Be sure that your correct mailing address is included with payment along with a contact phone number in case we have questions concerning your order.

If anyone has any questions concerning cookbook payments please contact CUSH Treasurer Cathy Gifford at CUSHOrg@aol.com

Updated Pages on the Website:
• Fun Games to play online.

• Testimonials:
http://www.cushings-help.com/testimonials.htm

"I hope you know how indispensable you are to a multitude of us who have suffered with Cushing's. You have to come through this and live a long life and find someone who will happily inherit the amazing tasks you perform...and then enjoy your retirement for a good long while!

Your webpage is so rich in support. No matter what link you click, there is important information and compassionate human company."

~ Dr. Dori Middleman

• Helpful Hints for Dealing with Cushing's: http://www.cushings-help.com/helpful_hints.htm

• News Items:

General Cushing's Info:

• From http://www.medscape.com/viewarticle/440104

Is the "Metabolic Syndrome" a Mild Form of Cushing's Syndrome?
The Curious Story of 11beta-Hydroxysteroid Dehydrogenase
Disclosures

Ashok Balasubramanyam, MD
Could a Single Defect Trigger Syndrome X?
"Syndrome X," or the "metabolic syndrome," originally described by Gerald Reaven, MD, has now expanded to include a cluster of at least 5 highly prevalent disorders: hypertension, dyslipidemia, diabetes, visceral obesity, and polycystic ovary syndrome (PCOS). Its enormous medical, social, and economic impact has stimulated several fields of research into its causes and treatment.

One intriguing question is: Could a single primary defect trigger a cascade of diverse events leading to these apparently disparate metabolic, cardiovascular, and reproductive defects? Since Cushing's syndrome also encompasses many of these disorders, it is worthwhile considering whether the metabolic syndrome could be a "forme fruste" of Cushing's. Circulating glucocorticoid levels are not elevated in persons with the metabolic syndrome; however, could it be possible that the corticosteroid action occurs at a local level, giving rise to the effects of excess glucocorticoid receptor stimulation in a tissue-restricted manner without elevating plasma levels of glucocorticoids?

From Curiosity to Central Player
About 2 decades ago, Stanley Ulick, MD, described a syndrome characterized by hypertension and hypokalemia and reminiscent of hyperaldosteronism. The cause, however, was not a primary defect in the renin-angiotensin-aldosterone system but an inactivating mutation in the enzyme 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2). This syndrome, which could also be reproduced by the consumption of licorice (the offending ingredient is glycyrrhizic acid), was due to the fact that 11beta-HSD2 normally converts cortisol to its biologically inactive congener cortisone in the kidney and placenta, thus protecting the mineralocorticoid receptor in renal tubules from excess stimulation by cortisol. (The mineralocorticoid receptor can be activated by glucocorticoids as well.) With a nonfunctional 11beta-HSD2 enzyme, patients with the mutation or consumers of potent licorice had excess stimulation of mineralocorticoid receptors by glucocorticoids, resulting in a syndrome of "apparent mineralocorticoid excess (AME)."

For a while, this syndrome and the enzyme at its basis remained in the realm of endocrine exotica. Recent investigations, both in humans and in mice, have returned it and its twin, 11beta-HSD1, to the limelight as possible players in the complex pathophysiology of the metabolic syndrome. A topical symposium at ENDO 2002 entitled "The Adipocyte as a Steroid Factory," as well as numerous abstracts, presented new, intriguing findings in this field.

Knockout Models of 11beta-HSD1 and HSD2
The group led by Professor John Mullins,[1] University of Edinburgh, Scotland, has engineered mice with homozygous deletions of either 11beta-HSD2 or 11beta-HSD1. Professor Mullins presented the physiologic and biochemical phenotypes of these mice. Not surprisingly, the 11beta-HSD2 knockout animal -- being unable to convert potent circulating 11-hydroxy glucocorticoids to their inactive 11-dehydrogenated forms in renal tubular cells -- has hypertension and hypokalemia, together with suppressed plasma renin and aldosterone. Less predictably, it also manifests renal tubular hyperplasia and hypertrophy, as well as aortic dissection (perhaps a manifestation of early-onset, severe hypertension).

The 11beta-HSD1 knockout animal has a different phenotype, reflecting the fact that this enzyme normally functions as the reverse of 11beta-HSD2, converting inactive cortisone to active cortisol within cells in the liver, adipose tissue, and brain. Lacking the ability to perform this localized glucocorticoid "re-activating" biochemical conversion, the 11beta-HSD1 knockout mouse is resistant to glucose intolerance when fed a high-fat diet. It also weighs less than its wild-type littermate despite eating more, and has a higher resting metabolic rate. Interestingly, wild-type mice downregulate 11beta-HSD1 expression in adipose tissues in response to high-fat feeding, indicating that this enzyme is subject to regulatory feedback by alterations in energy balance. Together, these findings suggest that an improperly regulated increase in 11beta-HSD activity or expression in liver, fat cells, or brain might contribute to the tendency to develop several features of the metabolic syndrome, such as visceral adiposity, hypertension, and insulin resistance.

Tissue-Specific Effects in the Liver and Adipose Tissues
Since an increase in 11beta-HSD1 expression or activity would be expected to have "localized" rather than systemic effects, in which of these organs -- liver, adipose tissues, or brain -- does the presence of an abnormal enzyme give rise to more generalized metabolic changes? Professor Mullins' group described the effects of liver-specific overexpression of 11beta-HSD1,[2] while Jeffrey Flier, MD,[3] of the Beth Israel Deaconess Medical Center, Boston, presented his group's data on adipocyte-specific overexpression of 11beta-HSD1.

