Theodore C. Friedman, M. D. , Ph. D Theodore C. Friedman, M.D., Ph.D. Professor of Medicine-UCLA Chairman, Department of Internal Medicine Charles R. Drew University Dr. Friedman’s Endocrinology Clinic Nuances of Cushing’s Syndrome MAGIC Adult Convention Las Vegas, NV April 21, 2013

Do Magic Convention Cushing’s Patients Know More Than Many Endocrinologists? I think so! I will show the conventional statement. You will give an answer. No cheating by looking at the handouts.

Is Cushing’s Syndrome Rare? Probably not Catargi et al. JCEM 2003, 88:5808-200 consecutive overweight patients with type 2 diabetes, but no other stigmata of hypercortisolism. 4 (2%) patients were found to have Cushing’s syndrome and another 7 are being evaluated. Reimondo et al. Clin. Endo 2007,67:225-229 found that 5% of diabetic patients failed to suppress to dexamethasone. Kadioglu et al. Endo Society 2004 86: P2-455- 100 consecutive obese patients. Cushing’s syndrome was diagnosed in 11%. Nishikawa et al. Endo Society 2004 86: P3-437- 1020 patients with hypertension. 11 had Cushing’s syndrome and 10 had subclinical Cushing’s syndrome (2%). These studies may have missed mild Cushing’s syndrome and may actually be low. Maybe Cushing’s syndrome is not so rare

Do patients with Cushing’s need to have all the signs and symptoms listed in textbooks? No Textbooks show severe cases. Most patients have some but not all signs and symptoms of Cushing's Patients are being diagnosed earlier and patients with mild Cushing’s may only have some of the signs and symptoms

Common symptoms I see Wired at night Trouble sleeping-trouble falling asleep or frequent awakenings Severe fatigue-new onset Abrupt weight gain-without other cause such as decreased activity or depression Decreased ability to exercise Menstrual abnormalities Cognitive changes- “brain fog” Decreased libido Symptoms of adrenal insufficiency-joint pains, can’t get out of bed, nausea and vomiting Depression, anxiety, mood-swings

All patients with Cushing’s are obese Patients who really watch caloric intake and exercise (often hard), do not gain much weight If you start thin, you probably will not become obese

All children with Cushing’s are short If a child gets Cushing’s before 10, most likely their growth rate will decrease. But if they start tall, they will end up tall Obesity leads to increased estradiol which accelerates growth rate Boys slow down growth rate around 14 and girls around 12. An older child with Cushing’s is unlikely to be short

Periodic Cushing’s is very rare and may not exist Friedman, T.C., Ghods, D.E., Zachery, L., Shayesteh, N., Seasholtz, S., Zuckerbraun, E., Shahinian, H.K., Lee, M.L., McCutcheon, I.E. (2010) High Prevalence of Normal Tests Assessing Hypercortisolism in Subjects with Mild and Episodic Cushing’s Syndrome Suggests that the Paradigm for Diagnosis and Exclusion of Cushing’s Syndrome Requires Multiple Testing. Hormone and Metabolic Research. 42: 874-881. We found that 65 of the 66 patients with Cushing’s syndrome had at least one normal test of cortisol status and most patients had several normal tests. The probability of having Cushing’s syndrome when one test was negative was 92% for 2300 h salivary cortisol, 88% for 24-h UFC, 86% for 24-h 17OHS and 54% for night-time plasma cortisol.

Periodic Cushing’s is very rare and may not exist These results demonstrated that episodic hypercortisolism is highly prevalent in subjects with mild Cushing’s syndrome and no single test was effective in conclusively diagnosing or excluding the condition. Rather, the paradigm for the diagnosis should be a careful history and physical examination and in those patients in whom mild Cushing’s syndrome/disease is strongly suspected, multiple tests assessing hypercortisolism should be performed on subsequent occasions, especially when the patient is experiencing signs and symptoms of short-term hypercortisolism.

