survive the journey

Cushing's Awareness: Testing

survivethejourney@gmail.com (RobinS) — Fri, 17 Apr 2015 09:19:00 -0400

What I want to do today is outline basic tests that most endocrinologists use for the diagnosis of Cushing's. The following chart 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 known times. Serum cortisol should be measured at 8 a.m., 4 p.m., and around midnight (most clinical studies use 11 p.m. - 1 a.m.). If you remember, this will show the diurnal variation (or lack thereof). If the diurnal rhythm 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/dL
4:00 p.m. 4.0 - 11 ug/dL
midnight close to zero

ACTH is pulsatile, and should be 9-54 pg/mL during the day. At midnight, however, the clinical studies say it should be less than 23 pg/dL or it is excessive. Refer back to "When tests don't even rate an A+ or a C-" to see how 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. © 2004 American Association of Neurological Surgeons], the last page says:

In patients with Cushing disease, 50% have a 9 a.m. plasma ACTH level within the normal reference range of 9 to 54 pg/ml (2–12 pmol/L) and the remaining patients have a slightly elevated ACTH level.[36] Due to the loss of circadian rhythm, however, nighttime ACTH secretion 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 cortisols are more difficult to do because the patient has to go to an open lab late at night, salivary kits offer a much easier 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 sensitive assay 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 run these and the lab, the ranges can vary. I also discussed these in "When tests don't even rate an A+ or a C-" . 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 analyzed differently 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 the literature and in the research saying various things. Basically, it boils down to the dosage used with the dexamethasone and the doctor doing it.

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

The objective of this study was to determine the sensitivity of the one mg overnight dexamethasone suppression test in patients with mild and/or periodic Cushing's syndrome...
Therefore, an overnight dexamethasone suppression test was performed in 17 consecutive patients presenting to an endocrinology clinic with signs and symptoms of hypercortisolemia who 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 periodic Cushing's syndrome suppress to overnight dexamethasone. Since patients with mild and/or periodic Cushing's syndrome are the patients in whom the identification of hypercortisolism is difficult, 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.

DO NOT LET A DOCTOR TELL YOU THAT YOU DO NOT HAVE CUSHING'S BASED ON THE RESULT OF JUST ONE OR EVEN A FEW "NORMAL" TESTS!! In this post, I explained the difficulties in diagnosing cyclic/episodic/mild/subclinical Cushing's. Be prepared to 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 of all lab results. Make sure you get a copy of each. Compare the results to your symptoms. If you are consistent, you can figure out your cycle fairly quickly. In order to do this, you must find a doctor who is willing to let you test when you need to test.

Cushing's Awareness: Growth Hormone Levels

survivethejourney@gmail.com (RobinS) — Thu, 16 Apr 2015 09:12:00 -0400

Ok...what's the big deal, anyhow? Why would anyone need to have their growth hormone levels evaluated? I'm going to stick to adults today because low growth hormone (GH) is a whole 'nuther ballgame with children.

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

Adult Growth Hormone Deficiency (GHD) is a very real problem. GH maintains a healthy balance of muscle, bones, and fat and if an adult is deficient, her body composition changes. The body has less muscle, visceral fat is deposited around the abdomen, and bones weaken. Other fats in the body are affected. "Good" cholesterol (HDL) decreases but "bad" cholesterol (LDL) increases. This is very hard on the cardiovascular 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 with GH replacement. GHD in adults leads to impairment in body composition and function, as well as to deranged lipoprotein and carbohydrate metabolism and increased cardiovascular morbidity. Based on evidence that GHD in adults is a
new syndrome which may benefit from GH replacement, health authorities in many countries have 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 or diagnostic. Since insulin-like growth factor-1(IGF-1) is stimulated by GH but does not fluctuate during the day like GH, it is useful in monitoring GH levels. Low levels are an excellent indication of a GHD problem. 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 about the 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 or after irradiation), who may present with organic isolated GHD as the first hormonal deficiency...may account for up to 25% of cases of GHD in the adult.

Consensus guidelines for the diagnosis and treatment of adults with GH deficiency II[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 for diagnosis.Patients with three or more pituitary hormone deficiencies and an IGF-I level below the reference range have a 97% chance of being GHD, and therefore do not need a GH stimulation 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 Journal of Managed Care [Volume 10:S424-S430 , October 2004 , Number 13 Suppl ] states:

Numerous pharmacologic agents can be used to assess GH production and secretion
by the pituitary in adults (Table 3). These include insulin, arginine, levodopa
(L-dopa), arginine plus L-dopa, arginine plus GHRH, and the glucagon test. None
display perfect sensitivity and specificity; however, the insulin tolerance test
(ITT) and arginine-GHRH are excellent tests.

The arginine-GHRH test was used by major pituitary centers around the world. It was less stressful with less risk for the patient but yielded reproducible and accurate results. However, it is now difficult if not impossible to find GHRH because the company which produced it is no longer doing so. Now, glucagon is the major agent with the ITT the least preferable option. The ITT side effects are numerous, and are potentially hazardous. It is labor intensive. If one has a history of seizures, hypothyroidism, panhypopituitarism or heart disease, it is not advisable to use that method. (See here.)

What are the differences in these two tests? In the ITT, the pituitary is provoked to produce GH by causing hypoglycemia in the patient with insulin. With the Glucagon stim test, glucagon is a peptitide hormone which essentially does the same thing. Why glucagon causes release of GH is unclear, at least according the the article linked.

Cushing's Awareness: Pituitary hormones and disorders

survivethejourney@gmail.com (RobinS) — Wed, 15 Apr 2015 20:01:00 -0400

Endocrine disorders usually involve a lot of testing, I thought I would spend some time the next few days talking about some of those tests. With Cushing's Disease, an adenoma can cause hypopituitarism and panyhypopituitarism as well as excess secretion of a hormone or hormones from the adenoma itself. In order to understand what tests are done and why you will first need to know 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 more hormones. 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 bodies functions. Panhypopituitarism, on the other hand, is the deficiency and/or total loss of all hormone production in the pituitary.

The pituitary gland is a bean-shaped (think lima bean) organ that is at the base of the brain. The gland anterior lobe, the intermediate lobe, the posterior lobe. The intermediate lobe is rudimentary in human beings but produces several hormones whose physiologic significance is only now being established.
The pituitary is attached to the hypothalumus (a part of the brain that affects the pituitary gland) by nerve fibers. The pituitary gland itself consists of three sections:

Anterior lobe:

growth hormone
prolactin - to stimulate milk production after giving birth
ACTH (adrenocorticotropic hormone) - to stimulate the adrenal glands
TSH (thyroid-stimulating hormone) - to stimulate the thyroid gland
FSH (follicle-stimulating hormone) - to stimulate the ovaries and testes
LH (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 kidneys
oxytocin - to contract the uterus during childbirth and stimulate milk production. It is also believed to be important for orgasm

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

Not only are these hormone levels important, but the levels of other hormones affected by these are measured. In the thyroid, TSH from the pituitary affects the levels of T3 and T4.