Overexpression of 11beta-HSD1 in the liver resulted in transgenic mice that had fatty livers and elevations in serum cholesterol and triglycerides, but only mild insulin resistance (normal glucose tolerance with mildly elevated plasma insulin levels). Interestingly, these mice developed hypertension, a key component of the metabolic syndrome. The mechanism likely to be responsible for the development of hypertension is increased intrahepatocyte glucocorticoid activity, which leads to increased expression of the angiotensinogen gene, which would upregulate the activity of the angiotensin-aldosterone system.

Dr. Flier and colleagues reasoned that adipocyte-specific overexpression of 11beta-HSD1 might produce a phenotype that would include additional components of the metabolic syndrome, such as visceral obesity. This hypothesis was based on the knowledge that visceral compartment adipocytes normally have greater expression levels of both 11beta-HSD1 and glucocorticoid receptor than do subcutaneous adipocytes.

The physiology and biochemistry of the adipose-11beta-HSD1 transgenic animals confirmed their hypothesis. As described by Dr. Flier (and reported previously in a paper in Science[4]), their body weight was increased from an early age, and this was associated with a significantly greater increase in mesenteric fat depots compared with subcutaneous or epididymal fat depots. Associated with these changes were increased concentrations of cortisol within adipocytes, but not in the systemic circulation. The blood did, however, contain elevated levels of other markers of the metabolic syndrome: free fatty acids, triglycerides, glucose, and insulin. Notably -- and unlike the liver-specific 11beta-HSD1 transgenic mice -- these animals had a pronounced tendency to develop frank diabetes with advancing age or when fed a high-fat diet. Further evidence that increased adipocyte glucocorticoid signal transduction was occurring was seen in altered patterns of adipose gene expression, as these mice had decreased circulating levels of both adiponectin and resistin. Importantly, from the standpoint of understanding the pathophysiologic cascade leading to these 2 metabolic syndrome components, the adipocyte-specific11beta-HSD1 animals, like the liver-specific 11beta-HSD1 transgenic mice, also developed fatty livers and hypertension. The hypertension appears to be associated with increased expression of the glucocorticoid-dependent angiotensinogen gene in adipocytes, with increased circulating levels of angiotensin II and aldosterone.

These remarkable findings suggest a paradigm whereby tissue-specific "apparent glucocorticoid excess," in the face of a normal hypothalamic-pituitary-adrenal axis, could produce the metabolic syndrome. The HPA axis produces normal levels of serum cortisol, which is normally converted by 11beta-HSD2 into inactive cortisone in adipocytes and the liver. However, abnormally increased activity of 11beta-HSD1 in the liver or adipocytes causes excess reconversion of cortisone to cortisol within these tissues, leading to the inimical tissue-specific and downstream metabolic effects of excessive glucocorticoid activity.

A Hypothesis for the Metabolic Syndrome in Humans?
Dysfunction of 11beta-HSD1 thus provides a persuasive, unifying, even causal hypothesis for the metabolic syndrome. But, except in the situation of a clearly definable gene defect, does this happen in humans, and, if it does, is the dysfunction a cause or an effect of the metabolic syndrome?

It is difficult, as always, to find causal links between putative functional molecular defects and phenotypic outcomes in human pathophysiology, but it is interesting to note that there may be associations between 11beta-HSD activity and expression and some components of the human metabolic syndrome. Professor Paul Stewart of the University of Birmingham, United Kingdom, who first suggested in a provocative paper[5] that the metabolic syndrome might represent "Cushing's disease of the omentum," presented data[6] that suggest that several such associations may exist.

Professor Stewart's group has amassed a large repository of paired human adipose tissue samples from subcutaneous and visceral compartments, together with an extensive clinical and metabolic database. Professor Stewart pointed out that the 11beta-HSD paradigm for the metabolic syndrome may prove to be useful clinically because of the strong correlation between the severity of known mutations in 11beta-HSD and their phenotypic expression. For example, the severity of the enzymatic defects in 11beta-HSD2 determines the severity of illness in patients with the homozygous form of congenital "apparent mineralocorticoid excess"; heterozygotes have a milder disease, and it is possible that persons with salt sensitivity represent an even milder form of the same syndrome. Biochemical studies in the paired human adipose tissue samples confirmed that 11beta-HSD1 activity is higher in adipocytes from the omental region than in adipocytes from subcutaneous sites, both basally and when treated with cortisol. There was also a corresponding increase in lipid accumulation in the omental cells.

The investigators then addressed the hypothesis that 11beta-HSD1 activity might be increased in persons with visceral obesity. As a surrogate for 11beta-HSD1 activity, they measured the ratio of cortisol to cortisone in the urine in subjects with and without visceral obesity. However, the results of this "global" index of 11beta-HSD1 activity did not support the hypothesis, since this ratio fell rather than rose in the obese subjects.

The investigators then attempted to look at tissue-specific effects with assays that indirectly probe the physiologic action of 11beta-HSD1 in the liver or adipocytes. First, they infused subjects with cortisone acetate and measured its conversion to cortisol, a function expected to be carried out by hepatic 11beta-HSD1. The results showed a lower, rather than higher, rate of conversion in the obese. To measure 11beta-HSD1 effects in adipocytes, they quantified the mRNA for 11beta-HSD1 as well as enzyme activity in omental fat samples. Again, these measures were inversely, rather than directly, correlated with fatness.

