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“ "You just don't feel nice about yourself at all," she said.

"And you can't understand why this is happening." ”

A fitness fanatic’s life turned into a “living hell” as she ballooned from size 10 to 18 in weeks mysteriously. 26-year-old Kathryn Weir was ashamed to leave the house and doctors were astonished as she began to put on weight on her stomach for no reason. Dark hairs also sprouted on her chest and back and her face became swollen and bloated. Her right leg even snapped because her bones were very brittle.

Kathryn Weir (Before)

Kathryn Weir (After having Cushing's Syndrome)

                                             

 

This was no different for Bev Green, who said she felt like a man after developing facial hair. Ms Green had always been slim and fit, thus, her sudden weight gain caused her to be so self-conscious, uncomfortable and terribly upset of her haywired body.

For years, both women struggled with their condition through one diet after another and doctors just could not understand what was wrong. It is all because Cushing's syndrome is difficult to diagnose because the symptoms are similar to many other ailments.

What is Cushing's Syndrome?

Cushing's Syndrome is a collection of symptoms that develop when the body is exposed to excessive levels of the hormone, cortisol, for a prolonged period of time ( >1.4 micrograms per litre of blood). Extremely rare, with only about 13 cases for every million people, Cushing's Syndrome can afflict animals too, such as dogs and horses. 

A bulldog with Cushing's Disease having swollen enormously, a hallmark of the disorder.

What is cortisol (the "stress hormone")?

Chemical structure of cortisol

Cortisol is a steroid hormone our body makes during times of psychological and physical stress, including exercising and fasting. It affects nearly every tissue and organ. Through gluconeogenesis and glycogenolysis, cortisol's chief function is to unleash a steady supply of glucose to help our bodies cope with whatever emergency or stressful situation at hand, thus earning the moniker, "fight-or-flight".

Biochemistry

Gluconeogenesis

In gluconeogenesis, new glucose is synthesised in the liver (and kidneys, but rarely) from non-carbohydrate sources such as glucogenic amino acids (especially Alanine and Glutamine), lactates and glycerol.

Cortisol supports gluconeogenesis in a number of ways:

1) Stimulating the expression of key enzymes of gluconeogenesis
Being a non-polar steroidal hormone, cortisol is able to pass through the hydrophobic cell membrane of liver cells and bind onto glucocorticoid receptors (GR) inside the cytoplasm. The GR changes conformation and becomes activated. Together, the cortisol-GR complex moves into the nucleus, and bind onto GR elements (enhancers) along the DNA molecule to upregulate transcription and hence, expression of genes encoding enzymes of the gluconeogenesis pathway, principally:

Pyruvate carboxylase (pyruvate + ATP ---------> oxaloacetate + ADP)

Phosphoenolpyruvate carboxykinase (oxaloacetate + GTP ----> phosphoenolpyruvate + GDP + CO2)

Glucose-6-phosphatase (glucose-6-phosphate -------> inorganic phosphate + free glucose)

***Note that these enzymes catalyse the non-reversible reactions of glycolysis and are thus instrumental for gluconeogenesis to proceed.

 

Steroid hormones like cortisol act as primary messengers to alter celullar activities.

2) Breakdown of muscle/tissue proteins to provide amino acid substrates

3) Breakdown of adipose tissue (fats) into fatty acids and glycerol substrates

Gluconeogenesis. Amino acids, lactates and glycerol enter at different points but are eventually converted to glucose.

How lactate is recycled back into glucose.

Glycogenolysis

Cortisol also promotes glycogenolysis, in which stored glycogen in the liver and muscles is converted back into free glucose and glucose-6-phosphate, by facilitating the activation of a key enzyme, glycogen phosphorylase.

Glycogenolysis

Cortisol also runs counter to another hormone, insulin, by restricting the amount of glucose non-muscle tissues can take up (by preventing the translocation of glucose transporter proteins to the cell membranes).

Feasting on glucose

As a result, the brain and the muscles now have a great supply of glucose at their disposal: through cellular respiration, glucose provides crucial energy for vigorous muscular contractions so that we can perhaps run faster to catch a leaving bus, or flee from a rampaging animal. Cognitive performance improves - we can now think and react much more quickly to save our own necks. ;)

Regulation of cortisol production

Cortisol is produced by the adrenal glands on top of each kidney but its production is regulated by the hypothalamus in the brain.  

