Cushing's Disease / Syndrome - A Knol by Robin S

2/26/12 Cushing's Disease/Syndrome ‑ a knol by Robin S

1/22knol.google.com/k/cushing‑s‑disease‑syndrome#

Cushing's Disease/Syndromeand related endocrine disorders

Cushing's Disease/Syndrome is caused by an overproduction of the hormonecortisol. There are several reasons why that happens. Other endocrine disordersmay be caused by or related to the cause for Cushing's.

Contents

What is Cushing's Disease/Syndrome?What is cyclic/episodic/intermittent Cushing's?How does diurnal variation/circadian rhythm vary in Cushing's?Testing 101: IntroductionTesting 101: ImagingTesting 101: Biochemical AnalysisTesting 101: IPSS (aka BIPSS)Testing 101: Growth Hormone DeficiencyWhat types of tumors are associated with Cushing's?

more

What is Cushing's Disease/Syndrome?

There are two terms used with Cushing's: Disease and Syndrome. They signify thesource of the illness, although the presentation is pretty much the same with both.Cushing's Disease is hypercortisolism due to a pituitary source of stimulation. Cushing'sSyndrome is hypercortisolism due to an ectopic or adrenal source. There really is a thirdtype of Cushing's called iatrogenic Cushing's which results from the overuse ofcorticosteriod medications. And actually another type called pseudo-Cushing's.

Cushing's Disease/Syndrome (CD/CS) is an endocrine disorder caused by chronicexposure of the body's tissues to excess levels of cortisol - a hormone naturally producedby the adrenal gland. Pituitary adenomas, usually benign, secrete increased amounts ofACTH (adrenocorticotropic hormone), a substance that controls the release of cortisol inthat feedback loop I mentioned the other day. It typically causes an overproduction of

cortisol. Tumors of the adrenal gland and ectopic ACTH producing tumors can cause similar problems withcortisol overproduction.

What are the symptoms? The most common symptoms are:

StriaeBuffalo humpHigh blood pressure (often hard to control even with medication)



High blood sugars and/or insulin resistanceInsomniaFatigueAltered diurnal rhythm (See following post)Secondary hypothyroidismLow hormones such as FH, LSH, testosterone, growth hormoneLow Vitamin DLow ferritinUnexplained muscle, bone, and joint painEasy bruisingDifficulty when drawing bloodUpper body obesityMuscle weaknessIncreased facial hair/body hair (hirsutism)Loss of hair on headLoss of menstrual cycle and/or ovulationLoss of libidogalactorrhea

Not everyone has all the symptoms. And the weight gain can vary by individual. Some folks don't gain alot. Others do.

Without prompt treatment for Cushing's syndrome, other complications may occur, such as:

Bone loss (osteoporosis), due to the damaging effects of excess cortisolHigh blood pressure (hypertension)Kidney stones



DiabetesUnusual infectionsHypothyroidism

When the cause of Cushing's syndrome is a pituitary tumor (Cushing's disease), it can sometimes lead toother problems, such as interfering with the production of other hormones that the pituitary controls. It canalso affect the optic nerves and carotid arteries if large. The majority of pituitary tumors that cause Cushing'sdisease are small (less than one cm in size).

Long-Term Remission Rates After Pituitary Surgery for Cushing's Disease: the Need for Long-TermSurveillance says:

Morbidity and mortality are higher in patients with Cushing's disease, with vascular disease a frequentcause of death.[2,32,33] Cardiovascular complications, including coronary heart disease, congestive heartdisease and cerebrovascular events, contribute to the morbidity and mortality of patients with undiagnosedor untreated Cushing's disease.[34,35] Early diagnosis and successful treatment of Cushing's disease istherefore most important.

What is cyclic/episodic/intermittent Cushing's?

Episodic/intermittent/cylic Cushing's has more aliases than a CIA operative. And I'm sure there are someI've left out. Episodic Cushing’s syndrome (CS) is a rare disorder, characterized by repeated episodes ofcortisol excess interspersed by periods of normal cortisol secretion. The so-called cycles of hypercortisolismcan occur regularly or irregularly with the phases ranging from days to years.

In comparison, "florid" or "classical" Cushing's shows evidence of continual or almost continualhypercortisolism. There is a school of thought which says these are really very rapidly cycling forms ofCushing's. However, there does not seem to be a consensus on that in the literature and in the research.Frankly, I don't know if anyone has done enough testing daily to figure it out.

According to some research done in the Netherlands, "As with classic hypercortisolism, cyclic CS is foundmore commonly among women than men, with a female to male ratio of 3:1 (Table 2). The disorder usuallybecomes manifest in the fifth decade, but may present from early infancy until older age (highest reportedage at presentation being 72 years)."

Other clinical studies say, "The features of endogenous hypercortisolism (especially, when mild) are proteanand coincide with many common clinical conditions like the dysmetabolic syndrome (1, 2). Screeningstudies in high-risk populations have discovered unsuspected CS in as many as 2–5% of patients withdiabetes mellitus (3–7) and suggest that mild CS is more common than previously appreciated."

In Cyclical Cushing's syndrome: an update the full text article says, "Cyclical Cushing's syndrome is apattern of hypercortisolism in which the biochemistry of cortisol production fluctuates rhythmically. Thissyndrome is often associated with fluctuating symptoms and signs. This type of case was initially thought tobe rare. It has, however, recently been recognized as occurring much more frequently. The phenomenon isimportant because it can, if not recognized, lead to errors in diagnosis and differential diagnosis of thesyndrome and in assessment of therapeutic outcomes. All of these can have very serious clinicalconsequences."



How does diurnal variation/circadian rhythm vary inCushing's?We hear a lot about cortisol and how lowering it by lowering stress can affect our weight. I'm sureyou've seen the ads for the cortisolslimming drugs/herbs, too. And we are talking about thesame hormone. What is cortisol, anyway?

Cortisol is a corticosteroid hormone produced by the adrenal cortex, the outer layer of theadrenal glands which are essentially lying on top of the kidneys. Without it we die. It is thehormone that responds to "stress", both good and bad. It affects levels of multiple otherhormones and electrolytes, which is another topic for another day. However, the short of it is, it isvery important in the homeostasis of the body.

