold standard” of diagnosis, mass spectrometry, in these cases.

But the new test “might be of use in determining whether people have enough of their own natural corticosteroid, in terms of deciding whether you need to give supplemental cortisol to people in an emergency situation,” he explained.

This could include patients presenting with suspected or underlying pituitary or adrenal disease or in people who have been on large doses of steroids who have then stopped taking them, so there will be a resulting suppression of their natural steroid production, he noted.

“That’s not an uncommon situation that we see in the emergency room. At the moment, if there’s suspicion, we might take a test but it takes a day or 2 to come back from the laboratory, and in the meantime we will give patients [presumptive] steroids. But you could do this test by the bedside,” he acknowledged.

And in developing countries, use of this test “is feasible, where cost comes into the equation and you might not have access to mass spectrometry; this could be an alternative and would help you to exclude or make these diagnoses,” he concluded.

This study was privately funded. Dr. Ehrenkranz and colleagues report no relevant financial relationships.

Joint Meeting of the International Society of Endocrinology and the Endocrine Society: ICE/ENDO 2014; June 24, 2014. Abstract OR48-2

From http://www.medscape.com/viewarticle/827580

Does a Normal Urine Free Cortisol Result Rule out Cushing’s Syndrome?

Endocrine Society’s 97th Annual Meeting and Expo, March 5–8, 2015 – San Diego
SAT-384:
Does a Normal Urine Free Cortisol Result Rule out Cushing’s Syndrome?
1 and 2

  • 1Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD
  • 2National Institutes of Health, Bethesda, MD
Presentation Number: SAT-384
Date of Presentation: March 7, 2015
Abstract:Background: Urine free cortisol (UFC) has been traditionally used as one of the first steps in the diagnostic evaluation of Cushing’s syndrome (CS) (1). False positive results, especially values less than twice the upper limit of normal (ULN), can be seen in uncontrolled diabetes, obesity, depression, alcoholism, increased fluid intake, overcollection and stress. False negative results have also been reported with incomplete collection, in mild or cyclic CS and in patients with renal insufficiency (2-3). We evaluated the diagnostic accuracy of UFC and 24-hour urine 17-hydroxycorticosteroids (17OHCS) in patients with CS.Methods: Retrospective study of all CS patients evaluated at the National Institutes of Health (NIH) from 2009 to 2014. Screening tests used for CS included UFC, 17OHCS, late night salivary cortisol (LNSC), midnight serum cortisol and low dose (1mg overnight or 2-day 2mg/day) dexamethasone suppression test (DST). Values above reference range for UFC, 17OHCS and LNSC, a midnight serum cortisol ≥ 7.5 mcg/dL, and post-dexamethasone cortisol values ≥ 1.8 mcg/dL were considered abnormal. Hourly 24-hour sampling for cortisol was performed in a few cases with a mild clinical phenotype and equivocal test results. UFC was measured using liquid chromatography/tandem mass spectrometry (LC-MS/MS). 17OHCS was measured using colorimetric methodology with Porter-Silber reaction (reported as mg/g of creatinine). Mean of the first two UFC and 17OHCS values (appropriate collection by urine volume and creatinine) obtained within 30 days of initial NIH presentation were used for the purpose of this study.

Results: Seventy-two patients were diagnosed with CS (aged 18-77 years, 51 females). Of these, 51 had Cushing’s disease (CD), 10 had ectopic CS while 2 had an adrenal source of Cushing’s based on pathology. Biochemical tests including inferior petrosal sinus sampling (IPSS) suggested ectopic CS but no tumor was found (occult) in 6 patients. IPSS was indicative of a pituitary source in 2 patients with failed transsphenoidal surgery while one patient did not complete evaluation for ACTH-dependent CS. UFC results were available in all, 17OHCS in 70, LNSC in 21, midnight serum cortisol in 68 and DST results in 37 patients. UFC was falsely normal in six and only minimally elevated (< 2 x ULN) in 13 patients (normal renal function, no history of cyclicity, all had CD). Of these 19 patients, 24h 17OHCS was abnormal in all, LNSC was abnormal in 12, midnight serum cortisol was abnormal in 18 and DST was abnormal in 12 patients. Hourly 24-hour sampling for cortisol performed in 3 of these patients revealed abnormal nadir (> 7.5 mcg/dL) and mean daily serum cortisol (> 9 mcg/dL) levels.

Conclusion: UFC can be falsely normal or only minimally elevated in mild CS. Multiple collections and use of complimentary screening tests including 24-hour urine 17OHCS and LNSC can help make a diagnosis and prevent delay in treatment.

(1) Newell-Price J, et al. Cushing’s syndrome. Lancet. 2006;367(9522):1605-17.  (2) Alexandraki KI, et al. Is urinary free cortisol of value in the diagnosis of Cushing’s syndrome. Curr Opin Endocrinol Diabetes Obes. 2011;18:259–63.  (3) Kidambi S, et al. Limitations of nocturnal salivary cortisol and urine free cortisol in the diagnosis of mild Cushing’s syndrome. Eur J Endocrinol. 2007;157(6):725-31

Nothing to Disclose: STS, LKN

Sources of Research Support: This research was in part supported by the intramural research program of NICHD/NIH

Read the entire article at http://press.endocrine.org/doi/abs/10.1210/endo-meetings.2015.ahpaa.9.sat-384

Experts recommend tumor removal as first-line treatment for Cushing’s syndrome

The Endocrine Society today issued a Clinical Practice Guideline (CPG) on strategies for treating Cushing’s syndrome, a condition caused by overexposure to the hormone cortisol.