In the adrenal gland, the level of cortisol is affected by the level of ACTH. It's that feedback loop I'm

always talking about. The level of cortisol at various times of the day (8 a.m., 4 p.m., and midnight) is an important tool for diagnosing Cushing's. See "When Cortisol is a Night Owl" for more on this.

In post-pubescent females, FSH acts on the ovarian follicles to produce estrogens and LH is instrumental in the production of progesterone. In males, LH is instrumental in the production of testosterone. The hypothalamus secretes gonadotropin-releasing hormone (GnRH) to the pituitary gland in pulses. These, in turn, stimulate the pituitary gland to secrete luteinizing hormone (LH) which then stimulates the Leydig cells of the testes to produce testosterone.

Link

That brings us to the hypothalamus. The hypothalamus is a region of the brain above the pituitary. It contains several types of neurons responsible for secreting different hormones. These are released into the blood in the capillaries 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)
Dopamine
Somatostatin

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

Altogether, these glands and their hormones comprise the Hypothalamic-Pituitary-Adrenal axis, also known as the HPA-axis. I have not touched on the adrenal hormones, yet, except to mention cortisol.
I will get there.

Cushing's Awareness: Heritable Cushing's

survivethejourney@gmail.com (RobinS) — Mon, 13 Apr 2015 20:19:00 -0400

There are several forms of known heritable Cushing's. The most well-known is MEN1. Carney Complex is also fairly well understood. The least studied, and newest researched is FIPA.

MEN1: (Multiple endocrine neoplasia, Type 1) According to Medscape, "the combination of parathyroid tumors, pancreatic islet cell tumors, and anterior pituitary tumors is characteristic of MEN1. Although usually inherited as an autosomal dominant disorder, MEN1 can also occur sporadically (without a family history) as a result of new mutations. It is also important to keep in mind that family members of an MEN1-affected individual may have been undiagnosed at the time of death. Patients with untreated MEN1 have a decreased life expectancy, with a 50% probability of death by age 50 years."

Carcinoid tumors can occur in patients with MEN1 and are located in the bronchi, gastrointestinal tract, pancreas, and thymus. In men, especially smokers, the thymus is most often affected. Thymic carcinoids[8] associated with MEN1 are often nonfunctional and aggressive. In women, bronchial carcinoids are most common. Carcinoids can actively secrete hormones such as serotonin, somatostatin, corticotropin, and growth hormone.

Carney Complex: Two genes have been associated with Carney complex. They are called PRKAR1A and CNC2. It is believed that about 60% of people with Carney complex have a mutation in the PRKAR1A gene and up to 6% may have deletions in this gene.There may be other genes associated with Carney complex, and studies are ongoing to learn more about it. It is an autosomeal dominant disease.

Fewer than 500 cases of Carney Complex have been reported. It is estimated that between 50% and 70% of cases of Carney complex run in families. The other percentage occurs by chance and may be due to a new gene mutation.

FIPA: (Familial isolated pituitary adenoma) This is an inherited condition characterized by development of a pituitary adenoma. FIPA can be caused by mutations in the AIP gene which is thought to act as a tumor suppressor. According to this FIPA site, "about 1 in 20 pituitary tumours do seem to run in families. If the condition only seems to affect the pituitary gland in the family, then the disease is known as Familial Isolated Pituitary Adenoma (FIPA). " It is an autosomal dominant disease with incomplete penetrance (not all patients who carry the abnormal gene will develop the disease).

There are also several mutations which occur to cause Cushing's, some very recently discovered. I'll talk about those next time.

Cushing's Awareness: Types of Tumors

survivethejourney@gmail.com (RobinS) — Sun, 12 Apr 2015 21:12:00 -0400

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

PITUITARY TUMORS/ADENOMAS:

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

Corticotroph (ACTH-Producing) Adenomas : The corticotroph adenoma secretes adrenocorticotropic hormone (ACTH), which results in Cushing Disease because it stimulates the adrenal glands to overproduce cortisol. These tumors are initially confined to the sella turcica, but they may enlarge and become invasive especially after bilateral adrenalectomy. This is called Nelson's Syndrome.
Somatotroph (GH-Producing) Adenomas: Somatotroph adenomas produce growth hormone (GH), resulting in gigantism in younger patients and 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, which results in hyperthyroidism without TSH suppression. Many are large and invasive and typically have other 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, they can 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 the surrounding structures such as optic nerves and carotid veins. They are not associated with clinical and 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.

ADRENAL TUMORS/ADENOMAS:

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

Adenoma: An adenoma is a benign nonfunctioning tumor of the adrenal cortex. Also called an adrenocortical adenoma, this tumor usually does not cause symptoms, and, if it is small, may not require any treatment. However, as it grows it can put pressure on parts of the gland causing it to under or overproduce hormones. The cause of adrenal adenomas is unknown, but the current accepted theory is that they arise because of mutations in certain genes. Adrenal adenomas are more common in some inherited diseases, including multiple endocrine neoplasia type I, Beckwith-Wiedemann syndrome and 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 of the pituitary or ectopic tumor may stimulate the adrenals to form tumors or become hyperplastic (more about hyperplasia in a bit).
Adrenocortical carcinoma: Although exceedingly rare this is the most common type of malignant adrenal gland tumor, affecting the cortex, also called an adrenal cortical carcinoma. Adrenocortical carcinoma can be a functioning or 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 secretes excessive 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 is very rare.
Rest Tissue: An island of adrenal cortical tissue separate from the adrenal gland, usually found in the retroperitoneal tissues, kidney, or genital organs.

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

Pituitary hyperplasia is defined as "a non-neoplastic increase in one or more functionally distinct types of pituitary cells. The acini, though expanded, remain intact", according to www.hormones.gr/123/article/article.html .

Adrenal hyperplasia, simply put, is enlargement of the adrenal glands due to Cushing's. It may be due to increased stimulation by the pituitary gland or for other reasons.