When the body is functioning normally, cortisol is regulated by the pituitary in a negativefeedback loop with ACTH (adrenocorticotropic hormone). Basically, the pituitary producesACTH when the body's cortisol level is low, which stimulates the adrenals to produce cortisol.ACTH is pulsatile, which means it is produced in spurts instead of evenly or consistently.

In a "normal" person, cortisol is the highest around 8 a.m. and decreases to about half that valuearound 4 p.m. By midnight (give or take an hour each way), cortisol should be about zero orclose to it with blood and salivary levels. This is a normal diurnal variation. It is also called thecircadian rhythm.

When one has Cushing's, this circadian rhythm is lost, and the normal diurnal variation changes.Cushing's patients have "flat" diurnal levels of cortisol, or even higher levels at night instead of inthe morning.

Endotext.com explains it really well. Their diagram shows thedifference between normal serum cortisol levels and the levels forthose who have Cushing's. (Click on the link to see the picturebetter.)

Where does that take us? Well, to testing. Because of this changefrom normal to warped diurnal rhythm (or lack of), testing cortisollevels can be very useful when diagnosing Cushing'sSyndrome/Disease.

The article, "Cushing's Syndrome" by John NewellPrice, Xavier Bertagna, Ashley B Grossman,Lynnette K Nieman, Lancet 2006; 367: 1605–17,Division of Clinical Sciences, University ofSheffi eld, Northern General Hospital, Sheffi eld, UK (J NewellPrice FRCP); says:

Midnight plasma cortisol or latenight salivary cortisol: Normal circadian rhythm of cortisolsecretion is lost in patients with Cushing’s syndrome. A single sleeping midnight plasma cortisolconcentration of less than 50 nmol/L effectively excludes Cushing’s syndrome at the time of thetest and this might be especially helpful in patients in whom there has been incompletesuppression on dexamethasone testing. Concentrations of more than 50 nmol/L are noted inindividuals with Cushing’s syndrome, even those who suppress serum cortisol on lowdosedexamethasone testing,96 but this cutoff lacks specificity because patients with acute illnessalso have values above this concentration. An awake midnight concentration of cortisol in



plasma of more than 207 nmol/L differentiates between Cushing’s syndrome and other causes ofhypercortisolaemia but can miss mild disease diagnosis in about 7% of cases. (The conversionfactor of ug/dL x 27.6 = nmol/L)

Testing 101: Introduction

Since determining endocrine disorders involves a lot of testing, I thought I would spend sometime talking about some of those tests. With Cushing's Disease, an adenoma can causehypopituitarism and panyhypopituitarism as well as excess secretion of a hormone or hormonesfrom the adenoma itself. In order to understand what tests are done and why you will first need toknow more about the pituitary and disorders associated with it.

Hypopituitarism is a disorder where the pituitary does not secrete enough or any of one or morehormones. The literature varies on this, however. Some define it as "two or more hormones".However, the bottom line is the patient is deficient and this will affect one or more of the bodiesfunctions. Panhypopituitarism, on the other hand, is the deficiency and/or total loss of allhormone production in the pituitary.

The pituitary gland is a beanshaped (think limabean) organ that is at the base of the brain. Thegland is attached to the hypothalumus (a part ofthe brain that affects the pituitary gland) by nervefibers. The pituitary gland itself consists of threesections: the anterior lobe, the intermediate lobe,the posterior lobe. The intermediate lobe isrudimentary in human beings but producesseveral hormones whose physiologicsignificance is only now being established.

Each lobe produces certain hormones.

Anterior lobe:

growth hormoneprolactin - to stimulate milk production after giving birthACTH (adrenocorticotropic hormone) - to stimulate the adrenal glandsTSH (thyroid-stimulating hormone) - to stimulate the thyroid glandFSH (follicle-stimulating hormone) - to stimulate the ovaries and testesLH (luteinizing hormone) - to stimulate the ovaries or testes

Intermediate lobe:

MSH(melanocyte-stimulating hormone)- to control skin pigmentation

Posterior lobe:



ADH (antidiuretic hormone) - to increase absorption of water into the bloodby the kidneysoxytocin - to contract the uterus during childbirth and stimulate milk production. It is also believed tobe important for orgasm

Each of these hormone levels can tell a diagnostician a lot about the state of the pituitary and what may behappening there. The level of each is like a piece of the puzzle, and some need to be measured regularly toget the overall picture.

Not only are these hormone levels important, but the levelsof other hormones affected by these are measured. In thethyroid, TSH from the pituitary affects the levels of T3 andT4.

In the adrenal gland, the level of cortisol is affected by thelevel of ACTH. It's that feedback loop I'm always talkingabout. The level of cortisol at various times of the day (8a.m., 4 p.m., and midnight) is an important tool fordiagnosing Cushing's. I've already talked about this some inother articles, and I'll elaborate more in later ones.

In post-pubescent females, FSH acts on the ovarian folliclesto produce estrogens and LH is instrumental in theproduction of progesterone. In males, LH is instrumental inthe production of testosterone. The hypothalamus secretesgonadotropin-releasing hormone (GnRH) to the pituitarygland in pulses. These, in turn, stimulate the pituitary glandto secrete luteinizing hormone (LH) which then stimulates

the Leydig cells of the testes to produce testosterone.

That brings us to the hypothalamus. The hypothalamus is a region of thebrain above the pituitary. It contains several types of neurons responsiblefor secreting different hormones. These are released into the blood in thecapillaries and travel to the anterior lobe of the pituitary.

Corticotropin-releasing hormone (CRH)Thyrotropin-releasing hormone (TRH)Growth hormone-releasing hormone (GHRH)Gonadotropin-releasing hormone (GnRH)DopamineSomatostatin

Each of these plays a role in the production of the hormones in the pituitary. Usually, those pituitaryhormones are tested rather than the hypothalamic hormones. The hypothalamic hormones are often used tostimulate the pituitary to see if it is producing those anterior lobe hormones, so they are valuable in thetesting process.

Altogether, these glands and their hormones comprise the Hypothalamic-Pituitary-Adrenal axis, also knownas the HPA-axis.



The adrenal glands sit on top of the kidneysand are sometimes called suprarenal glands.The adrenal gland is actually two glands thatare fused together into one gland. Theirtriangular shape is composed of two mainlayers as a result: cortex and medulla.