The CPG, entitled “Treatment of Cushing’s Syndrome: An Endocrine Society Clinical Practice Guideline,” was published online and will appear in the August 2015 print issue of the Journal of Clinical Endocrinology and Metabolism (JCEM), a publication of the Endocrine Society.

Cushing’s syndrome occurs when a person has excess cortisol in the blood for an extended period, according to the Hormone Health Network. When it is present in normal amounts, cortisol is involved in the body’s response to stress, maintains blood pressure and cardiovascular function, keeps the immune system in check, and converts fat, carbohydrates and proteins into energy. Chronic overexposure to the hormone can contribute to the development of cardiovascular disease, infections and blood clots in veins.

People who take cortisol-like medications such as prednisone to treat inflammatory conditions, including asthma and rheumatoid arthritis, can develop Cushing’s syndrome. The high cortisol levels return to normal when they stop taking the medication. This is called exogenous Cushing’s syndrome.

In other cases, tumors found on the adrenal or pituitary glands or elsewhere in the body cause the overproduction of cortisol and lead to the development of Cushing’s syndrome. The Clinical Practice Guidelines focus on this form of the condition, known as endogenous Cushing’s syndrome.

“People who have active Cushing’s syndrome face a greater risk of death – anywhere from nearly twice as high to nearly five times higher – than the general population,” said Lynnette K. Nieman, MD, of the National Institutes of Health’s Eunice Kennedy Shriver National Institute of Child Health and Human Development in Bethesda, MD, and chair of the task force that authored the guideline. “To reduce the risk of fatal cardiovascular disease, infections or blood clots, it is critical to identify the cause of the Cushing’s syndrome and restore cortisol levels to the normal range.”

In the CPG, the Endocrine Society recommends that the first-line treatment for endogenous Cushing’s syndrome be the removal of the tumor unless surgery is not possible or unlikely to address the excess cortisol. Surgical removal of the tumor is optimal because it leaves intact the hypothalamic-pituitary-adrenal axis, which is integral to the body’s central stress response.

Other recommendations from the CPG include:

  • Tumors should be removed by experienced surgeons in the following situations:— A tumor has formed on one or both of the two adrenal glands.— A tumor that secretes adrenocorticotropic hormone (ACTH) – the hormone that signals the adrenal glands to produce cortisol – has formed somewhere in the body other than the adrenal or pituitary gland.

    — A tumor has formed on the pituitary gland itself.

  • Patients who continue to have high levels of cortisol in the blood after surgery should undergo additional treatment.
  • People who had an ACTH-producing tumor should be screened regularly for the rest of their lives for high cortisol levels to spot recurrences.
  • If patients’ cortisol levels are too low following surgery, they should receive glucocorticoid replacement medications and be educated about adrenal insufficiency, a condition where the adrenal glands produce too little cortisol. This condition often resolves in 1-2 years.
  • Morning cortisol and/or ACTH stimulation tests, or insulin-induced hypoglycemia, can be used to test for the recovery of the hypothalamic-pituitary-adrenal axis in people who have low cortisol levels after surgery. Once the tests results return to normal, glucocorticoid replacement can be stopped.
  • People who have undergone pituitary surgery should be re-evaluated for other pituitary hormone deficiencies during the post-operative period.
  • Patients who have a pituitary tumor and have undergone surgery to remove both adrenal glands should be regularly evaluated for tumor progression using pituitary MRIs and tests for ACTH levels.
  • Radiation therapy may be used to treat a pituitary tumor, especially if it is growing. While awaiting the effect of radiation, which may take months to years, treatment with medication is advised.
  • To assess the effect of radiation therapy, the patient’s cortisol levels should be measured at 6- to 12-month intervals.
  • Medications may be used to control cortisol levels as a second-line treatment after surgery for a pituitary gland tumor, as a primary treatment for ACTH-secreting tumors that have spread to other parts of the body or suspected ACTH-secreting tumors that cannot be detected on scans. Medications also can be used as adjunctive treatment to reduce cortisol levels in people with adrenal cortical carcinoma, a rare condition where a cancerous growth develops in the adrenal gland.
  • People with Cushing’s syndrome should be treated for conditions associated with the disease, such as cardiovascular disease risk factors, osteoporosis and psychiatric symptoms.
  • Patients should be tested for recurrence throughout their lives except in cases where the person had a benign adrenal tumor removed.
  • Patients should undergo urgent treatment within 24 to 72 hours of detecting excess cortisol if life-threatening complications such as serious infection, pulmonary thromboembolism, cardiovascular complications and acute psychosis are present.

More information: The Hormone Health Network offers resources on Cushing’s syndrome at www.hormone.org/questions-and-answers/2012/cushing-syndrome

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