Chronic Stress is Chronic Illness - Wherefore Art Thy Regulatory Mechanisms?

So here's how mammals roll.  We perceive a threat, and then our brains jump into action.  First step - the brain's fear center, the amygdala, and the brainstem stimulate the paraventricular nucleus (PVN) to secrete corticotropin-releasing hormone (CRH).  CRH moseys on down to the pituitary gland, where CRH stimulates the production and release of adrenocorticotropic horomone (ACTH).  ACTH is released into the bloodstream on the fast track to the adrenal glands, where it tells the adrenal glands to pump out the steroid hormones.  Woo hoo!

But we can't jack ourselves up forever.  All bodily systems have innate negative feedback loops.  We eat a huge meal, and leptin regulates our appetite at the next meal to keep us at our body set point, as long as we don't fall too far from the evolutionary paradigm when it comes to what we eat, or we don't have certain kinds of medication or a metabolic disorder screwing up the system.

In the brain, the hippocampus (there's that part of the brain again!) and the left prefrontal cortex can send inhibitory signals to the PVN, telling it to lay off producing the CRH.  No CRH, no ACTH.  No ACTH, no adrenal gland production of steroids.  That would presumably shut down the acute stress response.  What is the signal to tell the hippocampus and the prefrontal cortex to shut off the steroid hormone tap?  Cortisol!  That's the negative feedback - get too much cortisol, we shut off production.  Pretty nifty. 

But here's the problem.  As we found out yesterday, prolonged cortisol exposure damages the hippocampus.  We just aren't designed to cope with prolonged stress forever.  And when we damage to hippocampus, we damage our negative feedback loop (1)(2).  The shut-off valve is broken, so we continue to release cortisol.

We all have different baseline stress levels.  Research suggests that up to 62% of our stress hormone activity levels are inherited.  Also, chronic dysregulation of the HPA axis and stress hormones in childhood will affect how the brain develops, causing increased vulnerability to further stress throughout life (3). 

(A sobering aside here - when I was in medical school in the late 90s, the first teenagers were showing up in the diabetes clinic with type II diabetes - insulin resistance and metabolic syndrome may have begun years earlier.  Before that, type II diabetes was called "adult-onset diabetes." Hyperglycemia damages the brain and raises cortisol levels.  We can't escape the conclusion that this may well be chemically similar to exposing a child's developing brain to repeated emotional trauma.  There's a bit of literature on type I diabetes and an increased incidence of psychological problems - but usually it is explained as an adolescent trying to exert independence with a risky illness and risky medicine (insulin).  I found this abstract on type II diabetes but I don't have access to the paper.)

Can diet change cortisol?  Is a crappy diet a source of chronic stress?  Well, cortisol can change diet in a group of socially housed female rhesus monkeys.  The stressed (subordinate) monkeys chose to eat more calories than the dominant monkeys (4).  Leptin administration seems to decrease subordinate monkey cortisol levels, but made no difference in the dominant ones (5). Dominant females also develop less atherosclerosis than subordinate monkeys (6).  (Note to self- foster good karma so that you do not have to come back as a subordinate female rhesus monkey).   

In human women, calorie restriction and dieting caused an increase in cortisol levels (7).  But longer studies of men showed that losing fat can actually lower cortisol levels (this would make sense, if losing fat decreases insulin resistance and hyperglycemia). Here's an interesting study comparing hormones and metabolism in 16 women with PCOS (polycystic ovarian disease which is often accompanied by insulin resistance).  They ate a high fat "western" meal or an isocaloric low fat, high fiber meal, and then the researchers measured blood glucose, insulin, testosterone, and cortisol for the next 6 hours.  The low fat meal resulted in glucose levels significantly higher and insulin levels twice as high as the high fat meal for several hours after the meal (Oops! Why do we recommend low fat high fiber diets for insulin resistance again?)  But both meals reduced cortisol equally.

But the heart of metabolic dysfunction is in the immune system.  Inflammation.  We know that chronic stress and acute stress can cause immune reactions and inflammation in addition to the whole stress  hormonal cascade (in fact it is thought to be caused by the hormonal cascade) (8).  We also know that high protein meals and tryptophan increase the stress hormone response.  Would an inflammatory protein (like casein) cause a cortisol response?  In this study, yes and no.  The more allergenic casein caused less of a stress hormone response than the supposedly less allergenic casein hydrolysate.  When the same proteins were administered to the same men through their noses (don't snort casein at home, kids!), there was no difference in hormonal response, suggesting that the signal to activate the stress hormones occurs in the gut, not the blood.  These were normal weight, healthy men, too, with no history of mental disorders and not on any medication.  Would there be a difference in someone who is chronically stressed?

The diet and inflammation area is in the midst of a flurry of research right now.  Hooray!  I'll keep an eye out for more info.  Right now we can say that a diet predisposing one to metabolic syndrome (via hyperglycemia) will definitely increase stress hormones, and the whole metabolic picture includes hippocampal damage and increasing risk of depression and anxiety.  We also know that chronic stress will likely predispose you to metabolic syndrome.  Does chronic exposure to an allergenic protein like wheat or a high level of inflammatory linoleic (omega 6) fatty acid directly cause chronic increased stress hormone response (and therefore metabolic syndrome and depression and anxiety via the robustly evidenced stress hormone route?).  I'll look further.