Cushing's Awareness: Subclinical Cushing's

survivethejourney@gmail.com (RobinS) — Sat, 11 Apr 2015 10:39:00 -0400

Subclinical Cushing's Disease/Syndrome has be a controversial diagnosis. Only in the past decade has the term been used. According to Pathophysiology and treatment of subclinical Cushing’s disease and pituitary silent corticotroph adenomas “subclinical has been used in the pituitary. Subclinical Cushing’s disease is defined by ACTH-induced mild hypercortisolism without typical features of Cushing’s disease." This places the cause of subclinical Cushing's with the pituitary.

The authors of Clinical Cushing’s syndrome: Current concepts and trends define subclinical Cushing's as coming from an adrenal incidentaloma.

Initial diagnostic evaluation of a patient with an adrenal incidentaloma aims to determine the functional status of the mass and the possibility of malignant disease. The vast majority of these lesions are benign nonhypersecreting cortical neoplasms. However, a significant percentage of cases present subclinical hormonal activity, mainly concerning glucocorticoid secretion.4-6 Subtle cortisol hypersecretion by adrenal incidentalomas is characterized by alterations of the hypothalamic-pituitary-adrenal (HPA) axis due to adrenal autonomy in the absence of the typical clinical phenotype of hypercortisolism, a disorder that has been defined as subclinical Cushing’s syndrome. (Underlining is mine.)

Late-Night Salivary Cortisol for Diagnosis of Overt and Subclinical Cushing’s Syndrome in Hospitalized and Ambulatory Patients also indicates subclinical as having a pituitary origin. But Subclinical Cushing's syndrome also indicates an adrenal incidentaloma as the source. It goes on to say, "Patients with subclinical Cushing's syndrome lack the classical stigmata of hypercortisolism but have a high prevalence of obesity, hypertension, and type 2 diabetes." (I thought those were classical symptoms of Cushing's.)

Subclinical Cushing's Disease is considered to be an epidemic disease. It has a prevalence of 0·2–2 per cent in the adult population, alone. (Systematic review of surgical treatment of subclinical Cushing's syndrome) However, there is no definite criteria for diagnosing it. Most use the dexamethasone suppression test as a frontline test, but the cut-off criteria for subclinical Cushing's have not been standardized. Subclinical Cushing's is also sometimes called "mild" Cushing's by some.

The article, 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, states:

We have recently described poor sensitivity of a single overnight dexamethasone test in detecting hypercortisolism in patients with mild or episodic Cushing’s syndrome [37]. Thus, our data suggest that current screening tests performed once are inadequate to detect or exclude hypercortisolism in patients with mild or episodic Cushing’s disease.

If there are such epidemic numbers of subclinical Cushing's, seems to me these learned folks need to get together and figure this out.

Cushing's Awareness: Relative Terms used to Define the "Severity" of Cushing's Disease

survivethejourney@gmail.com (RobinS) — Fri, 10 Apr 2015 21:46:00 -0400

There are several terms floated about in the literature/research about Cushing's Disease which try to indicate the severity of the disease. Here, I want to talk about and try to define the terms, then will later post about each so that I can talk about the research involved in each.

Florid: Also termed"classical", it shows evidence of continual or almost continual hypercortisolism. There is a school of thought which says these are really very rapidly cycling forms of Cushing's. However, there does not seem to be a consensus on that in the literature and in the research.
Cyclical: This refers to elevated cortisol levels present at regular intervals. The diurnal pattern is often reversed at regular intervals. In Cyclic Cushing syndrome: definitions and treatment implications, the authors state, "one will observe periodic episodes of “normal” test results. The duration of the cycles has been described as being 12 hours to 86 days".
Subclinical: This is defined by ACTH-induced mild hypercortisolism without typical features of Cushing’s disease, according to this Japanese research.
Mild: patients with Cushing’s syndrome whose cortisol tests were sometimes elevated and sometimes normal, according to this research. Dr. Friedman, et al, believe episodic and mild Cushing's occur together.
Episodic: According to Friedman's research, linked above, episodic refers to "elevated cortisol levels occurring without any temporal pattern."

Cushing's Awareness: When the Gold Standard Becomes Tarnished

survivethejourney@gmail.com (RobinS) — Thu, 9 Apr 2015 09:00:00 -0400

The following is a repeat of an old post, but it still has such relevance, especially when talking about "mild" or subclinical Cushing's Disease/Syndrome. It also is very relevant for cyclical Cushing's.

Urinary Free Cortisol (UFC) testing has long been the "gold standard" for determining the need for more evaluation in the diagnosis of Cushing's Disease/Syndrome (CS). However, recent research belies the paradigm, especially with cyclic/episodic and mild/subclinical CS.

A fairly recent testing protocol, late-night salivary cortisol (NSC), is often touted as a replacement for the late-night serum cortisol. The ease of use at home has made it a practical application for testing cortisol levels. It, too, has limitations in testing for cyclic and/or mild CS.

A third application, the dexamethasone suppression test (DST), is another standard by which practioners evaluate their patients for CS. Again, there are limitations when evaluating cyclic/mild CS.

In a recent study, the full text article examines the three tests mentioned above. They found UFC's were of limited value whe diagnosing "mild" CS.

However, UFC may not accurately reflect the cortisol secretory state in patients with even the modest impairment of renal function (8). In addition, most of the cortisol secreted during a 24-h period is between 0400 h and 1600 h. Subtle increases in nighttime secretion, as may be seen in mild CS, may not be detected or only intermittently detected in a 24-h urine collection.

Notice the majority of the tests fell below the "normal" line on the graph.

In turn, the NSC was more accurate, but there were many "normals" in the results, with multiple repeats with several patients before obtaining a "high" result. The authors speculate this is due to cyclic CS or a "variability around a mildly elevated set point."

Of the 11 patients evaluated, all had surgery, and 10 of the 11 had pathology proven CS. (Sometimes it is hard to get enough sample tissue for a decent pathology with pituitary surgery.)

The DST was evaluated in this same study with those patients who were tested via that means, but not all patients were. However, in another study, the use of the DST was found to be of limited value for those patients with cyclic/mild CS.

These results demonstrate that the great majority of patients with mild and/or periodic Cushing's syndrome suppress to overnight dexamethasone. Since patients with mild and/or periodic Cushing's syndrome are the patients in whom the identification of hypercortisolism is difficult, 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.

It is important to remember that no one test adequately evaluates a patient for Cushing's. Even more important, multiple tests may have to be repeated multiple times. The authors in the first article emphasize this when they say, "Obviously [NSC and UFC ] may need to be performed several times before the suspected diagnosis of endogenous hypercortisolism can be correctly identified."

Still a third study (Findling, et al) says, "Even more problematic is the interpretation of the results of these tests, particularly if they are not in agreement with each other. This is particularly so in mild Cushing's syndrome; if the symptoms are subtle, the biochemical abnormalities are likely to be subtle as well." This is a very long article, chock full of information.