When we experience stress, the hypothalamus releases corticotropin-releasing hormones (CRH) that stimulate the anterior pituitary gland (APG) to release adrenocorticotropic hormones (ACTH). ACTH in turn prompt the adrenal cortex to release cortisol.

When there is excessive cortisol, signals are sent back to the hypothalamus to wind down production of CRH. Accordingly, less ACTH will be released and thus less cortisol is produced, eventually stopping. This is known as the negative feedback loop of cortisol.

Cortisol production and negative feedback

 

What are the symptoms of Cushing's Syndrome?

• Rapid weight gain around central body trunk (face, stomach, chest) 
• round, puffy face ("moon face")
• arms and legs remain relatively slender

• "Buffalo hump" (fat deposits at back of shoulders and neck)
• Thin skins that bruises easily
• Reddish-purple stretch marks (striae) on buttocks, thighs, stomach
• Oedema (swelling) around ankles
• Perpetual thirst
• Muscle weakness and osteoporosis
• Diabetes
• High blood pressure (hypertension)
• Mood swings, irritable, anxiety
• Growth and thickening of facial/body hair in women (hirsutism)
• Prone to illnesses/infections
• Disturbances in mentrual cycle (women); infertility (men)

 

"Moon face" with facial redness ("plethora")

General symptoms of Cushing's Syndrome

Striae (stretch marks)

Behind the scenes: Pathophysiology comes in play

 Why is there:

Rapid weight gain
- Cortisol displaces fats from beneath the skin (subcutaneous) to the main organs of the central body trunk (visceral). This is so that the fats can be quickly broken down into glycerol and delivered to the liver for gluconeogenesis, since such organs are more vascularised than the skin.

- Cortisol deprives non-muscle tissues of glucose and so hunger signals are sent to the brain by starving cells. We gobble up much more food than we need and excess carbohydrates are stored as fats. 

Weight gain around the central body trunk

Striae and muscle weakness
The body gathers enough amino acids for gluconeogenesis by degrading proteins from the muscles and other tissue, as well as by impairing both amino acid uptake into the muscles and protein synthesis. Muscles lose mass and weaken, and the skin becomes fragile. As visceral fats continue to deposit, thin skin easily overstretches and blood vessels rupture, creating striae.




Susceptibility to illnesses/infections ; disturbances in reproductive system
Cortisol also shuts down activities non-essential to our "immediate survival", such as the immune and reproductive systems, so as to divert precious resources to the brain and muscles instead. Inflammatory responses, our body's defence mechanism against infections, are stifled while antibodies are made poorly and insufficiently.The patient's immune system becomes so weak he might be no different from a person with AIDS - tuberculosis, fungal and opportunistic infections, etc.

Thankfully however, the immune system can go back to normal once Cushing's Syndrome is being treated.

Inflammation is largely subdued

Hypertension (high blood pressure)
Cortisol enhances arterioles' sensitivity to epinephrine, the hormone that makes blood vessels constrict (vasoconstriction) to divert more blood to the brain and muscles. The heart also pumps faster to hasten delivery of glucose- and oxygen-rich blood to these regions.

What cause Cushing's Syndrome?

Excess cortisol comes either from external (exogenous) or internal (endogenous) sources.


Exogenous (external)
Long-term corticosteroid medication leads to a build-up of cortisol and accounts for over 90% of Cushing Syndrome cases. Corticosteroid drugs are essentially synthetic cortisol. They are anti-inflammatory, providing patients with lupus, rheumatoid arthritis, organ transplants, atopic eczema and the likes much-needed relief.

Prednisone, hydrocortisone and dexamethasone are corticosteroid drugs

Endogenous (internal)
The body produces excessive cortisol due to other medical complications:

1) Pituitary adenoma 
This is a small,benign (non-cancerous) tumour of the pituitary gland that secretes excessive ACTH. To make matters worse, this tumour is not governed by the negative feedback loop controlling cortisol production. Cushing's Syndrome specifically from this cause is termed Cushing's Disease.

2) Adrenal problems

• Adrenal hyperplasia

Cells of the adrenal glands divide faster and more frequently than normal, leading to enlarged adrenal glands that correspondingly produce more cortisol.

•  Tumours of the adrenal glands

Both benign and malignant (cancerous) tumours of the adrenal glands secreting excessive cortisol.