One normal test excludes the diagnosis of Cushing’s syndrome Our paper on episodic Cushing’s syndrome showed that most patients with confirmed Cushing’s syndrome are episodic with one or more normal values. Thus one normal value does not exclude Cushing’s. A series of normal values does make Cushing’s unlikely at the current time I usually like to see at least two separate high values for testing

You would have died from Cushing’s syndrome if you had it for this long Cushing’s Disease Is Not Necessarily a Progressive and Fatal Disease A Case of Documented Cushing’s Disease Untreated for 26 Years (Patel, et al. 2005, Endocrinologist 15:343-344. 1983 1996 2000 1977-Hospitalized for severe hypertension 1977-Overnight dex-8 AM cortisol=33 µg/dL 2003-Elevated 17-OHS X3 2003-4 mm pituitary tumor

Only severe Cushing’s patients should undergo testing and treatment Patients with “mild” Cushing’s syndrome have a low quality of life. Quality of life does not correlate well with cortisol measurements All patients with Cushing’s deserve to be diagnosed and cured

Imaging should only be performed after the diagnosis of Cushing’s is made Most of the patients I see have pituitary Cushing’s disease. 3T MRIs are high quality; most pituitary tumors are seen on MRI. Patients can have incidentalomas, so a tumor doesn’t make the diagnosis of Cushing’s, but does give an important piece of information. A negative MRI in a patient that has a normal or mildly elevated ACTH pretty much excludes Cushing’s (low ACTH=adrenal Cushing’s, high ACTH=ectopic)

Pituitary MRI In literature approximately 50% of patients with Cushing disease have a visible tumor on MRI (older, non-dynamic, lower power MRIs). 10% of normal volunteers have MRIs consistent with a pituitary adenoma (Hall et al. Ann. Intern. Med., 1994, 120:817-820). Now 3 Tesla dynamic MRIs can pick up small tumors are done. Patients without Cushing's syndrome or with adrenal/ectopic Cushing's can have a pituitary incidentaloma. Friedman, T.C., Zuckerbraun, E., Lee, M.L., Kabil, M.S., Shahinian, H.K. (2007) Dynamic Pituitary MRI Has High Sensitivity and Specificity for the Diagnosis of Mild Cushing's Syndrome and Should be Part of the Initial Workup. Hormone and Metabolic Research 39:451-456.

23 of 24 patients had had a MRI consistent with a pituitary lesion Pituitary MRI 12 10 8 Tumor size (mm) 6 4 2 Pt #

50% of patients with Cushing’s disease have normal MRIs I found that 90% of patients with Cushing’s disease had a visible tumor on MRI and 95% have an abnormal MRI Friedman, T.C., Zuckerbraun, E., Lee, M.L., Kabil, M.S., Shahinian, H.K. (2007) Dynamic Pituitary MRI Has High Sensitivity and Specificity for the Diagnosis of Mild Cushing's Syndrome and Should be Part of the Initial Workup. Hormone and Metabolic Research 39:451-456.

Make the diagnosis of Cushing’s syndrome before figuring out which type. ACTH is helpful to get early Imaging is helpful to get early A negative MRI in a patient that has a normal or mildly elevated ACTH pretty much excludes Cushing’s

70% of patients with Cushing’s have Cushing’s disease, 20% adrenal and 10% ectopic My experience is that 95% are pituitary 5% adrenals < 1% ectopic I probably have a selection bias. Pituitary patients are the hardest to distinguish between normals; ectopics and adrenal patients often have higher cortisol and may be easier to diagnose and stay local

You need a UFC greater than 3 times normal to have Cushing’s syndrome Only 4/66 patients in our study with confirmed Cushing’s had a UFC > 3X normal Most of my patients had UFCs between 1X and 2X

17-hydroxysteroids are an old test and should not be performed Mengden et al. (Clin Inv, 1992) showed that UFC was better able to distinguish Cushing’s syndrome from normal individuals than could 17OHS. The subjects in that study, however, had sustained and substantial hypercortisolism. We suspect that in high cortisol production states, the UFC assay would be a better assay to distinguish patients with Cushing’s syndrome from those without Cushing’s syndrome.