At face value, the results of these difficult human experiments would appear to refute the "overactive 11beta-HSD1" hypothesis. However, they could also be suggesting the existence of a compensatory downregulation of 11beta-HSD1 enzyme activity as a result of having achieved a critical level of visceral obesity.

Proof of the "overactive 11beta-HSD1" concept in humans is perhaps better tested in persons with congenital defects in 11beta-HSD1 activity. Professor Stewart presented the results of his group's investigations[7] of 8 women with mutations in the 11beta-HSD1 gene who appeared to have a total block in the conversion of cortisone to cortisol. These patients have a syndrome resembling PCOS, with elevated circulating androgens and variable increases in body mass index. The hyperandrogenic polycystic ovary condition could be due to diminished negative feedback to the pituitary by an excess of circulating cortisone compared to cortisol, leading to hyperstimulation of the androgenic steroid synthetic pathway in the adrenal cortex. Since PCOS is one component of the metabolic syndrome, this is at least a partial vindication of 11beta-HSD1 as a candidate initiator of the pathophysiology of the metabolic syndrome. Professor Stewart and colleagues are looking into other potential examples of 11beta-HSD11-related phenotypes, for example, in persons with a cluster of 3 polymorphisms in the intron of the gene for 11beta-HSD1.

A Therapeutic Future?
Whether 11beta-HSD defects hold out as important and common mediators of insulin resistance, visceral obesity, hypertension, and PCOS awaits further investigation, both in humans and in animal models of these conditions. Pharmaceutical companies, however, are not waiting for definitive evidence, as there is much active research already being directed at 11beta-HSD-1 and -2 as key therapeutic targets. The future is clearly exciting for further pathophysiologic, diagnostic, and therapeutic insights arising from the study of these unusual steroid-regulating enzymes.

References
Mullins J. Insights into steroid production and adipocytes from knockout models of HSD-1 and -2. In: Symposium: The adipocyte as a steroid factory. Program and abstracts of the 84th Annual Meeting of The Endocrine Society; June 19-22, 2002; San Francisco, California.
Paterson JM, Holmes MC, Morton NM, Seckl JR, Mullins JJ. Liver-specific over-expression of 11beta-HSD1 in transgenic mice produces insulin resistance, hyperlipidaemia and fatty liver. Program and abstracts of the 84th Annual Meeting of The Endocrine Society; June 19-22, 2002; San Francisco, California. Abstract P2-319.
Flier JS. Overexpression of 11 beta HSD-1 in adipose tissue produces visceral obesity and the metabolic syndrome in mice. In: Symposium: The adipocyte as a steroid factory. Program and abstracts of the 84th Annual Meeting of The Endocrine Society; June 19-22, 2002; San Francisco, California.
Masuzaki H, Paterson J, Shinyama H, et al. A transgenic model of visceral obesity and the metabolic syndrome. Science. 2001;294:2166-2170.
Bujalska IJ, Kumar S, Stewart PM. Does central obesity reflect "Cushing's disease of the omentum"? Lancet. 1997;349:1210-1213.
Stewart PM. Clinical consequences of 11beta-hydroxysteroid dehydrogenase in humans. In: Symposium: The adipocyte as a steroid factory. Program and abstracts of the 84th Annual Meeting of The Endocrine Society; June 19-22, 2002; San Francisco, California.
Draper N, Lavery GG, Bujalska IJ, et al. Apparent cortisone reductase deficiency and 11beta hydroxysteroid dehydrogenase type 1: a monogenic cause of polycystic ovary syndrome. Program and abstracts of the 84th Annual Meeting of The Endocrine Society; June 19-22, 2002; San Francisco, California. Abstract P2-495.

• From http://bioanalyticalscience.blogspot.com/2006/11/microbiology-experiment-protocol-set-4.html

Microbiology Experiment Protocol SET 4

ENZYMATIC METHOD FOR GLUCOSE ESTIMATION
Aim: To detect the blood glucose concentration by an in vitro enzymatic colorimetic
method.

Introduction:
Estimation of glucose in blood is done to detect any disorder in glucose metabolism, mainly diabetes. Glucose is formed from the digestion of carbohydrates and is converted to glycogen in liver. Glucose metabolism is regulated by various hormones like glucagon, insulin, adrenalin, thyroxine and epinephrine. Therefore the test for blood glucose is used as a screening Procedure / Protocol / Method to detect disorders of metabolism which may be the result of one
of several causes:
1) Inability of the islet cells of the pancreas to produce insulin.
2) Inability to the intestine to absorb glucose.
3) Inability of liver of accumulate and breakdown glycogen.
4) The presence of increased amounts of hormones (i.e. ACTH)

In most cases a degree of elevated blood sugar (hyperglycemia) indicates diabetes. The confirmation of the disease should be made by glucose tolerance test. Other conditions which may lead to increased blood glucose levels are:
1) Cushing's disease.
2) Acute stress (such as myocardial infarction or severe infections like meningitis, encephalitis.
3) Pituitary edema.
4) Hyperthyroidism.
5) Adenoma of pancreas
6) Pancreasitis.
7) Brain trauma or brain damage.
8) Chronic liver disease.

Lower levels of glucose (hypoglycemia) may result due to:
1) Overdose of insulin
2) Addison's disease
3) Bacterial sepsis
4) Islet cell carcinoma of pancreas (secretes excessive amount of insulin).
5) Hepatic necrosis.
6) Hypothyroidism.
7) Glycogenstorage disease
8) Psychogenic causes.

