A lot of people start having all of their health issues after a bout of chronic stress. There are many reasons for this, all of which are important.
An overactive nervous system:
Lowers immune function overall – making you more susceptible to infections and toxins.
Disrupts your sleep (which causes a bunch of downstream problems). Stress decreases slow wave sleep.
Disrupts your circadian rhythm (which causes a bunch of downstream problems).
Causes excess glutamate and cell death (via CRH, Kynurenine).
Causes a leaky gut mainly via CRH, slower gut flow, and less blood flow to the gut, which will cause food sensitivities and inflammation from food. Also, CRH likely causes less cannabinoid activation in the gut. CRH causes local inflammation in the gut. An overactive nervous system, over time, causes HCl production to decrease.
Decreases levels of good hormones and increases some bad ones, because they get shunted to cortisol, and because of circadian and sleep disruption. Also, CRH will directly cause hormonal dysregulation. The result is lower GnRH, LH, FSH, Pregnenolone, DHEA, Testosterone, Growth Hormone, Thyroid Hormones (T3, T4, TSH) and higher Prolactin and Estrogen.
Causes less blood flow in certain regions like your gut and liver. Less blood flow causes low oxygen and less nutrient delivery… Your blood gets shunted to your heart and muscles and your stomach, liver, etc… don’t have what it needs.
In the short term, you might feel dizzy or fuzzy, likely because of less blood flow to the brain and too much dopamine (See COMT gene).
Chronic stress will also cause neurotransmitter resistance, inflammation, impaired memory, and lower dopamine, acetylcholine, LTP, BDNF, neurogenesis and dendritic branching. Stress will also cause oxidative stress in your hippocampus or memory center via CRH.
Other negative effects:
- Cortisol Resistance
- Obesity – raises blood sugar, insulin, makes you hungry
- Depression – as a result of CRH, chronic HPA activation, dynorphin, lower BDNF, lower neurogenesis, lower dopamine, and GABA, serotonin, and glutamate resistance.
- Heart damage – by increased adrenaline, oxygen demand on the body, spasm of the heart blood vessels, and electrical instability in the heart. It also lowers heart rate variability and resting heart rate and increasing blood pressure
Chronic stress response activation (HPA) is believed to be a causal factor of anxiety disorders, bipolar, insomnia, PTSD, borderline personality, ADHD, major depression, burnout, chronic fatigue syndrome, fibromyalgia, IBS, alcoholism, and other diseases .
Many health problems are triggered by stress. This post can help you understand various mechanisms by which stress triggers these health problems.
The Stress Paradox
Cortisol is actually the most potent all-around anti-inflammatory so it’s paradoxical that stress would be harmful.
If cortisol is an anti-inflammatory and inflammation is bad then why is stress bad? It should be good!
This post goes into the biology of why stress is unhealthy – the details of it.
Notice that none of these reasons have to do with our adrenals being ‘fatigued’ or tired out. This is because adrenal fatigue is a myth.
1) Chronic Stress Suppresses Your Immune System
So this can be bad or good depending on the situation, but in general, it’s bad if it’s chronic.
By dampening your immune system, stress can reactivate viral infections or make worse an already present bacterial infection.
It’s known that people who are chronically stressed are also more likely to get sick.
Unsurprisingly, in the elderly, it was found chronic stress decreased their response to flu vaccines .
A weak immune system will not kill cancer cells well either. Hence, in animals, stress contributes to the initiation, growth, and spread (metastasis) of select tumors .
2) Stress Causes Inflammation
This is even though cortisol, which is stimulated by CRH, is anti-inflammatory . So the first part of the stress pathway is mostly inflammatory, but the second part is anti-inflammatory.
In rheumatoid arthritis, Hashimoto’s and UC, inflamed tissues contained large amounts of CRH .
CRH also increases TLR-4 (a significant source of inflammation), including in the intestines .
Mast cell activation plays a central role in asthma, allergic rhinitis, anaphylaxis, eczema, itching, hives, pain, and autoimmunity. They also suppress fertility and sperm motility in males .
In a mouse model of arthritis, blocking CRH reduced inflammation and markers of cartilage destruction .
In C diff infection, the bacteria release a toxin called “toxin A”. When you have the combination of toxin A plus CRH, it causes increased substance P, Intestinal (ileal) fluid secretion, cell damage, and neutrophils and myeloperoxidase to the gut .
3) Chronic Stress Causes Cortisol Resistance
When exposed to chronic stress, people release large amounts of cortisol and go on to develop cortisol resistance . This means that CRH will not be inhibited by cortisol like it normally should .
This means we’re less sensitive to a given amount of cortisol to reduce inflammation. Therefore, we need more cortisol to do its job .
Studies have found more markers of inflammation in chronically stressed (IL-1β, TNF-α, and IL-6), yet these people were more likely to get colds even though their immune system (inflammation) was more activated .