Why is this? Findling lists many reasons, including a study done by Cartagi, et al, where an extraordinarily large percentage of diabetic patients actually had CS. It is often too easy to pin a diagnosis of diabetes or hypertension without realizing it is a symptom.

The recognition of mild/subclinical and cyclic CS has changed the diagnostic approach. Sadly, too many patients are never seen by those who know that.

~~~~~~~~~~~~~~~~~~~~~~

(For more information on how these tests are done, see Testing 101: Biochemical analysis.

For problems/errors to watch for when testing, see When lab tests don't rate an A+, or even a C-..... )

Kidambi, S., Raff, H., Findling, J.W. (2007). Limitations of nocturnal salivary cortisol and urine free cortisol in the diagnosis of mild Cushing's syndrome. European Journal of Endocrinology, 157(6), 725-731. DOI: 10.1530/EJE-07-0424

Cushing's Awareness: Cushing's Awareness Day

survivethejourney@gmail.com (RobinS) — Wed, 8 Apr 2015 10:41:00 -0400

Today is Cushing's Awareness Day. Dr. Harvey Cushing was instrumental in the discovery and diagnosis of the disease. According to the NADF, "Dr. Harvey Cushing first described a woman with signs and symptoms of this disease in 1912, and in 1932 he was able to link the adrenal overproduction of cortisol to an abnormality in the pituitary."

Dr. Cushing was given the title of the father of modern neurological surgery. He developed many of the tools and techniques of surgical practice which are still in use today.

Cushing's Awareness Month: Causes of Cushing's

survivethejourney@gmail.com (RobinS) — Sat, 4 Apr 2015 22:46:00 -0400

Cushing's Awareness Month: Cyclical Cushing's

survivethejourney@gmail.com (RobinS) — Fri, 3 Apr 2015 08:32:00 -0400

Cyclical Cushing's syndrome: an update the full text article says,

"Cyclical Cushing's syndrome is a pattern of hypercortisolism in which the biochemistry of cortisol production fluctuates rhythmically. This syndrome is often associated with fluctuating symptoms and signs. This type of case was initially thought to be rare. It has, however, recently been recognized as occurring much more frequently. The phenomenon is important because it can, if not recognized, lead to errors in diagnosis and differential diagnosis of the syndrome and in assessment of therapeutic outcomes. All of these can have very serious clinical consequences."

Dr. Friedman, et al, in 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

"Periodic or cyclical Cushing’s syndrome refers to elevated cortisol levels present at regular intervals, while episodic Cushing’s syndrome refers to elevated cortisol levels occurring without any temporal pattern. A recent review article suggested that cyclic cortisol production is present in about 20–40 % of patients with Cushing’s syndrome [5]."

Cyclical Cushing's is not understood by many endocrinologists. It was once a controversial condition not accepted by many. However, in recent years, the research has given an acknowledgement of the condition. Dr, Friedman's research, linked above, says, "mild hypercortisolism may be quite devastating to the patient. Thus, we cannot advocate a “tincture of time” approach." This article goes on to recommend multiple, repeat testing for cyclical Cushing's because of the increased variability of cortisol levels. Many endocrinologists do one or two tests (or none at all) and determine evidence of hypercortisolism from that, rather than testing for cyclical Cushing's.

Cushing's Awareness Month: What is Cushing's Disease?

survivethejourney@gmail.com (RobinS) — Thu, 2 Apr 2015 22:00:00 -0400

There are two terms used with Cushing's: Disease and Syndrome. They signify the source 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's Syndrome is hypercortisolism due to an ectopic or adrenal source. There is a third type of Cushing's called iatrogenic Cushing's which results from the overuse of corticosteriod medications.

Cushing's also may have other labels: mild, subclnical, hereditary, episodic, familial, and more. As the month goes on, I'll discuss these. Regardless of the label, the list of possible symptoms is the same.

Cushing's is an endocrine disorder caused by chronic exposure of the body's tissues to excess levels of cortisol - a hormone naturally produced by the adrenal gland. Pituitary adenomas, usually benign, secrete increased amounts of ACTH (adrenocorticotropic hormone), a substance that controls the release of cortisol in that feedback loop, causing production of too much cortisol by the adrenal glands. What are the symptoms? The most common symptoms are:

Striae
Buffalo hump
red-faced all the time
sweaty or hard to control body temp
High blood pressure (often hard to control even with medication)
High blood sugars and/or insulin resistance
Insomnia
Fatigue
Altered diurnal rhythm (See previous post)
Secondary hypothyroidism
Low hormones such as FH, LSH, testosterone, growth hormone
Low Vitamin D
Low ferritin
Unexplained muscle, bone, and joint pain
Easy bruising
Difficulty when drawing blood
Upper body obesity
Muscle weakness
Increased facial hair/body hair (hirsutism)
Loss of hair on head
Loss of menstrual cycle and/or ovulation
Loss of libido
galactorrhea

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

My friend, Kate, who died way too early, made this video with my endocrinologist for a National Geographic documentary explaining Cushing's Disease:

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

Bone loss (osteoporosis), due to the damaging effects of excess cortisol
High blood pressure (hypertension)
Kidney stones
Diabetes
Unusual infections
Hypothyroidism

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

If Cushing's is not diagnosed and treated, there can be extreme, life-threatening complications.

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

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

Cushing's Awareness Month

survivethejourney@gmail.com (RobinS) — Wed, 1 Apr 2015 12:32:00 -0400

April is Cushing's Awareness Month. Bloggers all over the world are joining in to help others become aware. The list of bloggers can be found here, on the right side.

Awareness is vital, because so many people have Cushing's and do not know it. There is a much higher incidence of Cushing's than once thought. According to the authors of the study, "Cushing Syndrome: Maybe Not So Uncommon of an Endocrine Disease",

..[R]ecent studies have suggested a much higher prevalence among high-risk patient populations, such as patients with diabetes mellitus (particularly if poorly controlled), hypertension, and early-onset osteoporosis (particularly if with fractures).8–11 A study that screened 294 patients with type 2 diabetes mellitus and 189 age-, sex-, and BMI-matched controls by their ability to suppress cortisol determined that the prevalence of subclinical hypercortisolism was higher in diabetic individuals than in controls (9.4% vs 2.1%, respectively).10 Interestingly, the patients' hypercortisolism was primarily from an adrenal origin. Two hundred patients with poorly controlled diabetes mellitus (HbA1C >8%) were screened for hypercortisolism and 5.5% were diagnosed with CS, mostly of adrenal origin.9 In a study of patients with osteoporosis without clinically overt hypercortisolism, 4.8% of patients (11 of 219) had subclinical hypercortisolism and the prevalence was 10.8% if they also had a vertebral fracture.11 Finally, among 1020 hypertensive patients, 21 (2.1%) had increased levels of cortisol.1

Along with this, the study"Screening for Cushing’s Syndrome in Obese Patients", concludes "A significant proportion (9.33%) of patients with simple obesity were found to have Cushing’s syndrome. These findings argue that obese patients should be routinely screened for Cushing’s syndrome."

In the complete article "Cyclical Cushing's Syndrome: An Update", the authors state:

"Cyclical Cushing's syndrome is a pattern of hypercortisolism in which the biochemistry of cortisol production fluctuates rhythmically. This syndrome is often associated with fluctuating symptoms and signs. This type of case was initially thought to be rare. It has, however, recently been recognized as occurring much more frequently. The phenomenon is important because it can, if not recognized, lead to errors in diagnosis and differential diagnosis of the syndrome and in assessment of therapeutic outcomes. All of these can have very serious clinical consequences."

In a study done by Catargi, et al, an extraordinarily large percentage of diabetic patients actually had Cushing's.

As the month progresses, I will be sharing more research showing the higher prevalence of Cushing's, as well as other research and how it affects those who have it.

Adrenal Insufficiency United

survivethejourney@gmail.com (RobinS) — Sun, 28 Apr 2013 12:28:00 -0400

Since my bilateral adrenalectomy, I've realized very few medical personnel understand adrenal insufficiency and adrenal crisis. There are many reasons for the above, including a BLA. Some folks are born with it. Others develop it due to an auto-immune malfunction or trauma.

An organization new to me, but probably not so new, Adrenal Insufficiency United, is making a difference in the education of the aforementioned medical folks. They have put out a great educational publication and video for EMT's, doctors, and anyone else who needs to understand the problems with treatment of those with malfunctioning or absent adrenal glands.

Their publication about emergency care touches on just about everything plus relates real-life testimonies. They also have a video which gives great instructions on how to give an Act-o-vial solu-cortef injection (below). Kudos to these folks! Thank you!

Cushing's Awareness Month: Brain Tumors Can Make You Fat

survivethejourney@gmail.com (RobinS) — Tue, 2 Apr 2013 20:55:00 -0400