Estimation of blood glucose level after 2 hrs after meal, known as post prandial test, is an excellent screening test for diabetes. Glucose concentration in a fasting blood and specimen obtained 2 hrs after a meal is rarely elevated in normal individuals, but is significantly increased in diabetic patients.

Normal Values: Fasting serum - 70 to 110 mgs/ 100 ml.
2 hrs PP - less than 145 mgs/ 100 ml.
CSF (Non diabetic) : > 50mg/100ml
(50-70 mg/100ml)
Abnormal Values: Above the normal values in conditions mentioned above. Smoking
may raise the blood glucose level.

Principle:
Enzymatic methods for the determination of sugars are of advantages over chemical methods in that
1) They are far more specific
2) They can be used to follow reactions in which sugar is liberated and
3) They allow the determination of sugar in the presence of protein

Free glucose can be determined by glucose oxidase (Beta D-glucose oxygen oxidoreductase- l, l,3,4) obtained from the media of Penicillium notatum. This enzyme has an extremely marked affinity and specificity for glucose. The glucose 136 dehydrogenase from liver, which requires pyridine nucleotides has a much lower affinity for glucose and cannot be used for a quantitative assay. Another enzymatic Procedure / Protocol / Method for the detection of glucose is to use yeast hexokinase and then spectrophotometrically measure the glucose-6-PO4 with the glucose-6-PO4 dehydrogenase.

In the Single reagent system glucose oxidase converts glucose to gluconic acid and hydrogen peroxide. The peroxide in the presence of horse radish peroxidase forms a colored complex of hydroxy benzoate and 4 - aminophenazone. The intensity of the colour obtained is proportional to the glucose level.

The advantages of this method are that
(1) It is a single reagent system,
(2) No boiling or deproteinization of the sample is needed
(3) Highly specific for glucose.

Requirements:
1. Serum or plasma (sample to be tested)
2. Span diagnostic kit for Blood Glucose Estimation by GOD/POD method,
3. Test tubes,
4. Pipettes

Procedure / Protocol / Method:
Add the reagents constituted as per the instructions by the manufacturer in 3 test tubes as
shown in the table:
Blank Standard Test
Working reagent
(ml)
3.0 3.0 3.0
Standard (ml) -
Sample (ml) - 0.02ml 0.02ml

Mix well and incubate at 37°C for 15 min. Mix again and read the O.D. at 500 nm
against the D/W blank.
% T
Absorbance
The final colour is stable for 1 hr.
Calculations:
Glucose conc. in mg/100ml = O.Dtest x 100
O.Dstd.
Results:
Conclusion:
References :
Methods in enzymology -Vol 3 pg. 107 by Sidney Colowick and Kaplan

• From http://kayakman.livejournal.com/37091.html

CSR - Central Serous Retinopathy

What is CSR?

CSR is a condition which causes temporary or permanent impairment of vision. The symptoms are loss of sensitivity in dim light, usually in an oval shaped gray or brown area, blurring or distortion of the visual image. It is a result of the detachment of most of the layers of the retina (the back of the eye) from its supporting tissue as a result of the buildup of fluid. The buildup of fluid appears to be due to one or more small breaks in the retinal pigment epithelium.

The term "idiopathic CSR" which you may see used simply means that the cause is not known. It affects primarily males between 20-45 and is associated with stress. For example, airline pilots suffer from it at a high rate, and some people find that attacks go away if they go on vacation. There have been some attempts to classify different forms of the disease but they are tentative and not linked to different causes or treatments. Outcomes

Usually the fluid build up disappears after a few weeks to a few months with little long term damage. During this time the condition often fluctuates wildly on a daily or hourly basis. It particularly gets worse when under stress, tired or ill.

However recurrences are quite common and damage can accumulate over time. Significant, disabling damage can accumulate over time. If the detachment persists for too long the retina is starved of nutrients and can be damaged permanently, with a permanent gray area or a blind spot. The likelihood of recurrences is higher if the initial attack is more severe.

There are wide variations in the estimates of recurrence rates. Opinions also vary on the risk of the condition occurring in the other eye. Often patients are told that recurrences are rare, and that there is no need for concern. While this may be true in many cases, there is reason to doubt that this complacent attitude is correct.

A long term study of patients with CSR found that 50% of patients get the severe and extensive form of the disease after 12 years of evolution (Reference 1). It may be that the complacent attitude of clinicians is a result of the fact that they provide no effective treatment, so patients drift away and there is no long term visibility to the evolution of the condition. Standard Treatment

There is no effective clinical treatment for the condition.

Laser treatment has been used but research results suggest that the treatment does not improve the long term outcomes. The laser therapy effectively 'burns' the leak shut, but can cause damage.

It can be used to overcome the immediate problem, for example if an attack is preventing studying for examinations. This may also be useful if an attack goes on for a long time - more than a couple of months, depending on how severe the attack is. A long standing attack can cause permanent damage to the retina and in this case laser treatment may be a good idea as a way to prevent permanent damage.

Recently more refined laser treatments have been used as certain frequencies of light cause less damage than standard frequencies. Stress and CSR

CSR is associated with stress. Individuals who report being under stress and people who are in objectively stressful occupations such as airline piloting are susceptible to CSR. Stress includes pain, infection, excessive heat and cold, low blood sugar, excessive exercise, hunger and crash diets, jet lag, lack of sleep, psychological stress and also very intensive exercise.