The adrenal medulla produces two mainchemicals called catecholamines: epinephrine(also called adrenaline) and norepinephrine.Both of these chemicals are involved inregulation of the nervous system. Epinephrine controls the short-term stress

response (aka fight-or-flight response) with the help of norepinephrine, which is also involved in theregulation of mood.

The outer part of the adrenal gland, also called the adrenal cortex, produces steroid hormones that areinvolved in regulating a number of different body functions. Mineralocorticoids (such as aldosterone) helpregulate the salt levels in the body by controlling the absorption and excretion of salt and water in thekidneys which is important in the regulation of blood pressure. Glucocorticoids (such as cortisol) regulatesugar and fat stores within the body, act as a strong anti-inflammatory force, and play an important role infetal development, particularly in lung maturation. The adrenal cortex also produces several sex steroidhormones, including androgens (critical for male sexual development) and precursors to estrogen (criticalfor female sexual development).

Tumors of the adrenal glands arise from the cortex or the medulla part of the adrenal gland. Most are foundduring CT scans or other imaging for various reasons. Others are found due to the effects of theoversecretion of the chemicals or hormones they produce.

Steroids: Excess secretion of the steroid hormones produce a Cushing’s syndromeAldosterone: Excess secretion of aldosterone produce a Conn’s syndromeCatecholamines: Excess secretion of catecholamines produce a pheochromocytoma

A benign tumor called an adrenal adenoma is the most common and is sometimes called an “incidentaloma”if it is not causing any hormonal or chemical oversecretions. However, there is a newer line of researchwhich indicates these are not to be taken lightly and may be a result of other endocrine malfunctions. MarcSlawik and Martin Reincke write in Endotext.com:

In a study patients with incidentalomas who were suffering from subclinical Cushing´ssyndrome (SCCS) were significantly more obese (17). In addition, patients with incidentalomasmore frequently suffer from diabetes mellitus type 2 (2, 5) and it has been postulated that inthese individuals hyperinsulinism leads to an increased proliferation of adrenal cells (25).Taking these findings together there seems to be a clear association of incidentalomas withfeatures of the metabolic syndrome (obesity, arterial hypertension, NIDDM, dyslipidemia,dyscoagulation).

A recent news article from Harvard Medical School says:

The study, lead by Dr. Leslie Eldeiry, a clinical instructor at Harvard Medical School, whichwas conducted at Harvard Vanguard Medical Associates, found that"only 30 percent ofpatients underwent biochemical evaluation for adrenal hyperfunction," which is the production



of excessive amounts of hormone.

In 2002, the National Institutes of Health released guidelines recommending hormonalevaluation of all incidentally discovered adrenal masses. Despitethe 2002 NIHrecommendations, only 30 percent of patients were properly tested. Moreover only 18 percentof patients in the study who did not see an endocrinologist with adrenal nodules had hormonaltesting.

(New Research Indicates That Adrenal Nodules Not Being Adequately Evaluated )

The most common malignant tumors found in the adrenal gland are tumors that come from cancer cells thathave metastasized (or spread) from other parts of the body to the adrenal gland through the blood stream.

Rarely, cancers can arise directly within the adrenal glands themselves. Cancers of the adrenal cortex arecalled adrenal cortical cancers. Functioning adrenal cortical cancers (they secrete excess steroid hormones)are more common than non-functioning cancers.

The most common cancer of the medulla are pheochromocytomas. In children, neuroblastoma tumorscan develop within the adrenal medulla.

Testing 101: ImagingSince there is so much involved in the testing and diagnosis of Cushing's Syndrome/Disease, I thought I'dinsert some information on imaging here. Imaging alone cannot diagnose Cushing's. There must bebiochemical proof of it, also, which includes testing those chemicals and hormones I've mentioned.However, negative imaging does not rule out Cushing's, either.

A special type of Magnetic Resonance Imaging (MRI) , called a dynamic MRI is the preferred method forpituitary tumors/lesions/adenomas. With a dynamic MRI, a series of MRI images are taken quickly overseveral minutes after the infusion of gadolinium, a special contrast agent. Dynamic scans are used becausepituitary tumors and normal gland tissue absorb the dye at different speeds. The contrast between the normaltissue and tumor is easier to delineate with this type of imaging.Dynamic MRIs may be especially importantwhen a small tumor of the type that causes acromegaly or Cushing's disease is suspected.

According to recent research, a dynamic pituitary MRI has high sensitivity and specificity for the diagnosisof mild Cushing's syndrome and should be part of the initial workup. Because the pituitary gland is small,tumors/adenomas/lesions are even smaller and are difficult to spot. Therefore, it is essential the right type ofMRI is ordered for you. A pituitary gland MRI is not the same as an MRI of the brain. A brain MRI doesnot show the pituitary nearly as well.

A closed MRI is preferred over an open MRI because the resolution is better. However, since obesity is asymptom of Cushing's, it is sometimes difficult to find a decent MRI big enough. There are some newer"open" MRI's which are 1.5 Tesla and above. (Click here for locations.)Typically, most MRI scanners havea strength of 1.5 Tesla but the newer, 3.0 Tesla scanners are becoming more prevalent and if available,should be used.

A computed tomography (CT) scan of the adrenal glands is usually done to localize an adrenal tumor if ithas not been found and if a pituitary adenoma has been ruled out. If a discrete adenoma is seen in oneadrenal gland and not on the other gland, then that with the biochemical evidence may be enough for aunilateral adrenalectomy. (Just the adrenal gland with tumor is removed.)



If the biochemical evidence is supportive of a pheochromocytoma, again a CT scan of the adrenal glands isperformed. Most pheochromocytomas in the adrenal gland are easily visible with a CT scan. If the CT scandoes not show one, then there is a chance of an "extra-adrenal" (outside the adrenal gland)pheochromocytomas. The literature supports using one or more of the following methods to find the tumor.

iodine-131–labeled metaiodobenzylguanidine (131I-MIBG)positron emission tomography (PET) scanoctreotide scan (done more in the UK than in the US)abdominal MRI

Often, adrenal tumors are found when CT or MRI scans are done for something else.

Ectopic tumors are probably the hardest to locate. Often, only after pituitary and adrenal tumors are ruledout are they pursued. Metomidate PET is a highly selective and potentially promising approach ofadrenocortical tumours that has been introduced in only few PET centres up to now. A gold standardtechnique in localizing ectopic ACTH-producing tumors has not been determined, but CT, MRI, andsomatostatin receptor scintigraphy (SRS) are all used in various combinations to try to find the tumor(s).