17-hydroxysteroids are an old test and should not be performed (2) However, at lower cortisol production rates, the 17OHS assay may be able to detect mild hypercortisolism in some patients with normal 24-h UFC levels. UFC measurements will increase only mildly until a point of saturation of cortisol binding to CBG is exceeded 17OHS measurements which are not dependent on cortisol exceeding the threshold of binding to CBG are more likely to be linear with cortisol production.

17-hydroxysteroids are an old test and should not be performed (3)

Blood draws raise your cortisol and should not be used to assess cortisol Meeran et al. (Br J Clin Pract 1993; 47: 246-247 ) found that serum cortisol did not rise until 4 min after a venipuncture in volunteers subjects awaken from sleep who had blood drawn by venipuncture. Serum cortisol is not affected by venipuncture, unless multiple unsuccessful attempt have been done.

A pic-line is the best way to measure cortisol Cortisol is not raised by venipuncture In my mouse studies, cortisol was raised by having a line placed. Most important is the midnight cortisol, other times are not that helpful. Avoid pic-lines Have to correct for time zone differences

Morning cortisols are helpful for making the diagnosis of Cushing’s Friedman, T.C. and Yanovski, J.A. (1995) Morning Plasma Free Cortisol: Inability to Distinguish Patients with Mild Cushing Syndrome from Patients with Pseudo-Cushing States. J. Endocrinol. Invest. 18:696-701. Cushing’s syndrome is a disease of high cortisol at night. Morning samples are not helpful for diagnosing Cushing’s

4 PM cortisols are helpful for making the diagnosis of Cushing’s 4 PM cortisols are probably a little higher in Cushing’s patients compared to patients suspected of Cushing’s, but too much overlap No literature on cut-offs Only use night-time cortisols

You need to do a 24 hr (and not shorter durations) urine for UFC to assess cortisol status 24 hr UFC are one of the main tests for the diagnosis of Cushing’s syndrome. Many patients with Cushing’s have high cortisol during the night and low cortisol during the day, so the 24 hr UFC is cancelled out I have patients collect a 10 hr sample from 10 PM (discard first void) to 8 AM A value > 16 ug/mg Cr is consistent with Cushing’s syndrome I have not published this yet, but it works well.

Testing for Cushing’s can be done at any time-whether having symptoms or not Most patients with Cushing's are episodic. Need to do testing when in a high. Record symptoms in a diary, so they can go back to see their symptoms when they get a high.

Testing for Cushing’s can be done at any time-whether having symptoms or not Wired at night Weight gain Acne Anxiety increase/mood swings/irritability Euphoria/more energy than usual Very few aches and pains Insomnia/inability to stay or fall asleep. Energy levels that “perk up” after sunset. “Speed talking” – mind is going faster than your brain can process the thoughts to speak them. Water weight gain – edema High blood pressure High blood sugar if diabetic

Patients who suppress to overnight dexamethasone do not have Cushing’s syndrome Friedman, T.C. (2006) Experimental and Clinical Endocrinology and Diabetes 216: 356-360. 14/17 patients with proven Cushing’s suppressed to dexamethasone with a cortisol < 5 Conclusion: test not helpful for excluding Cushing's syndrome. If someone has a high value after dexamethasone, may help with the diagnosis of Cushing's syndrome, but those patients usually are severe and can be diagnosed anyway If patient suppresses to overnight dexamethasone, adrenal adenoma or ectopic is unlikely.

Overnight dexamethasone test 0800 h cortisol (g/dL) Patient #

Dex-CRH test is the gold standard test for diagnosing mild Cushing’s syndrome Dex-CRH test was only tested in those with severe, sustained Cushing's. Many of my patients with confirmed Cushing's had a low cortisol in the dex-CRH test. CRH is currently not available

Petrosal Sinus Sampling can be used to make the diagnosis of Cushing’s disease Petrosal sinus sampling (IPSS) samples blood draining the pituitary. NIH study in the 90s showed that normal volunteers, patients with pseudoCushing's and patients with Cushing's had similar petrosal sinus sampling results. They had a central to peripheral gradient of ACTH, lateralization, and response to CRH. Thus, petrosal sinus sampling can not be used to distinguish between normals and those with Cushing's. It can be used to distinguish between pituitary and ectopic Cushing's or pituitary and adrenal Cushing's, but those can usually be done by other methods. It can help with lateralization (which side the tumor is on), but MRI can usually give that information.