Stress causes the adrenal cortex to secrete cortisol and this may be the link between stress and CSR. There have been some studies which suggest that the link is instead due to the increased adrenaline that comes with stress but these studies appear to be flawed due to lack of control for blood pressure.

High endorphin levels (a result of pain or excess exercise) or opiate levels (from use of heroin or morphine as drugs or as pain killers) are also associated with CSR.

CSR sufferers have usage rates for tranquillizers much higher than the general population, are more susceptible to high blood pressure, and are more likely to be users for cortisone steroid medications.

High cortisol levels are often but not always a result of stress. See below for the linkage between cortisol and CSR.

Cortisol and CSR

What is Cortisol?

Cortisol is a hormone secreted by the adrenal cortex which assists the body to deal with various stresses. It reduces inflammation and immune system function and triggers the breakdown of protein into sugars.

A certain amount of cortisol is necessary for life. Without cortisol even a small amount of stress will kill you. Addison's disease is a disease which causes low cortisol levels, and which is treated by cortisol replacement therapy.

Cortisol Associated with CSR

CSR is associated with high cortisol levels. That is, people with high cortisol levels are more likely to suffer from CSR, and people with CSR generally have high levels of cortisol.

CSR sufferers have high levels of cortisol made by their own adrenal gland (50-80% higher than the average, and outside the normal range) (Reference 3).

CSR is also associated with treatment by corticosteriods ("cortisone") for other conditions such as allergy and inflammation. These drugs go under names like Hydrocortisone, Cortisone and Prednisolone. There have been several cases where CSR has recurred during each of several courses of treatment with cortisone drugs and gone away each time the treatment was stopped. Usually, doctors will claim that nasal sprays and skin creams are not absorbed into the body and will not therefore cause adverse side effects. However in a number of cases this information has turned out to be unreliable and CSR attacks have ceased when the treatment was terminated. Doctors do sometimes have a psychological tendency to believe that their treatments are more effective, less painful and less damaging than they really are.

CSR is also associated with pregnancy (which generates very high cortisol levels in some cases). The high levels are cortisol in pregnancy and the body's need to protect against this may explain why women are less prone to getting CSR than men.

The association of objective and subjective stress with CSR also points to cortisol because stress raises cortisol levels. In addition, a high level of CRF, the hypothalamic hormone which drives cortisol levels, causes a subjective experience of stressfulness.

The incidence of CSR in people suffering from Cushing's syndrome is about 5%, a very high level. Cushing's syndrome consists of very high cortisol levels usually caused by a tumor in the pituitary gland or in the adrenal glands. Again this confirms the linkage between cortisol and CSR, but also suggests that high cortisol is not enough to cause the disease on its own. Presumably some other weakness plays a part.

Adverse Effects of Excess Cortisol

Cortisol is a powerful chemical and has numerous adverse effects in excess. It is therefore recommended that cortisone medication be taken in as small a dose as possible for as short a time as possible. A partial list of the adverse effects of cortisol follows:

Immune system suppression.
Loss of muscle tone.
Accumulation of body fat,
Depression and anxiety. Initially, however cortisol can produce a short term euphoric effect.
Increased permeability and fragility of the linings of blood vessels.
Loss of bone mass, leading to osteoporosis.
Damage to the hippocampus, a brain area associated with memory.
Controlling Cortisol Levels
Cortisol Regulation by the body

The body's control of cortisol levels is complex. The PVN area within the hypothalamus secretes a substance called CRF (corticotropin releasing factor). This is picked up by the pituitary gland which then secretes ACTH (adrenocorticotropic hormone). In turn this causes the adrenal cortex to secrete cortisol.

The hypothalamus acts as the body's stress detector and drives cortisol production in this way as a response to stress.

Negative feedback mechanisms exist between the body's cortisol levels and the pituitary and hypothalamus to keep the cortisol levels within reasonable bounds in normal circumstances. The negative feedback is more effective in controlling high cortisol that results from psychological stress than high cortisol that results from physical damage such as blood loss or illness.

One unfortunate fact about the body is its tendency to resist any change. For example if you go in a diet the body increases subjective hunger and decreases metabolic rate, thus 'helping' you not to lose weight. The same thing applies with many of the techniques to reduce cortisol levels. They may work for a while but then the body adapts and levels return to the original values. So it may be necessary to keep revising your strategies.

Factors that elevate cortisol

Drugs like caffeine and nicotine tell the hypothalamus that you are under stress, leading to increased cortisol levels, as well as increased adrenaline levels. The increase in cortisol levels from consuming 4-5 cups of coffee per day may be of the order of 50-60% and the increase is highest in people who are already prone to high levels of cortisol. There are anecdotal reports that other stimulants are also associated with CSR attacks e.g. ephedrine (found in decongestants and herbal weight loss preparations).

Stress increases cortisol levels. This includes all the forms of stress described above. However the body is better able to control cortisol levels that result from psychological stress than those that result from physical stress.

Cortisone steroid drugs mimic the effect of high cortisol levels.

There is a lot of evidence that a stressful childhood leads to a permanently increase susceptibility to stress and increased CRF levels from the hypothalamus leading to higher cortisol levels. The stresses in childhood can range from separation from the mother through to physical and sexual abuse, hunger and disease. This can sensitize the hypothalamus and make it "trigger happy". Stress in CSR Sufferers

While many CSR sufferers live objectively stressful lives as pilots etc, others suffer from high levels of subjective stress although their lives do not appear to be inherently stressful. For these people, it is not entirely clear why they would have high levels of subjective stress.