Th17 inflammation and other types of inflammation can get out of control by cortisol resistance.
4) Stress Decreases Thyroid Hormones
Thyroid function is usually decreased during stress.
Thyroid hormones are one of the most important aspects of health and performance. It plays a large role in cognitive function, metabolism, gut health, immunity, heart function, libido and many other facets of the body.
T3, T4, and TSH levels decrease with stress via cortisol .
Stress also causes reverse T3 to increase and lessen free T3. Low free T3 can cause a lot of problems. For example, you’re at 4X increased the risk of heart disease if you have low t3.
5) Stress Kills Your Sleep
When we’re stressed we usually get less and worse sleep. This is the mother of all health problems.
Stress causes you to get less sleep by making it harder to fall asleep.
This can cause inflammation and oxidative stress in the body and also locally in the hypothalamus . Oxidative stress builds up, destroys or weaken our mitochondria and may make our hypothalamus work less well.
But there’s more. CRH, which is released by stress, also destroys your sleep by decreasing slow wave sleep and increasing REM .
CRH inhibits GHRH in males, but not in females. GHRH is needed to produce growth hormone and it increases slow wave sleep. Additionally, in cells, cortisol inhibits growth hormone release in response to GHRH .
6) Stress Causes Depression
There’re many ways in which chronic stress leads to depression.
CRH also causes major depression .
This is because chronic HPA activation makes us less sensitive to serotonin i.e. serotonin resistance .
Cortisol induces glutamine synthase, which reduces glutamate levels in the brain (not good if it’s too low or too high) .
Chronic stress causes GABA resistance as well, which then increases HPA activation  and feeds this vicious cycle. (chronic stress leads to alterations in GABAergic input to the paraventricular nucleus which causes disinhibition of the HPA axis).
Chronic stress can cause glutamate resistance, which in turn can also cause depression .
Depression can then cause oxidative stress and a cascade of negative effects like fatigue, low energy, etc…
7) Stress Harms Your Gut
When the flow is decreased in the small intestine, bad bacteria overgrow by feeding on carbs and you fart .
CRH causes your gut to be ‘hypersensitive’ and you experience gut pain more. When given a drug that blocks CRH, the pain goes away .
CRH exerts relaxing activity on ileal smooth muscle cells .
8) Stress Increases Blood Glucose and Makes You Fat
Acute or chronic stress can cause insulin resistance, which will cause elevated blood sugar levels and its associated harms .
Also, stress can decrease insulin in some people, which will also increase blood sugar .
So you’ve got a double whammy of low insulin and insulin resistance. Both of these will raise blood sugar.
Stress has dual effects on appetite. CRH is an appetite suppressant, while cortisol itself is an appetite stimulant .
When cortisol increases, blood sugar goes up and that causes insulin to be secreted .
NPY, insulin, and cortisol are 3/4 the top hormones responsible for appetite .
- Raises your blood sugar and insulin 
- Makes you hungry and crave sugar 
- Reduces your ability to burn fat 
- Increases your belly fat and makes your liver fatty 
- Increases the rate at which you store fat 
- Raises the level of fat and triglycerides in your blood 
Cortisol secretion is also elevated in obesity, but blood levels are normal because it gets deactivated. In fat tissue itself, cortisol is elevated .
9) Stress Damages the Heart
A 2010 study found that blood cortisol predicts increased death from heart disease .
Stress hormones such as adrenaline have damaging effects if the heart is exposed to high levels for a long time .
Stress can also cause increased oxygen demand on the body, spasm of the heart blood vessels, and electrical instability in the heart .
All of these markers are believed to independently cause an increased risk of death from Heart Disease and increase the risk of death in general.
10) Chronic Stress Harms Your Cognitive Function
The hippocampus (memory center) contains many cortisol receptors. While normal cortisol levels are healthy, excess cortisol overwhelms the hippocampus and actually causes it to decay.
Studies of the elderly show that those with elevated cortisol levels display significant memory loss. The damage is usually reversible.
Chronic stress impairs learning and memory in humans and rodents and disrupts long-term potentiation (LTP) in animal models .
These effects are associated with structural changes in hippocampal neurons, including reduced dendritic branching. This is caused by CRH .
Cortisol/Glucocorticoids, which are downstream of CRH, impair declarative memory retrieval and working memory (WM) performance .
Stress also decreases neurogenesis or the ability to create new neurons in our memory centers (hippocampus) .
Stress decreases the level of BDNF in your brain. BDNF is important for various cognitive functions .
Stress can induce long-lasting epigenetic changes by decreasing gene expression in the brain (by increasing HDAC4). These changes are reversed by an HDAC inhibitor (such as Hi-Maize resistant starch) .
In kids, chronic stress can result in permanent harm, while in adults it’s mostly reversible. (It may be reversed in kids by unclogging CRH from CRF1) .