All patients with Cushing’s disease should undergo petrosal sinus sampling prior to surgery No, it usually doesn’t add much information It is invasive and expensive It can not be used to diagnose Cushing's. I use it in those with confirmed Cushing’s and an ACTH in the range of pituitary Cushing's, but negative MRI. It usually needs to be done in a high. Since episodic patients can not predict when in a high, I get a UFC or salivary the day/night before to see if in a high and try to interpret based on that.

Patients with high cortisol need extensive testing to determine the type of Cushing’s In my practice, most patients are pituitary (>95%). Morning ACTH <10, likely adrenal Cushing’s. Morning ACTH >100, likely ectopic Cushing’s. Morning ACTH 20-100, likely pituitary Cushing’s. Positive pituitary MRI makes pituitary Cushing’s likely, but can have incidentalomas Suppression to overnight or low dose dexamethasone makes ectopic or adrenal Cushing's unlikely I use ACTH and pituitary MRI to make my decision, use petrosal sinus sampling if unclear.

Any surgeon can operate on a patients with Cushing’s syndrome Its crucial to go to an experience surgeon. Someone who has done at least 200 pituitary cases and 50 Cushing’s cases. Surgically, Cushing's tumors are the hardest to remove. Often multi-lobulated, with out much of a capsule. I have a network of experienced surgeons who I work with and who trust my workup.

All patients cured from Cushing’s syndrome should have a morning cortisol less than 4 The traditional approach has been patients with Cushing’s disease have sustained high cortisol which suppresses the normal corticotrophs. When the tumor is removed, the normal corticotrophs are quiescent and ACTH and hence cortisol is low. Most of my patients are episodic, during normal cortisol production, corticotrophs continue to secrete ACTH (no quiescence) Most of my cured patients have a morning cortisol between 10-15. I am concerned when the morning cortisol is >20 or morning ACTH > 30.

All patients cured from Cushing’s syndrome will have an ACTH-staining tumor found on pathology Classic approach is that ACTH-staining tumors are needed to prove Cushing’s disease. My experience is most of the time, cured patients have equivalent or negative pathology. May be the tumor staining for ACTH was removed in the “sucker” or missed in pathology. Or that in patients who are episodic, if the tumor is not in an active stage, staining will be negative. I am trying to set up a study looking at staining for ACTH precursors, which may be still positive in episodic Cushing's.

If the post-op cortisol is greater than 10, cortisol replacement should be stopped I find that if cortisol replacement is not given, patients develop adrenal insufficiency, even with a post-op cortisol in the 10-15 range. Patients may experience lower cortisol later in the day that gets missed by a morning sample Its always prudent to replace, then taper if no signs of adrenal insufficiency

Cured Cushing’s patients need cortisol replacement for at least 1 year The lower the post-op cortisol, the longer patients need to stay on Cortef, before tapering. Patients with a post-op cortisol between 10 and 15 can usually taper off in about 3 months. I use a morning cortisol and symptoms of adrenal insufficiency as a guide. A few of my patients (especially after a second surgery), continue to have undetectable cortisol levels and need lifelong Cortef.

Cured Cushing’s patients should get a cosyntropin test before stopping cortisol replacement Cosyntropin test works because low ACTH leads to adrenal atrophy, which then leads to a blunted cosyntropin response. Cosyntropin response lags behind a morning cortisol (patients can often taper off Cortef with a blunted cosyntropin test). It doesn’t change management; is a person who tapered off Cortef, has no symptoms of adrenal insufficiency and has a normal morning cortisol going to resume Cortef because of a blunted cosyntropin test.

Brand Cortef and generic hydrocortisone are equivalent Like most generics, they have the same active ingredients as the brand, but different fillers and binders. Small differences in absorption of hydrocortisone may make a big difference. I recommend brand Cortef for most patients.