This may be due to an inherent metabolic tendency to over-produce adrenaline and cortisol which produce subjective feelings of stress via brain receptors for those hormones.

Another explanation is that a stressful childhood can lead to an overactive hypothalamic stress detector, leading to the production of adrenaline and cortisol in relatively normal circumstances. There is considerable animal research to suggest this does occur.

It is also possible that the person may have poor strategies for dealing with stresses. Studies have suggested that many CSR sufferers have 'Type A' personality which describes a tendency to be unable to relax. Do not assume that the cause is psychological though. In the past many conditions thought to be of psychological causes have turned out to have significant or dominant physical causes, for example severe depression and schizophrenia. In a sense then, psychological explanations are the explanation of last resort for the clinician who has no answers, and often amounts to a strategy of 'blame the patient'. The so-called 'schizophrenogenic mother' is a notorious example of this syndrome.

Having said that, there are a lot of effective stress management techniques available. See below. Finding Someone Qualified

The condition is fairly unusual so it is difficult to find someone who is fully qualified to treat it, or even to diagnose it. It is quite common for serious and obvious illnesses to go undiagnosed for years. A recent study found that the average time to diagnose Cushing's Syndrome, a very serious illness sometimes associated with CSR, was 3 1/2 years.

There are several conditions that can be confused with CSR, such as Age Related Macular Degeneration and diabetic retinopathy, which are more common. It is important to have the diagnosis confirmed and tests are available to verify the leakage of fluid that is characteristic of CSR.

A retinologist, not just an ordinary ophthalmologist, can diagnose the condition. Because the condition initially causes a quite subtle loss of vision, an ophthalmologist may even tell you that there is nothing wrong.

You should then be able to get your cortisol tested without too much trouble to confirm the link with high cortisol in your case, unless you are using cortisone medication or are already aware of a high cortisol level.

In theory the best person for dealing with the high cortisol is an endocrinologist. However the levels of cortisol in CSR are generally not high enough to qualify as a case of Cushing's syndrome. Cushing's syndrome is the classic high cortisol disease. As anti-cortisol drugs can have adverse side-effects, you are likely to find a high degree of reluctance to provide any treatment.

This is very frustrating. Doctors prescribe cortisone treatments quite freely, even though it has severe side effects. On the other hand there is a high degree of reluctance to prescribe anti-cortisol treatments even when cortisol levels are high, in the name of 'accepted clinical practice'.

The other problem with endocrinologists is that in most cases of CSR the root cause of the high cortisol seems to be the hypothalamus which is part of the brain, and so is not in the jurisdiction of the endocrinologist. The brain is also far more complicated than the endocrine system.

Potentially a neurologist may be able to help if, as appears often to be the case, the condition is driven in many cases by an overactive hypothalamus. However you will probably find an even greater reluctance to do anything about the hypothalamus than is the case for the adrenal gland and its cortisol. The hypothalamus is very complex and plays a critical role in many vital body functions.

If you have high cortisol levels but do not have the tumor characteristic of Cushing's disease, your condition is likely to be labeled as "pseudo-Cushing's syndrome". The term is unfortunate because the high cortisol and the damage that results, is just as real as in the real thing. Pseudo-Cushing's syndrome is believed to be due to excessive alcohol consumption or psychological depression or stress. However a recent study has established that a significant proportion of the population has a genetic predisposition to high cortisol levels, so it may not all be in your mind after all.

On the positive side, practitioners will most likely find your condition interesting. What you can do
Reduce stress levels. This is easier said than done. How do you measure your stress level? You need to find some objective thing that relates to stress e.g. overeating, nervous habits etc, or you could monitor your cortisol levels as a proxy for stress. To the extent that CSR sufferers are type A personalities, they are "Stress junkies" and may find ways to bring stress/excitement back up to a level they feel happy with. So you need to find a way to have a less stressful life that does not seem dull.

Studies tend to suggest that biofeedback, meditation, taking a philosophical approach to adversity etc are not that effective in controlling this condition. However in my experience by reducing both objective stress and by working on how you react to stress, it is possible to help control the attacks. Your mileage may vary but I have found the techniques in "Ultimate Power" by Tony Robbins very helpful, and yoga also helps, though the slow pace of it is infuriating to the Type A personality.

In the case of excess alcohol consumption reducing alcohol intake is effective in dealing with pseudo Cushing's syndrome.

Monitor cortisol levels. For this you need a friendly doctor to order the tests. However do some extent you can get a feel for your cortisol levels. Some signs of high cortisol are a dark or sunken look around the eyes, fatigue but having trouble sleeping, and lack of motivation. See other symptoms on the Checklist.

Give up caffeine and other stimulants - cocoa, coffee, tea, chocolate etc. Also give up smoking if you smoke. Caffeine is a dangerous, addictive and destructive drug. Even the levels in decaf may be harmful - the author has been able to turn CSR on and off by starting and stopping coffee drinking and even decaf has the same effect.

Caffeine has a number of effects. One is the stimulating effect on the pituitary which peps you up and drives up cortisol. The other is the increased levels of dopamine, which is the same neurotransmitter that makes heroin, amphetamines and cocaine so appealing to many. This is one reason why you may find caffeine difficult to give up.