Chronic stress in animals also impairs various higher order thinking processes (time and recognition memory) controlled by the prefrontal cortex (PFC). This occurs as a result of glutamate resistance (49).
Cortisol also induces glutamine synthase, which reduces glutamate in the brain (not good if it’s too low or too high) .
Chronic stress can also cause glutamate excitotoxicity by impairing the ability of transporters to clear synaptic glutamate and by decreasing the rate by which it converts to glutamine (which is not excitotoxic) .
GABA resistance probably also contributes to glutamate excitotoxicity.
In the short term, stress can increase dopamine levels in the medial prefrontal cortex, which is responsible for abstract thinking. Too much dopamine is bad and you will not function well emotionally.
In the long term, dopamine release is inhibited and you result in lower dopamine. This is the mechanism by which stress induces ulcers (by lowering dopamine) .
Chronic stress also decreases the number of binding sites for dopamine transporters , which I think should lead to less dopamine.
Regarding stress and dopamine, your genetic predisposition comes into play. If you are GG for the COMT gene, you will have less dopamine. Stress will, therefore, increase dopamine to optimal levels. However, if you’re A/G or A/A (70% of the population) then stress will cause too much dopamine, which will harm cognitive performance .
The neurotransmitter acetylcholine is released by nerve cells in the brain when people or mice are under mild stress or concentrating on learning something new. To prevent the nerves from firing excessively, however, the neurotransmitter is quickly broken down by an enzyme called acetylcholinesterase (AChE) .
This initial increase in acetylcholine is known to trigger the production of more AChE. Indeed, AChE activity increased in the mice by two to three times in the 50 minutes following stress and was elevated for up to 80 hours .
Stress, therefore, in the long term, decreases acetylcholine (by increase AChE) .
This is believed to be part of the cause of PTSD .
Cortisol stimulates liver detoxification by inducing tryptophan oxygenase, which also has the effect of reducing serotonin levels in the brain . This chronic stress also causes serotonin resistance .
11) Stress Lowers Good Hormones: Pregnenolone, DHEA, Testosterone and Growth Hormone
Pregnenolone, Progesterone, and DHEA are anti-inflammatory, antioxidant, anti-stress, wakeful promoting, mood and cognitive enhancing. You can supplement with Pregnenolone to restore your levels.
Testosterone is also an anti-inflammatory, anti-oxidant and improves our mood and cognition.
In chronic stress growth hormone is decreased .
Growth hormone is important to have balanced and is critical to cognitive function.
12) Stress Can Make You Infertile and Lower Your Libido
Studies show that a decreased sex drive is a common complaint in people who have stressful jobs and work long hours .
In stress, there is suppression of sex hormones (LH, FSH), leading to disruption of the normal menstrual cycle and male hormones .
LH stimulates testosterone production, which partly explains why testosterone is low in animals with chronic stress .
These hormonal changes lower libido, especially lower testosterone .
Prolonged exposure to stress can lead to complete impairment of reproductive function .
GnRH (releases LH, FSH) can’t make its way to the pituitary to release LH and FSH if there’s increased CRH .
More significantly, stress increases GnIH, which directly inhibits GnRH .
This subsequently suppresses sperm count, ovulation, and sexual activity .
13) Stress Increases ‘Bad’ Hormones: Prolactin, Estrogen
Estrogen has many important functions and balance is important, but people generally have too much rather than too little. Hence, this becomes a ‘bad’ hormone.
14) Psychological Stress Causes Oxidative Stress
Stress has long been suggested to exacerbate symptom expression in people with chronic inflammatory disorders. Psychological stress was found to significantly increase superoxide release (from PMN cells) in animals .
It’s known that oxidative stress causes psychological stress. But the opposite is true as well – psychological stress also causes oxidative stress.
Stress increases nitric oxide in the hippocampus (memory center), which then results in oxidative stress (by forming peroxynitrite) .
This then goes on to cause resistance to cortisol (glucocorticoid resistance), which means that we need more cortisol to do its job.
In some cases, CRH itself can increase oxidative stress (superoxide release by macrophages) .
Oxidative stress is involved in pretty much every disease. PQQ is amazing at combating it and rebuilding our mitochondria.
Chronic stress increases oxidative stress in women. The women who ate a high junk food diet (HPF) AND were chronically stressed had double the level of oxidative stress compared to those who ate a junk food diet and weren’t stressed .
15) Stress Disrupts Your Circadian Rhythm
Excessive and/or chronic stress can lead to a disturbance of the circadian rhythm .
This is actually extremely important because it’s the circadian rhythm that’s mostly responsible for variations in health issues.
By stress dysregulating your circadian rhythm, all kinds of negative events can happen.