A while back (years? months?) a group of Cushing's survivors had a discussion about the various steroid replacements available after surgery to treat the disease. Replacement is usually temporary after pituitary surgery unless the whole pituitary is taken or affected. After BLA is another story. A Cushie friend of mine took the data I put together and did a great job analyzing it. Her story:

Which steroid replacement is best?

This blog entry is going to be a little technical in nature, but by the end I hope to explain why it's important to use bio-identical hormones when dealing with diseases like Cushing's that sometimes require replacement of vital-to-life medications. Stick around with me on this one, I promise it will be worth it.

This chart demonstrates what a normal diurnal rhythm looks like. Through most of the night from about 10pm to 6am, your cortisol levels are negligible. Around 6am your body starts to wake up, providing.... (Click here to read the rest of her research.)

Cushing's Awareness Month: Living With Stripes

survivethejourney@gmail.com (RobinS) — Mon, 1 Apr 2013 20:22:00 -0400

April 8 is Cushing's Syndrome (Disease) Awareness Month. April 8 is Awareness Day. Many "Cushie" bloggers will be sharing this month as often as they can. What I would like to do is highlight another blog each day this week so you can see what others out there do.

One of my friends, whom I first met several years ago through our common disease and whom I have now met in "real life", has a fairly new blog called "Living With Stripes". She shares some great info. One of her posts starts out like this:

“Our study shows that BLA (bilateral adrenalectomry) for persistent Cushing's disease provides patients with considerable improvement in their Cushing-related symptoms with concordant increase in their quality of life. After BLA, patients may attain the same (or better) quality of life as patients initially cured by transsphenoidal pituitary tumor resection. We think that BLA is a safe and effective treatment of the 10% to 30% of patients who fail initial therapy for Cushing's disease, and should be considered preferentially over other available therapies” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1877068/

I like that statement!

Today I am 25 days post-op my BLA surgery and my mantra is ‘slow and steady’. I thought I would outline this step of my journey for those who may be considering a BLA as treatment for their persistent Cushings.....
To read more, click here...

Korlym: New drug to treat Cushing's Disease

survivethejourney@gmail.com (RobinS) — Fri, 18 May 2012 10:08:00 -0400

I know several folks who have recently started taking the new FDA-approved drug, Korlym, to treat Cushing's Disease. Korlym is a new name for the "old" drug mifepristone and was developed by Corcept Therapeutics Incorporated.

Korlym blocks the activity of cortisol and is proven to reduce high blood sugar (hyperglycemia), a key symptom of Cushing's. Korlym has a unique way of working. Instead of reducing cortisol levels, it blocks the action of cortisol, thus preventing the effects of excess cortisol.¹

Korlym has many side effects and cannot be taken by everyone. Once the patient stops taking Korlym, she will continue to have Cushing's. The biologic half-life of Korlym is approximately 85 hours. If a patient suffers adrenal insufficiency or crisis, massive amounts of hydrocortisone or dexamethasone are needed to alleviate these and will have to be continued for the duration of the drug in his system.

To follow a patient who has just started taking Korlym, you will find her blog here: Cushing's Disease

Day 29 of the Cushing's Awareness Challenge: Life goes on

survivethejourney@gmail.com (RobinS) — Sun, 29 Apr 2012 17:54:00 -0400

Life goes on...

Life doesn't stop because one gets a rare illness or is diagnosed with a disease. However, mine seems to be delineated by before Cushings, after Cushing's, before BLA and after BLA. Before Cushing's is a gray area. I'm not sure exactly when I started getting symptoms. Some of my symptoms went as far back as childhood but others were more recent when I realized what was wrong with me. I was 47-48 at that time. I'm sure I had symptoms of Cushing's (verified by my photo evidence) from the age of 24.

Skipping ahead past those years between ages 47 and 52 when I was going through testing, diagnosis, pituitary surgery to remove the tumor, recurrence, and re-testing/diagnosis though my BLA, I am in the after BLA era. Does anyone else see her life this way? I know most folks look at graduation, job, marriage, children, etc. as the defining moments of their lives. And my children, plus my grand-child, are definitely more important to me, but I still categorize them in the pre-BLA/post-BLA eras.

Isn't it crazy that one event can be so momentous in one's life? I sit here typing this after a day of being lonely and wishing I was closer to my family and my grandson. Part of me wants to make the big leap and just "do it". Life is short. Just do it. The other, conservative part of me says, "You have to make it to retirement. You have to have something to live on and you don't want to lose this money." And once I do this, which I will someday, I know it will be a defining moment and I'll classify it post-move. I think that's a good thing. I'm tired of living my life around a disease.

Day 28 of the Cushing's Awareness Challenge: Getting it right...

survivethejourney@gmail.com (RobinS) — Sat, 28 Apr 2012 14:38:00 -0400

The Cushing's Awareness Challenge is winding down, and I haven't posted every day. I have tried to post at least twice a week. I have been so busy with work plus dealing with allergies I haven't had time or felt like posting when I have time.

I do believe my allergies are worse since my BLA. Perhaps the high cortisol treated them? I don't know. I do know this spring allergens are worse in my area than they usually are. Everything seemed to bloom and spout pollen all at once.

Someone asked me the other day why we are so concerned about awareness for Cushing's. "Isn't is a really rare disease?"

"No", I said, "It's just rarely diagnosed."

And there is research to back up my statement. One recent research article is one you should take to your doctor if you believe you have Cushing's. It talks about the reality of testing for Cushing's Disease/Syndrome and that it requires a lot of testing. One can have a lot of normal tests and still have Cushing's.

As I go through my daily life, I see a lot of people who have the signs of Cushing's. It's a daily conundrum deciding whether to approach a person about it or not. Many times when I have, I've been met with cynicism or been ignored totally. Other times, folks want information. A few times, I've been contacted by these saying either a) my doctor thinks I'm full of it or b) my doctor thinks you may be right but doesn't know what to do from here. It's tough, having this disease. Although there are a lot of textbooks for doctors describing how to test and diagnose, so many of us aren't truly textbook cases. That's the problem with textbooks. They are a "one size fits all" type of diagnosis/testing. We come in all sizes, shapes, and genders. We don't fit the textbook mold. Slowly, the textbooks are changing. Recent research is changing how doctors test and diagnose. In my opinion, it's going to take another generation or two of doctors to really get it right. Until then, many people won't be diagnosed and treated.

Day 24 of the Cushing's Challenge: When the "gold standard" becomes tarnished....

survivethejourney@gmail.com (RobinS) — Tue, 24 Apr 2012 20:18:00 -0400

However, UFC may not accurately reflect the cortisol secretory state in patients with even the modest impairment of renal function (8). In addition, most of the cortisol secreted during a 24-h period is between 0400 h and 1600 h. Subtle increases in nighttime secretion, as may be seen in mild CS, may not be detected or only intermittently detected in a 24-h urine collection.

Notice the majority of the tests fell below the "normal" line on the graph.

Of the 11 patients evaluated, all had surgery, and 10 of the 11 had pathology proven CS. (Sometimes it is hard to get enough sample tissue for a decent pathology with pituitary surgery.)

These results demonstrate that the great majority of patients with mild and/or periodic Cushing's syndrome suppress to overnight dexamethasone. Since patients with mild and/or periodic Cushing's syndrome are the patients in whom the identification of hypercortisolism is difficult, 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.

How important is it to screen for "mild" CS? "Mild" is a misleading term, sometimes more appropriately called subclinical CS. Findling, et al, point out a huge population where CS is generally overlooked and the depressing mortality for those same folks.

Dr. Theodore Friedman, et al, , in their research 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 point out no one test is conclusive for testing for Cushing's Disease/Syndrome:

The probability of having Cushing’s syndrome when one test was negative was 92 % for 23:00 h salivary cortisol, 88 % for 24-h UFC, 86 % for 24-h 17OHS, and 54 % for nighttime plasma cortisol. 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.

Why is CS generally overlooked, then? Findling lists many reasons, including a study done by Cartagi, et al, where an extraordinarily large percentage of diabetic patients actually had CS. It is often too easy to pin a diagnosis of diabetes or hypertension without realizing it is a symptom.

The recognition of mild/subclinical and cyclic CS has changed the diagnostic approach. Sadly, too many patients are never seen by those who know that. And most of all, there really is no such thing as "mild" Cushing's. It damages the body just as much as "florid".