Avoid "cortisone" treatments (corticosteriod treatments) for other diseases if you can avoid them as they may "have disastrous results" (Reference 13) for CSR sufferers. Generally cortisone treatments are heavy medicine and can cause numerous side effects including depression, immune system damage, loss of muscle tone and accumulation of fat, osteoporosis and damage to certain parts of the brain. Unless you are actually deficient in cortisol, be wary of using these treatments.

Avoid unnecessary stress. This includes disease, excessive exercise, crash diets, jet lag, pain, lack of sleep, as well as psychological stress. Meditation and other relaxation techniques may assist, in spite of the studies mentioned above. In relation to psychological stress, the big stressors are babies, job changes, moving house, financial difficulties, death of someone close, marriage and divorce. You cannot go through life and avoid all these things, but you may be able to time them better and avoid clusters of big stressors. Financially you may choose to get less involved in "keeping up with the Joneses" type activities, and avoid high levels of debt. Pets in particular dogs have been shown to reduce stress levels, and taking a dog for a walk is also good for you.

CSR may get worse even during a cold or sore throat so it is important to avoid being exposed to these diseases. Tooth decay is another form of infection and should be treated as soon as possible. Any form of infection will push up cortisol levels.

Review your use of aspirin. Reduce if excessive. There is some evidence that aspirin may increase the leakage of fluid from capillaries. However aspirin can reduce high cortisol levels that result from pain (Reference 12), and can be an alternative to steroid medications.

The following vitamins and minerals may assist within a balanced program of supplements: Minerals zinc, magnesium, manganese, calcium, and vitamins B6, Pantothenic Acid (B5) and vitamin C. A person with high cortisol levels will also be susceptible to osteoporosis and should take care to get adequate calcium, vitamin D and Magnesium as well as protein. Bioflavinoids may also help as a deficiency is known to increase the fragility of capillary and other membranes.

Here are some recommendations from "Prescription for Nutritional Healing: A Practical A-Z Reference to Drug-Free Remedies Using Vitamins, Minerals, Herbs, and Food Supplements" by James and Phylis Balch. Note that some of these are pretty high doses especially A C and B - be careful and always wean gradually of vitamins due to the risk of induced deficiency with sudden withdrawal.

Calcium 1000mg daily
Magnesium 500mg daily (a 2:1 ratio of Ca to Mg helps microcirculation in the eye)
Selenium (100-200 mcg daily) and Superoxide dismutase (SOD) as directed on the label. Potent free radical scavengers. Free radicals have been implicated in damage to the retina and microcirculation in the eye.
Vitamin A 75,000 IU daily. If you are pregnant, do not exceed 10,000 IU daily. Use emulsion foam for easier assimilation and greater safety in higher doses.
Vitamin C 2,000 mg three times daily
Vitamin E 400 IU daily
Vitamin B complex 100mg daily. Improves intraocular cellular metabolism
Fresh fruits, yellow and yellow-orange vegetables.
Desiccated liver - numerous nutrients
Free form amino acids - for protein
Zinc - 50mg daily
Carrot juice
Cut out sugar and white flour
Limit ultraviolet rays, by using glasses that keep them out, but do not wear dark sunglasses, because you need some light to keep the pineal gland working, to avoid seasonal affective disorder and insomnia.
Avoid drugs that damage the eyes - ACTH (Acthar, Cortrosyn)
Include green vegetables (broccoli, raw cabbage, carrots, cauliflower, squash, sunflower seeds and watercress.
Increase lean protein consumption. This may improve the integrity of the membranes that retain the sometimes-leaking fluid. Cortisol is known to 'burn' protein so this seems like a prudent precaution in any case. This is particularly an issue if you are on a low protein diet, such as many vegetarian diets, or the Pritikin Diet or its variants such as the Ornish Diet.

Some people have found that drinking vegetable juices such as carrot, celery, parsley, spinach along with wheatgrass juice also helps.

An endocrinologist may be able to reduce your cortisol level via medications but it is unlikely they will be prepared to do so. See drug treatment below.

Tranquillizers, including diazepam, Prozac and tri-cyclic anti-depressants, may also reduce cortisol levels. Theanti-stress herb St John's Wort is also reported to reduce CRF and Cortisol levels, with fewer side effects than prescribed medicines.

Drug Treatment

There are not many good drugs to control cortisol levels. They all seem to have side effects. The most benign seem to operate on the adrenal, but have the problem that they indirectly cause the pituitary to emit larger amounts of ACTH, which may not be good because ACTH drives the production of other hormones, which may cause fluid retention or masculinization. There is some research going on in this area because high cortisol levels seem to speed the progress of AIDS.

The following drugs have been suggested as possible aids to CSR treatment. Note that none can be considered proven treatments and all may have side effects, and should be used only with great caution if at all.