This is a bare-bones outline of possible imaging. The research is always telling diagnosticians more, and thebiochemical evidence is very, very important in the diagnosis. Imaging is fallible and only as good as theequipment and the person reading the results. It is always good to get multiple opinions from respectedsurgeons who do a lot of pituitary or adrenal surgeries when reading imaging studies.

What is dynamic MR Imaging?

Those of us who have suffered or still suffer withpituitary adenomas have heard way too many times"your MRI is normal". I did, for years. Yet, I ultimatelydid have a proven adenoma which caused myCushing's disease. If the MRI had shown even aninkling of the tumor to the trained eye, perhaps a doctorwould have taken my symptoms more seriously.

So, what makes a difference, then?Two things made a huge difference for me. First, mycurrent endocrinologist insisted on a dynamic MRI.Secondly, I sent the films and/or CDs to neurosurgeonswho remove a lot of pituitary adenomas. What my localradiologist called a "normal" MR image of my pituitarywas actually deemed NOT NORMAL by three world-

renowned neurosurgeons.

What is a dynamic MRI?In order to understand that, you need to first understand what an MRI is. Typically, pituitary MRI's are done"without contrast" and "with contrast". The Magnetic Resonance Imaging is done with no radioactivity(aka x-rays). It uses a strong magnetic field produced by a large magnet to send radio waves through thebody which "jiggle" the body's atoms. When these atoms move back into place, they send out radio wavesof their own which are picked up by the scanner and fed into a computer. This computer then usesprogrammed algorithms to turn them into pictures. To learn more about it, visit How Stuff Works.

A contrast is often used with MR imaging, especially of the head, to enhance the images. Solutions of



gadolinium compounds are typically used as contrast agents. Tumors enhance after gadolinium is givenbecause they tend to absorb the contrast agent either more quickly or less quickly than "normal" tissue. Thisleads to a "contrast" between the two types of tissue.

What makes a dynamic MRI different from any MRI using contrast?Typically, a series of images are taken prior to contrastand then the MR imaging is stopped while contrast isinjected. Once that is finished, the MRI proceeds withanother series of images. With the dynamic protocol,the contrast is infused over a period of time while theMR imaging is taking place. In one study thegadolinium solution was injected via IV over a periodof 180 seconds. In another study the gadolinium wasdripped via IV between 2 and 3 minutes.

Why does that make a difference?

Pituitary tumors and normal gland tissue absorb thegadolinium at different speeds. The contrast betweenthe normal tissue and tumor may be easier to see in theearlier images when compared to the later ones.Usually the pituitary adenoma enhances slower thanthe gland. (However, there have been documented

cases of just the reverse if the tumor encases a blood supply.) When the tumor enhances slower, a "darkspot", in layman terms, shows up on the pituitary. These are called areas of "hypointensity". This istransitory and if not imaged as it happens, the tumor will enhance to match the gland. (In the picture, theupper image does not clearly show a tumor. The lower image shows the tumor well including its contactwith the right internal carotid artery.)

Although I did not mention the strength of the MRI scanners being used, it's probably obvious that thestronger they are (measured in Tesla), the better they work. A 3T scanner is preferable if available, but theauthors of the studies used scanners as low as 0.5T in their studies. A scanner is only as good as thoseoperating it, those reading the scans, and the protocols used not matter how strong it is.

Testing 101: Biochemical AnalysisI have talked about many of the tests previously. What I want now is outline basic tests that mostendocrinologists use for the diagnosis of Cushing's. The following chart is general, and not totally inclusive,but it may help understand why certain tests are run:



This chart is talking about the comparision of serum cortisol and plasma ACTH to known ranges for knowntimes. Serum cortisol should be measured at 8 a.m., 4 p.m., and around midnight (most clinical studies use11 p.m. - 1 a.m.). If you remember, this will show the diurnal variation (or lack thereof). If the diurnalrhythm is not normal, this is one clue for the diagnosis of Cushing's.

According to Esoterix Labs, normal adult ranges for serum cortisol are:

8:00 a.m. 8.0 – 19 ug/dL4:00 p.m. 4.0 - 11 ug/dLmidnight close to zero

ACTH is pulsatile, and should be 9-54 pg/mL during the day. At midnight, however, the clinical studies sayit should be less than 23 pg/dL or it is excessive. Refer to "When tests don't even rate an A+ or a C-" to seehow to make sure ACTH is tested properly. Often, it's hard to get a valid result.

In The Biochemical Investigation of Cushing Syndrome[Neurosurg Focus 16(4), 2004. © 2004American Association of Neurological Surgeons], the last page says:

In patients with Cushing disease, 50% have a 9 a.m. plasma ACTH level within the normalreference range of 9 to 54 pg/ml (2–12 pmol/L) and the remaining patients have a slightlyelevated ACTH level.[36] Due to the loss of circadian rhythm, however, nighttime ACTHsecretion is abnormal. A midnight plasma ACTH levelgreater than 23 pg/dl (5 pmol/L)confirms the presence of an ACTH excess.

Salivary cortisol tests are also done to determine diurnal/circadian rhythm. Since midnight serum cortisolsare more difficult to do because the patient has to go to an open lab late at night, salivary kits offer a mucheasier alternative. However, serum cortisol tests tend to work better for cyclical patients because the serum



level has to be pretty high before the cortisol is readable in saliva. Esoterix has developed a more sensitiveassay for testing salivary cortisol which may offer a comparable output.

There are four FDA-approved labs for testing salivary cortisol (Quest, ACL Labs, Esoterix, and Labcorp),and each uses it's own method with varying ranges. The ranges for Esoterix are below:

24-hr Urinary Free Cortisol (UFC) is another test that is used. Again, depending on the method used to runthese and the lab, the ranges can vary. These are also discussed in "When tests don't even rate an A+ or aC-" . These are used to get an average value of the excess cortisol secreted in a 24-hour period.

Some researchers also use a 10-hour UFC to see if excess is just secreted overnight. These are analyzeddifferently by looking at the cortisol/creatinine ratio. A ratio of 15 or higher is considered diagnostic.

There is some question about the validity of the dexamethasone suppression test, with various factions in theliterature and in the research saying various things. Basically, it boils down to the dosage used with thedexamethasone and the doctor doing it.