~~~~~~~~~~~~~~~~~~~~~~

(For more information on how these tests are done, see Testing 101: Biochemical analysis.

For problems/errors to watch for when testing, see When lab tests don't rate an A+, or even a C-..... )

Day 23 in the Cushing's Awareness Challenge: Why do we overeat? Underexercise? Is it a matter of willpower?

survivethejourney@gmail.com (RobinS) — Mon, 23 Apr 2012 21:37:00 -0400

I'd like to talk to you a bit about what it is like with Cushing's high cortisol surging through one's system and the hunger it brings.

Have you ever been on steroids for anything? Do you remember the hunger you felt on them? That's all I remember feeling in my life prior to my bilateral adrenalectomy. I have always been hungry. Ok, let me clarify "always". Let's say 80% of my life I was hungry. Between the flu and what I now know were "lows*", I had periods of no hunger. But for the most part, I was somewhere between stomach-growling hungry to ravenous, bite-my-arm-off hungry.

Does that mean I had no willpower? No. I managed, with the help of my very nutritionally wise mother, to stay at a normal weight even through college. I did put on the freshman 15 in my sophomore year of college, but also managed to lose it by essentially living on caffeine and a diet of books. (Study, that is.) Labs are not good places to eat, and I basically lived in one.

Was that easy? NO! I confess to binge eating at times. I don't think I ever purged. I don't remember doing that. I was so absolutely hungry and nothing would sate my appetite. Nothing. I know my mother knew it, too. I remember slipping into the kitchen when I was small and "stealing" bread or crackers hoping she wouldn't notice. She never mentioned it, but she was sharp. She knew. I would panic at the thought of not being able to have food even at a young age.

Snacks were forbidden when I grew up unless we picked an apple off the tree or a tomato out of the garden. We ate three nutritional meals a day, drank skim milk, and lived outside. Yes, I exercised. Only we called it "play", then. Bicycles were star ships and swings were space stations. Lightening bugs were made by God to be chased. Dusk was a time for hide-and-seek. But I digress...

After college and graduate school, I got married. Had babies. Couldn't lose weight. You can read all about that in Metamorphosis. The thing is, I was hungry all the time. But I DID NOT EAT all the time. Sure, it absolutely possessed my every thought, my every action and my every plan. I had to know food was available even if I didn't eat it. And yes, sometimes I lost control and I overate. I wanted so much to be free of that obsession with food.