St John's Wort is reported to reduce CRF and Cortisol levels. Recently it has been claimed that St John's Wort leads to an increase in anti-oxidants and therefore may increase the risk of cataracts, although there was no direct evidence that cataracts are caused by St John's Wort.
Acycloguanosine. This is an anti-viral and in two cases CSR resolved unusually quickly with Acycloguanosine treatment. Reference 4. I am personally somewhat sceptical about this as it was only two cases and there is no known reason why anti-virals should assist.
Procaine HCl (AntiCort). Anti Cortisol drug developed for use in AIDS cases (who often have high Cortisol). Reference 5 refers to an unpublished study by Alfred T Sapse.
Acetazolamide (also known as Diamox) - a diuretic, Methazolamide, Dichlororphenamide. Anti glaucoma medication. May also be of assistance in CSR. Other anti glaucoma medications include Timolol and Pilocarpine Reference 6.
Picogenol. Picogenol is an antioxident extracted from Pine Bark. The active ingredients are called proanthcyadins (or similar) that are also found in grape seeds.
Beta blockers. There is some speculation that beta blockers may have a calming effect on CSR sufferers. See the link to the Review of Opthalmology article below.
Diazepam based tranquillizers like Valium may reduce CRF production and thereby reduce cortisol levels. Tri-cyclic antidepressants may also have similar effects.
Imipramine, antidepressant, has been reported to reduce CRF levels.
Indomethacin, a non steroidal anti inflammatory is reported to be useful in reducing the length of attacks. See the Optometry handbook
Cushing's syndrome (very high cortisol levels) has been treated with cyproheptaline (a 5-hydroxytramine receptor blocker)
Alpha helical CRF has been used as a CRF antagonist in experimental work.
Acetyl-L-carnitine, which is supposed to assist with the use of fat as a fuel and is available in health food stores, and phosphatidylserine (seriphos) may reduce cortisol
The abortion pill RU-486 works by interfering with the body's cortisol receptors so it may also be useful.
Bilberry - shown to improve both night and normal vision - see "Prescription for Nutritional Healing" by James and Phylis Balch. Bilberry can make one feel tired and lethargic, although night vision may be improved.
Eyebright - see "Prescription for Nutritional Healing" by James and Phylis Balch
Bayberry bark, cayenne (capsicum) red raspberry leaves - see "Prescriptio n for Nutritional Healing" by James and Phylis Balch
"The Diet Cure" by Julia Ross Bayberry recommends Seriphos (phosphorylated serine, a CRF antagonist), GABA "a natural valium", l-tryptophan or 5-HTP (anti stress preparations - 5-HTP is similar to l-tryptophan which is hard to get), d-phenylaniline (increases endorphins). This is a very interesting book, about a number of conditions.
Links
About.com
Harvard
Laretina
Harvard 2
Optometry handbook
Review of Ophthalmology article discussing beta blockers etc
Discussion - Bulletin Board
Scientific American Article on Depression, includes material on CRF
Brain Chemicals - biopsychiatry.com
Medical Journal Search - BioMedNet
Google Search Engine - search for "Central Serous Retinopathy"
Macular Degeneration, Vision information and links
References
"Long term follow-up of central serous retinopathy in 150 patients" Castro-Correia J, Coutinho MF, Rosas V, Maia J in Doc Opthalmol 1992 81:4 379-386.
"Systemic findings associated with central serous chorioretinopathy". Tittl MK, Spaide RF, Wong D, Pilotto E, Yannuzzi LA, Fisher YL, Freund B, Guyer DR, Slakter JS, Sorenson JA Am J Ophthalmol 1999 Jul 128:1 63-8.
"Endogenous cortisol profile in patients with Central Serous Chorioretinopathy" by Garg SP, Dada T, Talwar D, Biswas NR; Br J Opthalmol 1997 Nov 81:11 962-4.
"A new therapeutic approach to CSR, a hypothesis", by Rathschuler Lai Ghiglione Rossi Ciurlo, In Int Opthalmol 1990 Mar 14:2 125-9.
ScienceNewsOnline article "The Cortisol Connection"
"Serous Retinal Detachment. Value of Acetazolamide" Gonzalez, C. J Fr Opthalmol 1992 15:10 529-36.
"Type-A behaviour and Central Serous Chorioretinopathy" Yaannuzzi LA, Retina 1987 Summer 7:2 111-31
"Central serous chorioretinopathy in endogenous hypercortisolism" Bouzas EA, Scott MH, Mastorakos G, Chrousos GP, Kaiser-Kupfer MI; Arch Opthalmol 1993 Sep 111:9 1229-33
"The etiology of central serous retinopathy" Yoshioka H; Nippon Ganka Gakkai Zasshi 1991 Dec 95:12 1181-95 (this study has been criticized for its lack on control of blood pressure; this may subvert its findings that high adrenaline can cause CSR in rabbits; this article is in Japanese).
"Loss of vision due to central serous retinopathy following psychological stress" Gelber GS, Schatz H; Am J Psychiatry 1987 Jan 144:1 46-50
"Stress-like adrenocorticotropin response to caffeine in young healthy young men" Lovallo WR et al, Pharmacol Biochem Behav 1996 Nov 55:3 365-9. (Many other studies have come to similar conclusions).
"(title unknown)" Langer P et al, Acta Endocrinol, 1978:88:698-702
"Sarcoidosis and central serous retinopathy: a dangerous combination" Sharma DP, Rao N, Roy M; Sarcoidosis Vasc Diffuse Lung Dis 1998 Sep 15:2 189-91
"Retinal Sparing by Selective Retinal Pigment Epithelial Photocoagulation" Ridler J et al, Arch Opthalmol 1999:117:1028-1034
"Central Serous Retinopathy (choroidopathy) in pilots" Gross M et al, Aviat Space Environ Med 1986 May 57:5 457-8
"The metabolic syndrome--a neuroendocrine disorder?" Bjorntorp P, Rosmond R Br J Nutr 2000 Mar 83 Suppl 1 S49-57

A mom battles for her life
Rare disorders: She must commute across the country for treatment
By Carey Hamilton
Article Last Updated:11/28/2006 02:23:04 AM MST