An Update on the Overnight Dexamethasone Suppression Test for the Diagnosis of Cushing'sSyndrome: Limitations in Patients with Mild and/or Episodic Hypercortisolism [T. C. Friedman, ExpClin Endocrinol Diabetes. 2006 Jul;114(7):356-60] says:

The objective of this study was to determine the sensitivity of the one mg overnightdexamethasone suppression test in patients with mild and/or periodic Cushing's syndrome...

Therefore, an overnight dexamethasone suppression test was performed in 17 consecutivepatients presenting to an endocrinology clinic with signs and symptoms of hypercortisolemiawho were later proven to have Cushing's syndrome...

[These patients] failed to suppress to a value less than this cut-off point (sensitivity of 41 %).These results demonstrate that the great majority of patients with mild and/or periodicCushing's syndrome suppress to overnight dexamethasone. Since patients with mild and/orperiodic Cushing's syndrome are the patients in whom the identification of hypercortisolism isdifficult, our results from this relatively small study suggest that this test should no longer be



used to exclude these patients from further workup for Cushing's syndrome.

Previously I explained the difficulties in diagnosing cyclic/episodic/mild/subclinical Cushing's. Be preparedto do a lot of testing. If you are cyclic, you will have to figure out the symptoms of your "highs" versus your"lows". The only way to do that is to JOURNAL your symptoms and TEST! Keep very detailed records ofall lab results. Make sure you get a copy of each. Compare the results to your symptoms. If you areconsistent, you can figure out your cycle fairly quickly. In order to do this, you must find a doctor who iswilling to let you test when you need to test.

Watch out for lab errors:When testing for Cushing's, there are some standard tests that most up-to-date, in-the-know endocrine centers/doctors abide by. Of course, when onegets into the current research, combines the complexities ofmild/episodic/cyclic Cushing's with florid/classical and then adds a dash tonof no-one-uses-the-same-protocols, no wonder it gets confusing.

The Urinary Free Cortisol (UFC) test has long been touted as the "goldstandard". The current concensus among those who test episodic (et al)Cushing's the most is that it is NOT, but for the sake of argument and time,let's go with it. Everyone being tested for Cushing's will have to do UFC's.You are a rare one if not.

The UFC is a 24-hour collection of urine. That part is pretty easy. You discard the first void, start timingfrom there and collect every single drop or those 24 hours, ending at the same time you started. Whathappens to that urine is the big debate, both before and after collection. My endocrinologist and at least twoother major endocrinologists who are experts in the field recommend refrigeration if it's not going to the labimmediately (and possibly even then) but NO PRESERVATIVE.

Well, getting labs to agree to that is not going to happen. The absolute no-no that I've been told over andover is hydrochloric acid (HCl) as a preservative. Boric acid is accepted by most labs. Acetic acid ismentioned occasionally. In a study done by ARUP Institute, they found "Cortisol concentrations in samplesstored with the acids were higher by 30% than in samples stored without acid, possibly as a result of partialhydrolysis of sulfate and glucuronide conjugates. " Esoterix, the diamond of endocrine labs, prefers nopreservative at all.

What is a UFC measuring anyway? Well, "free" cortisol is used by the body for various functions, but thethought behind the test is that this free cortisol is spilled into the urine if there is excess. So, if there is excessfree cortisol spilled into the urine, an average can be measured for a 24-hour period.

UFC's are not just used to measure cortisol, though. Most endocrinologists also want to test the amount ofcreatinine in the urine, and many want to also test 17-hydroxycorticosteriods (17-OHC's). When that is thecase, now the lab protocol must include them and determine if a preservative and which preservative isnecessary or optional.

Also, the type of testing determines preservative use. Radioactive immunoassay (RIA) is now outdated, butis still being used. HPLC Tandem Mass Spectrometry is the most current, with Liquid ChromatographyTandem Mass Spectrometry (LCMSMS) running a close second.

Bacteria degrade the cortisol quickly at room temperature, and getting a lab to refrigerate it is tenuous. Youhope they will but often they don't. Measure/aliquoting a correct sample is another problem if there is morethan one jug for a collection. The aliquot must be a mix of all samples so there is a proper average and the



TOTAL volume for all jugs used in the 24-hour collection has to be recorded.

From experience and observation, I offer my opinion: Find a lab which will use one of the preferredmethods above (not RIA), will refrigerate the urine until tested, will not add a preservative, and whichunderstands all must be THAWED and MIXED before aliquoting it. If the urine aliquot/sample is sentelsewhere, it needs to be sent FROZEN to be thawed before measured, and the total amount of urine thatwas presented needs to be recorded.

Another test that is used extensively for the measurement of cortisol, especially with diurnal variation orlack of, is serum cortisol. This one is pretty straight forward as long as the person reading the lab resultsunderstands what they really mean.

The article, "Cushing's Syndrome" by John Newell-Price, Xavier Bertagna, Ashley B Grossman, LynnetteK Nieman, Lancet 2006; 367: 1605–17,Division of Clinical Sciences, University of Sheffi eld, NorthernGeneral Hospital, Sheffi eld, UK (J Newell-Price FRCP); says

An awake midnight concentration of cortisol in plasma of more than 207nmol/L differentiates between Cushing’s syndrome and other causes ofhypercortisolaemia but can miss mild disease diagnosis in about 7% of cases.(The conversion factor of μg/dL x 27.6 = nmol/L)

Essentially, serum cortisols only have valid ranges for the 8 a.m. and 4 p.m. time periods in most labs. Theresearch and leading endocrinologists acknowledge the validity of midnight serum cortisols, also. So, as Isaid before, the 8 a.m. should be the highest of the three, with the 4 p.m. about half of the 8 a.m. value. Themidnight value should be close to zero.

The problem is that the labs don't know about the midnight range of zero, so IF one can find a lab willing todraw a midnight serum cortisol fairly frequently for testing, they won't know to put "zero" on the range andflag it as high if it's above that. 7.5 μg/dL (207 nmol/L) is diagnostically high. If you have someoneordering tests for you who does not understand this, you may get a call saying "it was normal". Ask for theactual report.