There’re differences among people in how stress dysregulates the circadian rhythm. A higher corticosterone release in response to stress resulted in a lengthier time for the circadian rhythm to normalize .
16) Stress Causes a Leaky Brain Barrier
Acute stress increases Brain Barrier permeability that is dependent on CRH and mast cells .
17) Stress Causes Bone Loss
Cortisol is a hormone that decreases osteoblasts and therefore will lead to decreased bone density (by inhibiting periosteal cells) .
18) Stress Delays Wound Healing
High levels of perceived stress and increases in cortisol have been found to lengthen wound healing time in healthy, male adults .
Those who had the lowest levels of cortisol the day following an injury had the fastest healing time .
In dental students, wounds (punch biopsies) took an average of 40% longer to heal when performed three days before an examination as opposed to wounds on the same students during summer vacation .
Wounded mice that underwent a restrained stress test took an average of 3.10 days longer to heal than control mice .
Socializing animals speeded wound healing time, mitigating the effects of the stressor .
19) Stress Reduces Beneficial Minerals
As it is, our modern diets are extremely imbalanced in that we get too much salt and too little potassium. HPA activation will, therefore, worsen this imbalance.
Cortisol also decreases calcium uptake in the kidneys and more of it is released in the urine instead of being utilized. Normally, aldosterone increases calcium reabsorption, but cortisol competes with it .
What’s particularly insidious about this is that most people don’t get enough of potassium (4,700mg), magnesium (400mg), calcium (1,000mg) or zinc (15mg).
If you type in your diet to Cronometer, you will see that you aren’t getting enough of all of these minerals consistently (with the exception of magnesium if you have a healthy diet).
I was deficient in all of them no matter how well balanced my diet was. I was only getting enough magnesium with a balanced diet, but I still did better after supplementing with it.
20) Stress Ruins Your Skin
Stress causes all kinds of skin issues, including acne, baldness, and inflammatory skin disorders.
CRH is believed to be an important cause of acne, psoriasis, eczema, alopecia areata, skin tumors and hives (urticaria) .
Stress increases the risk of kidney stones. One mechanism is from vasopressin, which is released by the pituitary gland when stressed and causes our urine to be less diluted. Another mechanism is because cortisol decreases calcium uptake and more of it is released in the urine, which will cause calcium stones.
Collagen is a molecule that makes connective tissue. It is vital for structural support and is found in muscles, tendons, and joints, as well as throughout the entire body. Cortisol inhibits collagen .
In rats, cortisol caused 10X greater collagen loss in the skin than in any other tissue .
Cortisol stimulates stomach acid secretion, which probably explains the stress-ulcer connection .
Cortisol shuts down the reproductive system, resulting in an increased chance of miscarriage and (in some cases) temporary infertility .
Cortisol decreases amino acid uptake by muscle and inhibits protein synthesis. This means we won’t build muscle as well .
Cortisol also inhibits IgA and IgM in the blood (IgA is good for inducing tolerance to proteins) .
Cortisol increases copper by stimulating many copper enzymes (chronically elevated copper isn’t good) .
CRH increases vasopressin, which is what makes you thirsty after stress. Vasopressin can also increase the release of CRH.
Epinephrine and norepinephrine will positively feedback to the pituitary and increase the breakdown of POMCs into ACTH and β-endorphins .
IL-1 is the most potent HPA activator .
Stress and the Immune System
Cortisol weakens the activity of the immune system by:
- Causing the thymus to decay, which is responsible for immunity.
- Inhibiting IL-12, interferon gamma and alpha, TNF and Th1 cells .
- Increasing IL-4, IL-10, and IL-13 by Th2 cells .
- Inhibiting Histamine secretion.
- Reducing production of T-cells by making them unresponsive to IL-1, which lessens IL-2 (a T-cell growth factor) .
- Inhibiting Natural Killer Cells (by inhibition of natural cytotoxicity receptor. Prolactin activates) .
- Inhibiting NFκB 
Not all of the effects of stress are bad. This post isn’t about the good effects of stress, but here’re a few bits.
CRH and vasopressin (increased by stress) break apart a precursor protein (POMC) into ACTH and β-endorphins. So stress can increase endorphins as well (good).
Recommendations to Reduce Stress
- Breathing program – Andrew Weil – Stress Management
- Full Catastrophe Living – Kabat-Zinn – Stress Management/Self-improvement
- Guided Mindfulness Meditation – Kabat-Zinn – Stress Management
- Happiness: A Guide To Developing Life’s Most Important Skill – Matthieu Ricard
- Mindfulness for Beginners – Kabat-Zinn – Stress Management/Self-improvement
- Open focus – Les Fehmi – Stress Management
- Where You Go, There You Are – Kabat-Zinn – Stress Management/Self-improvement… I went from being stressed 24/7, with panic attacks, to not having any stress/anxiety after adopting attitudes from the book.
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