Patients who failed pituitary surgery should get radiation Pituitary radiation may take up to 5 years before leading to normal cortisol levels-my patients don’t want to wait that long. Pituitary radiation may lead to memory loss. Pituitary radiation almost always leads to hypopituitarism, especially growth hormone deficiency. A second pituitary surgery or bilateral adrenalectomy are usually preferred. Nelson’s syndrome following bilateral adrenalectomy is rare in my patients with small, slow growing tumors and can be treated with surgery if needed.

Pasireotide (Signifor) is the best drug for Cushing’s disease Pasireotide is a recently approved drug for Cushing’s disease. Almost all patients on it get diabetes. Its effect on lowering cortisol is mild and variable. Its expensive Ketoconazole is a better choice.

Ketoconazole is a dangerous drug and should only be used in those with severe Cushing’s Ketoconazole is safe, with the main side effect being increased liver tests, which usually occur at doses > 1000 mg/day and are reversible. It does interact with a lot of drugs, but these interactions can usually be dealt with by changing the other drug or watching for side effects It has a short-half life so it can be given at night, when cortisol is inappropriate high in Cushing’s patients. I usually give 200 mg at 8 and 10 PM and have patients take 5-10 mg of Cortef in the AM, if needed.

Ketoconazole should only be used in those with confirmed Cushing’s Ketoconazole can be used diagnostically to determine which symptoms a patient has are due to high cortisol. I use it in patients who Im pretty sure, but not completely sure has Cushing's and I want them to get symptomatic relief. I’m concerned if someone doesn’t get better on ketoconazole, if they really have Cushing's. I have kept patients on ketoconazole for up to 3 years without problems. I often stop it for a round of testing, or if a patient develops a tumor on MRI.

Ketoconazole can be given once a day in the morning Cushing's syndrome is a disease of high cortisol at night. Ketoconazole has a half-life of 6 hours. I give ketoconazole at night in almost all patients.

All patients who fail their first pituitary surgery should have a second pituitary surgery, especially right away. Some patients have a delayed lowering of cortisol and maybe cured even if its not that apparent. I usually reserve a second surgery for those patients with a visible tumor on MRI. This is often not apparent until months after surgery.

Bilateral adrenalectomy is a dangerous procedure and should be reserved for those who still have high cortisol after radiation. Old data suggested that 10% of patients with bilateral adrenalectomy died. Done laproscopically, bilateral adrenalectomy is quite safe, with minimal complications. It results in an immediate and definitive cure in almost all patients. Patients with one or more failed pituitary surgeries are good candidates for bilateral adrenalectomy. I do like more tests confirming hypercortisolism than I do for bilateral adrenalectomy.

Bilateral adrenalectomy just replaces one disease (Cushing's) with another (adrenal insufficiency). Cushing’s disease gives the worse quality of life of any Endocrine diseases Cortisol and fludrocortisone replacement is not difficult with easy monitoring. Almost all my patients who had an adrenalectomy are glad they did.

Patients with bilateral adrenalectomy just need cortisol replacement Fludrocortisone (florinef) is crucial. Some patients benefit from DHEA

The best way to monitor fludrocortisone replacement is by measuring electrolytes Electrolytes change late. A renin level is the best way to monitor fludrocortisone replacement. A high renin means more fludrocortisone is needed and a low renin means less fludrocortisone is needed. Can be done sitting or standing.

Bilateral adrenalectomy leads to a permanent cure in all Cushing’s patients Remnant tissue (regrowth of adrenal tissue) in the adrenal bed may occur. I have 3 out of about 40 patients who developed it. In the great majority, bilateral adrenalectomy does lead to a permanent cure.

Patients with Cushing's should listen to their doctor’s advice and not go on the internet. The internet is a great source of information for patients. Support groups-Cushing’s Help and CSRF are excellent. Doctors who state that patients shouldn’t use the internet are behind the times.

For more information/to schedule an appointment www.goodhormonehealth.com mail@goodhormonehealth.com

Who runs the best pituitary patient conference? The Magic Foundation