A third test that is important in the diagnosing of Cushing's and differentiating between types isAdrenocorticotropic Hormone (ACTH). The lab technician must use an EDTA (lavender top) plasmatube only! Collection in nonsiliconized tubes can result in falsely low results as ACTH adheres to glass. Itneeds to be mixed by inversion and centrifuged immediately after collection. IT MUST NOT GETWARM. The tubes should be on ice prior to drawing the blood, and put immediately back in the ice until itis separated and then frozen. The plasma must be separated and frozen immediately. If it is shipped, itshould be shipped on dry ice while still frozen. ACTH breaks down easily in heat, and if not collected andpreserved on ice, proteolysis (degradation of proteins by cellular enzymes) can reduce the plasmaconcentration.

The salivary cortisol test is another test used very similarly to the serum cortisol tests. It, too, can helpshow diurnal rhythm (or lack thereof). The protocol is pretty simple and straight-forward regardless of thelab. There are only a few labs who use an FDA approved test for these salivary cortisol levels. The labs areEsoterix, ACL Laboratories, LabCorp (who now owns Esoterix), and Quest. It is very easy for a doctor toset up an account with any of these and order the testing kits for patients. The patient simply collects "spit"until s/he gathers enough for the container or "salivette". Some of the labs use a tampon-like material(salivette) for the patient to soak with saliva and place in the tube. Both methods of collection are reliable.However, it is important that one does not touch the salivette with hands and should not eat, drink or rinsethe mouth for thirty minutes prior to collection.



A word of caution. Although the cortisol supposedly does not break down very quickly, many get muchhigher results when they first froze the samples, then shipped them overnight. Since bacteria will breakdown cortisol, it stands to reason this can happen with the salivary test, too.

Another inconsistency with salivary cortisols that many folks testing have observed is they have had highserum cortisols the same nights we have done salivary cortisols. I did several while sitting and having blooddrawn. My serum cortisol was high. My salivary cortisol was "normal". Only when my serum cortisol (atmidnight) was around 16 μg/dL or higher did my salivary cortisol show high levels, too. The clearance isdifferent, thus the outcomes can vary.

What advice do I have for testing? You must be proactive in your testing process.

Know the proper protocols Take print-outs of the proper protocols with you. You can find them for just about any lab. If youcan't, the Mayo site and ARUP labs have great details. Labcorp and Esoterix also have may good,informative articles. If your doctor wants it done a certain way, get him/her to put that in writing Insist on the proper protocol. This is YOUR TIME and YOUR MONEY (even with insurance) thatis paying for a service to be done right. You may need to catch that high and you don't want anyoneto mess it up. Call the lab ahead of time and speak with the lab manager. Explain your situation courteously and askif they are familiar with the tests and protocols. Go over them together, talk about when you will bein, and what you need to do to make sure those protocols are followed. This will save you manyheadaches down the road. A good relationship with your lab will go a LONG way. Call the lab manager again if you do encounter problems and discuss the issues. Courtesy still goesfurther than anger. However, I've been known to use some of that southern "charm" my mothertaught me. Ahem... For midnight serums, it is difficult to find a lab, other than the local hospital lab, open late at night.Again, call them ahead of time, explain the testing protocol and why you need to come in atmidnight. Get the paperwork done ahead of time so you can go in and get it done quickly once youare there. A little kindness goes a long way. A treat, some cookies, a gift basket or something simple as a cakeshared with the lab folks occasionally will brighten their day. Say thank-you when it is done right. Again, that goes a long way.

Don't be surprised if drawing blood is difficult.This is typically due to the effect of the cortisol on the veinsso try to keep your arms warm and stay hydrated. Warm bags of rice, a warm fleece jacket, or whatever ittakes to keep those arms warm are helpful.

Testing 101: IPSS (aka BIPSS)Once the biochemical evidence for Cushing's Disease/Syndrome confirms the diagnosis, differentiation ofthe source or reason for the high cortisol must be ascertained. There are numerous possible scenarios forquestionable source(s). I'll try to outline a few of the more common ones.

Scenario 1: Normal or high ACTH, high cortisol with abnormal circadian rhythm, no evident pituitary



tumor on MRI or questionable hypointense area which may or may not mean a tumor, no evident adrenaltumor.**Possible sources of high cortisol: ACTH-secreting pituitary adenoma, ectopic ACTH-secreting tumor

Scenario 2: Normal or high ACTH, high cortisol with abnormal circadian rhythm, visible pituitary tumoron MRI, no evident adrenal tumor.**Possible sources of high cortisol: ACTH-secreting pituitary adenoma, ectopic ACTH-secreting tumor

Scenario 3: Normal ACTH, high cortisol with abnormal circadian rhythm, visible pituitary tumor on MRI,visible adrenal tumor.**Possible sources of high cortisol: ACTH-secreting pituitary adenoma, adrenal tumor

There are more possible scenarios. The point I'm trying to make is that the evidence is not always cut-and-dry, and the source of high cortisol needs to be determined. One tool for doing this is the Bilateral InferiorPetrosal Sinus Sampling (BIPSS) aka IPSS.

In CLINICAL REVIEW: Cushing’s Syndrome: Important Issues in Diagnosis and Management[The Journal of Clinical Endocrinology & Metabolism 91(10):3746–3753, © 2006 by The EndocrineSociety], the authors state:

....mild to moderate hypercortisolism, a normal or slightly elevated plasmaACTH, and normokalemia has at least a 95% likelihood of having Cushing’sdisease. In contrast, a patient with prodigious hypercortisolism, hypokalemia, and markedelevations of plasma ACTH may be more likely to have an occult ectopic ACTH-secretingtumor.

Approximately 40-50% of pituitary tumors do not show on MRI, although the dynamic protocol used insome specialty centers increases the odds. Couple that with the 10% chance of an incidentaloma anddiagnosticians find the need for more validation.

The aforementioned authors also say "Inferior petrosal sinus ACTH sampling with CRH stimulation is theonly study having the potential to yield a diagnostic sensitivity and specificity for Cushing’s disease higherthan its pretest probability". They are talking about the IPSS.

What is an IPSS?

An IPSS is a test to sample the amount of ACTH draining into the inferior (vs. the superior) petrosal sinusesfrom the pituitary. Two catheters (one on each side) are threaded from the groin area up each side of thebody to a major vein in the petrosal sinus area.