I managed to lose that obsession one time on phentermine. However, I started gaining weight even then. I was in a "low*", either induced by the phentermine or just coincidentally, prior to that gain. I vote for the latter.

My disease accelerated. I became "florid" or "classical" as my neurosurgeon coined it. I daily went from periods of nausea in the morning to periods of starvation by afternoon. Ok...it felt that way. I WANTED FOOD! I wanted to EAT! But did I? Most of the time, no. I counted calories, I measured food, I watched my carbs, I measured fat grams, I ate high fiber, I tried to exercise.

Let me emphasize: I TRIED to exercise. Have you ever walked through mud? How about walking in the waves in the ocean? That's how my legs felt when I tried to do anything. That started a long time ago, but I persisted in trying to build them up. Even when I was at my worst before my first surgery to remove my pituitary surgery, I did water aerobics and/or swam several times a week. I did that until the pain became unbearable. I even hired a trainer who eventually told me something was very wrong with me because I could not build muscle.

Did I lack willpower? I don't think so. Only a few people know the magnitude of the will it took to find someone to help me, understand me, diagnose me and get me on the road to recovery. I fought hard every day to lose weight. I fought hard to get well. I fought hard to live! To work! To be here for my daughters, my grandson, my brother, and my parents. I fought the "establishment" called medicine, too. And I still fight for all that. And I am not alone. Zebras do exist.

I am no longer hungry for food. Since my BLA in June 2010, I can exercise plus I am seldom starving. I often have to remind myself to eat. I am hungry for understanding, however. Not just for me, but for all who fight as I do for others to see beyond the obesity to the true problem of Cushing's Disease/Syndrome.

*"lows": periods in the cycle of cyclic/intermittent/episodic Cushing's where cortisol is low.

Day 21 of the Cushing's Awareness Challenge: eHow doesn't know how...

survivethejourney@gmail.com (RobinS) — Sat, 21 Apr 2012 14:11:00 -0400

A must read on another blog, Brain Tumors can make you Fat!, points out the problem with eHow's information on Cushing's Disease/Syndrome.

The title of your article is "How to Avoid Cushing's Disease." So, in your expert opinion, how does reducing your salt intake prevent a disease that is caused by an overproduction of cortisol? Could you please cite your source for your readers on what tells you avoiding salt will help a person avoid hypercortisolemia?

You don't want to miss this.

Day 18 of the Cushing's Awareness Challenge: Fiona Apple may just have it right...

survivethejourney@gmail.com (RobinS) — Wed, 18 Apr 2012 22:05:00 -0400

He said 'It's all in your head' and I said 'So's everything' but he didn't get it --Fiona Apple in "Paperbag".

Pituitary tumors have a large spectrum pathology. These "little buggers" may cause large problems, also. Dr. Shereen Ezzat of the Toronto Cancer Institute has been studying pituitary tumors for several years, and presents the case for epigenetic disruption of gene expression which causes alterations of normal pituitary cells. Using the information he and others have gathered, he is hopeful treatments for these lesions/tumors can be developed. Since the morbidity/mortality of most with pituitary tumors is greatly increased, and the only long-term therapies so far are surgical or radioactive, improved treatment is anxiously sought by those of us with Cushing's or presently in remission.
According to Dr. Ezzat, pituitary tumors comprise 10% of the tumors surgically removed intercranially with increased morbidity due to invasion of surrounding structures. As a Cushie community, we know this only too well first-hand. All too often the only recourse for the hypercortisolemia due to ACTH producing tumor cells is a bilateral adrenalectomy. Radiation is often a secondary treatment to decrease tumor growth or Nelson's syndrome.
In another article, Dr. Ezzat says, "Some pituitary adenomas grow rapidly, producing symptoms of an intracranial mass, loss of normal anterior pituitary hormone production, and visual-field disturbances due to stretching of the overlying optic chiasm. They can invade downward into paranasal sinuses, laterally into the cavernous sinuses (thereby disrupting coordinated eye movement) and upwards into the brain. They can cause death by invasion of the brain."
But size does NOT always matter with these tumors. Dr. Ezzat also says "they can cause mood disorders, sexual dysfunction, infertility, obesity and disfigurement, hypertension, diabetes mellitus and accelerated heart disease. If untreated, hormone-excess syndromes can be lethal."
In the pre-print, recent article, Epigenetic Control in Pituitary Tumors , Dr. Ezzat discusses epigenetically-mediated gene dysregulation as a cause for the production of pituitary tumors. He explores the role of fibroblast growth factors and histone gene silencing and discusses the implications of the need to find the process or mechanism involved in order to develop new therapies.

Shereen Ezzat, M.D. (2008). Epigenetic Control in Pituitary Tumors Endocrinology Journal DOI: http://dx.doi.org/http://www.jstage.jst.go.jp/article/endocrj/advpub/0/0804240101/_pdf

Day 17 of the Cushing's Awareness Challenge: Adrenalectomy Improves Quality of Life for Cushing's Patients Although It May Take Years

survivethejourney@gmail.com (RobinS) — Tue, 17 Apr 2012 17:51:00 -0400

Although adrenalectomies are only a first-line treatment for those with ACTH-independent tumors in Cushing's Syndrome (ectopic and adrenal tumors, benign and malignant), they are also often a treatment for those with Cushing's Disease when pituitary surgery fails to totally remove the source of excess ACTH.

Hypercortisolemia, the result of excess ACTH from the pituitary or from overproduction in ectopic or adrenal tumors, is very debilitating for those who suffer from CS/CD. According to the authors, "Untreated Cushing’s syndrome can cause significant physical and mental morbidity and mortality, with a mortality rate in untreated that is 4 times greater than the baseline population."

This study looked at the outcomes of 60 patients who underwent either a unilateral (53%) or bilateral adrenalectomy (47%) to treat their Cushing's. Except for one patient, all adrenalectomies were done laproscopically. The median follow-up time was 41.4 months. At that median time, 9 patients had died. 4 patients had died from the progression of malignant disease, 2 from unknown causes, 1 from pulmonary embolus 2 months after surgery, and 2 five months post-op from severe complications due to pituitary (ACTH-dependent) Cushing's Disease.

Around 75% of the common physical signs/symptoms of Cushing's resolved after surgery, but the central obesity only had a resolution rate of 57%. Diabetes was cured in 79%, hypertension "improved dramatically or was cured in 67%."

Symptoms took anywhere from a few weeks to 4 years to resolve with most of the physical changes resolving in a mean of 7-9 months. There was a great variability with no good predictor of this variability.