3) Ectopic ACTH
Certain tumours originating outside the pituitary gland ("ectopic") begin producing ACTH of their own accord, leading to excessive ACTH which eventually overstimulate cortisol production. Some rare forms of lung cancer have this effect.

18-month-old Aditya Kumar of India suffers from Cushing's Syndrome.Facial and body hair develop much sooner than they should.

So what are the cures??

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If cushing’s syndrome  is caused by exogenous administration of corticosteroids (man-made drugs which resemble cortisol to treat inflammatory conditions)

• one has to reduce the intake of corticosteroids

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• one may need treatment for some symptoms of Cushing syndrome, for example, medication to lower blood pressure

If cushing’s syndrome is caused by tumour (endogenous Cushing’s syndrome)

• cortisol-inhibiting drugs e.g. metyrapone
• radiotheraphy to shrink the tumour using X-rays e.g. stereotactic radiosurgery to treat pituitary tumours
  

  

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• surgery to remove cortisol or ACTH producing tumors with immediate and high post-operative cure rates of 78% to 97% (best results with microadenomas and experienced neurosurgeons).
  
  
  

  How can I prevent myself from getting Cushing's Syndrome? 

  
  

  1. Exogenous cushing’s syndrome may be prevented by reducing the intake corticosteroid to an absolute minimum required dose for patients who require corticosteroid treatment.

  
  
  

  2. Unfortunately, there is no way to prevent cushing’s syndrome but one can diagnose it earlier. Do a blood test and urinalysis to check your body’s cortisol level accurately if you are gaining weight suddenly (even when you exercise  frequently and/or your eating habits are normal).

  
  

  

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   Good news! In 2012, Abortion Drug is approved to treat patients with Cushing's Syndrome!
  
  

  

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  Yes, there is an increase in global clinical response when using Mifepristone, which is used in medical abortions to treat patients with the “stubborn” Cushing’s Syndrome. Mifepristone inhibits the effect of cortisol in tissues by binding to the glucocorticoid receptor.  This treatment does not lower the level of cortisol though but lowers the effects of the excess cortisol (e.g. high blood glucose levels).  

  
  
  

  

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  Mifepristone is marketed as Korlym for the Cushing's indication.

  
  

  
  
  

  
  

  
  

  

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  It is highly unlikely for women with Cushing’s Syndrome to become pregnant as high levels of cortisol cause irregular periods and infertility. Even so, pregnant women should never consume Korlym in an attempt to treat Cushing’s syndrome as the drug will terminate pregnancy.

  
  
  

  Korlym is approved by The U.S. Food and Drug Administration to control high blood sugar levels in adults with endogenous Cushing’s Syndrome. These people would have type 2 diabetes or glucose intolerance, who were unresponsive to previous surgery or are not suitable for surgery. Based on a study sponsored by Corcept Therapeutics, treating Cushing's syndrome with mifepristone shows an early and progressive clinical improvement in most patients. There were actually no approved medications to treat this disorder until the FDA approved Korlym.

  
  
  

  
  

Hear ye Hear ye! Things about cortisol you ought to know

Fab or flab?

Undoubtedly a friend in times of emergency, cortisol is also denounced by some as "public villain number one" for how it potentially makes us fat.

High levels of cortisol usually correspond with low levels of serotonin, the neurotransmitter of the brain associated with pleasure and happiness. Interestingly enough, to boost serotonin levels, our bodies are again overpowered by hunger pangs urging us to eat voraciously. The purpose is to trigger the release of insulin, which promotes cellular absorption of excess glucose and amino acids. 

This way, more tryptophan (the amino acid used to manufacture serotonin) are likely to cross the blood-brain barrier and into the brain, now that there are significantly fewer amino acids competing with it for entry.

Unfortunately in today's society, most of us lead lives that are far more sedentary than those of our ancestors and sources of stress are seldom those we can literally run away from (think school, work, bills - yawns-). Unused glucose pile unceremoniously on our bellies, arms and thighs as FLAB.

http://www.ambergristoday.com/content/teen-talk/2012/january/30/teenagers-suffer-stress-too

http://www.myhealthnews.co.uk/medicine/obesity-vaccine-invented/01295/

-Gulps- Alcohol!

Bingeing on alcohol can also spark symptoms not unlike those of Cushing's Syndrome! But because these symptoms go away as soon as binge-drinking stops, such a condition is known as Pseudo-Cushing's Syndrome.

Celebrating the end of a stressful bout of exams with booze may not be such a good idea after all...