Corticotropin-releasing hormone (CRH), a natural hormone secreted by the hypothalamus, naturallystimulates the anterior pituitary gland to produce ACTH. If only the pituitary, not a tumor, is secretingACTH, the levels of ACTH in the petrosal sinus area and in the rest of the body should be very close. If thelevels of ACTH in the petrosal sinus area is higher than in samples from a peripheral area of the body , thenan adenoma/tumor on or close to the pituitary is probably secreting ACTH.

Since CRH is released in pulses naturally and will not be active all the time, CRH is added during the IPSSto stimulate the pituitary to secrete ACTH during the testing period. After drawing blood from the cathetersand from a peripheral area (arm or leg) to give a baseline level of ACTH and cortisol, CRH is injected. Sothat levels of ACTH are recorded from both the petrosal sinus area and the peripheral area, blood is drawnfrom each area at a specified interval (5-15 minutes, usually) to determine these levels over time. This



usually takes about 2 hours.

The blood samples are kept on ice and sent immediately to the lab for determination of ACTH levels. Therewill be three major comparisons: 1) Right petrosal sinus samples 2) Left petrosal sinus samples 3) Peripheralsamples

If the ratio of the right-to-peripheral sample OR the ratio of the left-to-peripheral sample is greater than 2before the addition of CRH, the value is diagnostic for Cushing's Disease (pituitary source).

If the ratio of the right-to-peripheral sample OR the ratio of the left-to-peripheral sample is greater than 3after the addition of CRH, the value is diagnostic for Cushing's Disease (pituitary source).

The IPSS may also be used tentatively for lateralization. This means it can help predict which side the tumormay be on. However, this is only about 70% accurate. For this to work, the tumor will drain more on oneside than the other. However, some tumors drain into both sides, or there are multiple tumors. Sometimes,the anatomy is not predictable and the tumor may drain into the sinus on the opposite side.

How valid is the IPSS?

Multiple studies cite the usefulness of the IPSS in determining source, but not as a diagnostic tool.Biochemical evidence needs to show there is hypercortisolism prior to the use of the IPSS. The rate of false-positives is relatively small, but there are false-negatives. In other words, some patients who have hadproven Cushing's Disease had a negative IPSS. This is usually due to the infamousepisodic/cyclic/subclinical/mild "version" of Cushing's.

In the article, Petrosal sinus sampling for diagnosis of Cushing's disease: evidence of false negative results,[Clin Endocrinol (Oxf). 1996 Aug;45(2):147-56], the authors say:

Only when a significant IPS:P ACTH ratio is present can Cushing's disease tbe established byIPS sampling. The absence of a significant IPS: P ACTH ratio does not necessarily implyectopic secretion of ACTH, nor does it exclude Cushing's disease. The results of lateralizationby IPS sampling do not remove the need for a thorough transsphenoidal examination of thecontents of the sella turcica.

In the Endocrinologist [11(5):388-398, September/October 2001] researchers at the University of Virginiasay " In experienced centers, the diagnostic sensitivity and specificity of IPSS approaches 100%. Theindications for IPSS are debated, with some advocating use when standard dynamic tests are inconclusive,and others advocating use only when pituitary magnetic resonance imaging (MRI) is inconclusive. "

Testing 101: Growth Hormone Deficiency



Ok...what's the big deal, anyhow? Why would an adultneed to have her growth hormone levels evaluated?

As a review, growth hormone is secreted by thepituitary gland. Some pituitary tumors secrete too muchGH which causes gigantism in children andacromegaly in adults. However, on the flip side, sometumors suppress the pituitary and too little is secreted.Even if the tumor does not do that, surgery to remove atumor may cause the pituitary to quit or lessen it'ssecretion of GH. Radiation is also used on pituitarytumors that cannot be totally removed or if there ishyperplasia, and it, too, can damage the pituitary.

Adult Growth Hormone Deficiency (GHD) is a veryreal problem. GH maintains a healthy balance ofmuscle, bones, and fat and if an adult is deficient, herbody composition changes. The body has less muscle,visceral fat is deposited around the abdomen, andbones weaken. Other fats in the body are affected."Good" cholesterol (HDL) decreases but "bad"cholesterol (LDL) increases. This is very hard on thecardiovascular system (remember, the heart is a muscle)and the cerebrovascular system.

In Diagnosis of adult GH deficiency [V. Gasco, et al, Pituitary (2008) 11:121–128], the authors state:

Adults with growth hormone deficiency (GHD) have impaired health, which improves withGH replacement. GHD in adults leads to impairment in body composition and function, as wellas to deranged lipoprotein and carbohydrate metabolism and increased cardiovascularmorbidity. Based on evidence that GHD in adults is anew syndrome which may benefit from GH replacement, health authorities in many countrieshave approved the therapeutic use of GH in hypopituitaric patients with severe GHD.

Not only is the physical health of a GHD adult affected. Social isolation, excessive tiredness, anxiety,depression, and apathy are also symptoms of GHD.

Growth hormone secretion is pulsatile which means random measurements of GH levels are not helpful ordiagnostic. Since insulin-like growth factor-1(IGF-1) is stimulated by GH but does not fluctuate during theday like GH, it is useful in monitoring GH levels. Low levels are an excellent indication of a GHDproblem. However, normal levels do not mean there is no deficiency.

The Growth Hormone Research Society met in 2007 in Australia and penned a consensus statement aboutthe problems, testing, and treatments associated with adult GHD. In their consensus statement, they write:

...the patient with objective evidence of hypothalamic–pituitary disease (e.g., on imaging orafter irradiation), who may present with organic isolated GHD as the first hormonaldeficiency...may account for up to 25% of cases of GHD in the adult.



Consensus guidelines for the diagnosis and treatment of adults with GH deficiencyII[European Journal of Endocrinology (2007) 157 695–700]

In this same consensus statement, they say:

Not all patients suspected of having GHD,however, require a GH stimulation test fordiagnosis.Patients with three or more pituitary hormone deficiencies and an IGF-I level belowthe reference range have >97% chance of being GHD, and therefore do not need a GHstimulation test.

The Insulin Tolerance Test has, in the past, been the "gold-standard" for measuring true GHD. However,there have been some problems with its reproducibility and specificity.