The remark that I find so telling is this:

In fact, we had several patients with ‘‘subclinical’’ Cushing’s who took over 2 years for their symptoms to resolve.

Too often those of us who suffer with Cushing's are told to wait until the disease "gets worse" before being diagnosed/treated.

The authors point out the complication rates which are typically higher for Cushing's patients than for others who undergo adrenalectomies for whatever reason. Immunosuppression leads to greater risk of infection. Addisonian crisis is another prevalent complication. However, overall they conclude that adrenalectomies are a safe and effective treatment option, but both physicians and patients must not expect overnight improvements. This is another case of where slow and steady wins the race.

R SIPPEL, D ELARAJ, E KEBEBEW, S LINDSAY, J TYRRELL, Q DUH (2008). Waiting for change: Symptom resolution after adrenalectomy for Cushing's syndrome Surgery, 144 (6), 1054-1061 DOI: 10.1016/j.surg.2008.08.024

Day 16 of the Cushing's Awareness Challenge: When lab tests don't rate an A+, or even a C-.....

survivethejourney@gmail.com (RobinS) — Mon, 16 Apr 2012 22:17:00 -0400

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 one gets into the current research, combines the complexities ofmild/episodic/cyclic Cushing's with florid/classical (you know...the CIA operative "thang" I've mentioned before), and then adds a ~~dash~~ ton of no-one-uses-the-same-protocols, no wonder it gets confusing.

The Urinary Free Cortisol (UFC) test has long been touted as the "gold standard". 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 timing from there and collect every single pee-pickin' drop (I know...it's "pea"...couldn't resist) for those 24 hours, ending at the same time you started. What happens to that urine is the big debate, both before and after collection. My endocrinologist and at least two other major endocrinologists who are experts in the field recommend refrigeration if it's not going to the lab immediately (and possibly even then) but NO PRESERVATIVE.

Well, getting labs to agree to that is like the debacle in D.C. right now over Medicare. It ain't gonna happen. The absolute no-no that I've been told over and over is hydrochloric acid (HCl) as a preservative. Boric acid is accepted by most labs. Acetic acid is mentioned occasionally. In a study done by ARUP Institute, they found "Cortisol concentrations in samples stored with the acids were higher by 30% than in samples stored without acid, possibly as a result of partial hydrolysis of sulfate and glucuronide conjugates. " Esoterix, the diamond of endocrine labs, prefers no preservative at all.

What is a UFC measuring anyway? Well, "free" cortisol is used by the body for various functions, but the thought behind the test is that this free cortisol is spilled into the urine if there is excess. One can get into the effect of cortisol binding globulin (CBG) and all sorts of other scenarios which make that not true for many folks, but I won't in this post. So, if there is excess free 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 of creatinine in the urine, and many want to also test 17-hydroxycorticosteriods (17-OHC's). When that is the case, now the lab protocol must include them and determine if a preservative and which preservative is necessary or optional.

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

I can tell tales about labs and how they handle this urine. Bacteria degrade the cortisol quickly at room temperature, and getting a lab to refrigerate it is a crap shoot (pee shoot?). You hope they will but often they don't. Measure/aliquoting a correct sample is another problem if there is more than one jug for a collection. I often collected more than one jug when my cortisol was high. 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.

Some won't accept the collection if it doesn't have the what the person who is working at that time thinks is the correct preservative. I've been known to leave with my jugs in tow, call the lab manager, and go back when s/he is there. God forbid my hard work is wasted. Sadly, I have many friends with Cushing's who have had collections wasted due to inadequacy and nonunderstanding of proper protocols. Not MISunderstanding, mind you. NONunderststanding.

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

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

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

An awake midnight concentration of cortisol in plasma of more than 207
nmol/L differentiates between Cushing’s syndrome and other causes of
hypercortisolaemia 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. The research and leading endocrinologists acknowledge the validity of midnight serum cortisols, also. So, as I said 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. The midnight value should be close to zero.

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

As for the bloodwork itself, it should be drawn into a red-top or green-top tube. However, all is not lost if another tube is used. Most of the time, it can be used anyhow for this test. Temperature really isn't a factor if the test is run in a timely manner. The serum needs to be separated from the cells and the sample cannot be anticoagulated. If it's not run within an hour, this should be done and the serum refrigerated up to 24 hours or frozen if longer.

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

The salivary cortisol test is another test used very similarly to the serum cortisol tests. It, too, can help show diurnal rhythm (or lack thereof). The protocol is pretty simple and straight-forward regardless of the lab. There are only a few labs who use an FDA approved test for these salivary cortisol levels. The labs are Esoterix, ACL Laboratories, LabCorp (who now owns Esoterix), and Quest. It is very easy for a doctor to set 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 rinse the mouth for thirty minutes prior to collection.

A word of caution. Although the cortisol supposedly does not break down very quickly, a number of us got much higher results when we first froze the samples, then shipped them overnight. Since bacteria will break down cortisol, it stands to reason this can happen with the salivary test, too.

Another inconsistency with salivary cortisols that many of us have observed is that we have had high serum cortisols the same nights we have done salivary cortisols. I did several while sitting and having blood drawn. My serum cortisol was high. My salivary cortisol was "normal". Only when my serum cortisol (at midnight) was around 16 μg/dL or higher did my salivary cortisol show high levels, too. The clearance is different, 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 you can'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) that is paying for a service to be done right. You may need to catch that high and you don't want anyone to mess it up.

Call the lab ahead of time and speak with the lab manager. Explain your situation courteously and ask if they are familiar with the tests and protocols. Go over them together, talk about when you will be in, and what you need to do to make sure those protocols are followed. This will save you many headaches 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 goes further than anger. However, I've been known to use some of that southern "charm" my mother taught 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 at midnight. Get the paperwork done ahead of time so you can go in and get it done quickly once you are there.

A little kindness goes a long way. A treat, some cookies, a gift basket or something simple as a cake shared with the lab folks occasionally will brighten their day. The late-night lab I used was full of readers. I saw good books everywhere, so I took in a stack every now and then after I'd finished them along with some candy or something.

Say thank-you when it is done right. Again, that goes a long way.

Don't be surprised if drawing blood is difficult. If you are one of the Cushies who has issues with that due to the affect of the cortisol on the veins, try to keep your arms warm and stay hydrated. My blood draws were very difficult on the best of days, and I was prepared for that. Warm bags of rice, a warm fleece jacket, or whatever it takes to keep those arms warm are helpful.
Well, the report card isn't in on the labs, yet, because the rubric hasn't been standardized, but you get an A for effort!!!

I apologize for missing a few days. I was just too busy, which is a delight unto itself.