In Clinical Presentation and Diagnosis: Growth Hormone Deficiency in Adults the American Journalof Managed Care [Volume 10:S424-S430 , October 2004 , Number 13 Suppl ] states:

Numerous pharmacologic agents can be used to assess GH production and secretionby the pituitary in adults (Table 3). These include insulin, arginine, levodopa(L-dopa), arginine plus L-dopa, arginine plus GHRH, and the glucagon test. Nonedisplay perfect sensitivity and specificity; however, the insulin tolerance test(ITT) and arginine-GHRH are excellent tests.

The arginine-GHRH test is being used by major pituitary centers around the world. It is less stressful withless risk for the patient but yields reproducible and accurate results.

What are the differences in these two tests? In the ITT, the pituitary is provoked to produce GH by causinghypoglycemia in the patient with insulin. With the A-GHRH test, arginine is a somatostatin antagonistwhich essentially does the same thing. Combined with GHRH (to stimulate GH production), it is now thetest of choice (see article linked above).

Just how many kinds of tumors are there associated with Cushing's? Wait, are we talking about pituitarytumors? Or adrenal tumors? How about ectopic tumors? Are you beginning to get the picture of why thisillness is so hard to diagnose?

What types of tumors are associated with Cushing's?

PITUITARY TUMORS/ADENOMAS:

So, let's talk about tumors. These are also sometimes called adenomas. Pituitary adenomas are classifiedseveral ways. They may be classified by pathology, by size, and by hormone production. I'm going to keepit simple here and list the basic types of tumors by the hormones they produce. Bear in mind that manypituitary adenomas produce more than one hormone. This production is not held in check by the body'snormal feedback loops, thus they aren't controlled.

Corticotroph (ACTH-Producing) Adenomas :



The corticotroph adenoma secretes adrenocorticotropic hormone (ACTH), which results in CushingDisease because it stimulates the adrenal glands to overproduce cortisol. These tumors are initiallyconfined to the sella turcica, but they may enlarge and become invasive especially after bilateraladrenalectomy. This is called Nelson's Syndrome. Somatotroph (GH-Producing) Adenomas: Somatotroph adenomas produce growth hormone (GH), resulting in gigantism in younger patientsand acromegaly in adults. These tumors may also extend beyond the sella. Thyrotroph (TSH-Producing) Adenomas: Thyrotroph adenomas secrete thyroid-stimulating hormone (TSH), also known as thyrotropin, whichresults in hyperthyroidism without TSH suppression. Many are large and invasive and typically haveother types of adenoma cells included, such as ACTH and/or GH. Lactotroph (PRL-Producing) Adenomas: Lactotroph adenomas secrete prolactin (PRL) and are typically an intrasellar tumor. However, theycan become large enough to enlarge the sella turcica. Nonfunctioning (Endocrine-Inactive) Adenomas: These tumors cause symptoms when they extend beyond the sella, which results in pressure on thesurrounding structures such as optic nerves and carotid veins. They are not associated with clinicaland biochemical evidence of hormone excess. Carcinomas: Pituitary carcinomas, although extremely rare, are usually endocrinologically functional, and ACTH-producing and PRL-producing tumors are the most frequent. Other Tumors: Other tumors of the pituitary include craniopharyngiomas, meningiomas, and germ cell tumors. Evenrarer are the granular cell tumors, pituicytomas, and gangliogliomas. Most rare includegangliocytomas, lymphomas, astrocytomas, and ependymomas.

ADRENAL TUMORS/ADENOMAS:

When a tumor in an adrenal gland overproduces hormones, the tumor is called a functioning tumor. Atumor in an adrenal gland that does not produce hormones is, understandably, called a nonfunctioningtumor. A tumor can start in an adrenal gland (called a primary adrenal tumor) or it can begin in anotherorgan, such as the lungs, and then metastasize (spread) to the adrenal glands. I'm going to focus on primaryadrenal gland tumors.

Adenoma: An adenoma is a benign nonfunctioning tumor of the adrenal cortex. Also called an adrenocorticaladenoma, this tumor usually does not cause symptoms, and, if it is small, may not require anytreatment. However, as it grows it can put pressure on parts of the gland causing it to under oroverproduce hormones. The cause of adrenal adenomas is unknown, but the current accepted theoryis that they arise because of mutations in certain genes. Adrenal adenomas are more common in someinherited diseases, including multiple endocrine neoplasia type I, Beckwith-Wiedemann syndromeand the Carney complex.

Chronic adrenal stimulation by ACTH leads to bilateral adrenocortical hyperplasia and, if long-standing, nodular transformation according to recent research. Thus, an ACTH producing tumor ofthe pituitary or ectopic tumor may stimulate the adrenals to form tumors or become hyperplastic (moreabout hyperplasia in a bit). Adrenocortical carcinoma:



Although exceedingly rare this is the most common type of malignant adrenal gland tumor, affectingthe cortex, also called an adrenal cortical carcinoma. Adrenocortical carcinoma can be a functioningor nonfunctioning tumor. If the tumor is functioning, it may produce more than one hormone. Pheochromocytoma: A pheochromocytoma is a rare tumor that develops in the core of an adrenal gland. It secretesexcessive amounts of catecholamines, usually epinephrine and norepinephrine. Neuroblastoma: Neuroblastoma is a disease in which malignant cells form in nerve tissue of the adrenal gland. It isvery rare.

If that isn't enough, there is another form of tumor that isn't a tumor. It's called hyperplasia. These tumorcells may invade the pituitary or the adrenals in nests throughout the gland.

Pituitary Hyperplasia: A Review Adrenal Hyperplasia To learn more:Cushing's Help and SupportCushing's Help and Support Foundation

Comments

Sign in to write a comment

hammad saleem

Coronary Artery Disease: New ways of Treatment

Great article

Have a look at this video for more insightshttp://www.youtube.com/watch?v=pjUndFhJkjM

Thanks

Sep 22, 2011 3:52 AMReport abusive comment0Post reply to this comment

Internet Medical Publishing



Invitation to submit your Knols to the journal "Open Journal of Medicine"

We´d like to invite you to submit your knols to the journal "Open Journal of Medicine" by clicking the link"Submit a knol to this collection" at the bottom of this page http://knol.google.com/k/internet-medical-publishing/open-journal-of-medicine/1bbsle13m97c0/391#view Best,iMedPub

Last edited Dec 24, 2009 4:17 AMReport abusive comment0Post reply to this comment

Documents

Cushing's Disease / Syndrome - A Knol by Robin S