Cortisol and Chronic Stress - Cortisol Resistance

Concrete evidence linking chronic stress to inflammation and modern disease
Chris Kresser: [..] So, the other day, I saw a new study with the title Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk (http://www.pnas.org/content/early/2012/03/26/1118355109.abstract), and since I’ve been thinking a lot about stress and the effects of stress on disease, I thought it would be a good idea to talk a little bit about this study because it’s really interesting, and it takes our traditional concept of how stress contributes to disease and kinda turns it on its head. It’s some relatively new information. I’ve seen a few other studies with a similar theme, and if anything, it just reinforces what we’ve been talking about in terms of the connection between stress and disease and the importance of managing stress and either reducing the symptoms of a disease that we already have or helping to cure it entirely or preventing the risk of acquiring a new disease. So, stress is associated with just about every modern disease that you can name, from depression to cardiovascular disease to type 2 diabetes to autoimmune conditions like rheumatoid arthritis and Crohn’s disease and multiple sclerosis to upper respiratory infections and even the common cold. And up until pretty recently and still now, I think, most people think that stress causes disease by dysregulating the hypothalamic-pituitary-adrenal axis, but this notion that stress acts simply by elevating cortisol levels is becoming less and less likely, at least in the current scientific literature. So, what this new paper and other recent papers suggest is that it’s actually the sensitivity of cells or the target tissue to cortisol, not absolute levels of cortisol that’s most important. So, glucocorticoid resistance, which is a decrease in sensitivity of immune cells to glucocorticoid hormones like cortisol, makes it more difficult to shut off the inflammatory response. So, let me break that down. When you’re insulin resistant, you’re producing enough insulin, but your cells are resistant to the effects of insulin, so it’s like insulin’s knocking on the door, but nobody’s inside or whoever’s inside isn’t listening, so the door doesn’t get open, and insulin can’t perform its function. The same is true with leptin resistance, and there’s even thyroid hormone resistance where thyroid hormone can’t activate the cellular receptors for thyroid hormone, so even though there’s plenty of thyroid hormone circulating around, you experience all the signs and symptoms of hypothyroidism because thyroid hormone isn’t affecting the receptor.

So, this study and others like it suggest that there’s a similar phenomenon with cortisol resistance. So, it’s not high levels of cortisol, per se, that are contributing to an increased susceptibility of disease, but it’s instead the insensitivity of cellular receptors to cortisol that’s the problem, because one of cortisol’s jobs is to turn off the inflammatory response once it gets started. So, let’s say you catch a cold or you get a cut or you have some kind of injury or illness, and inflammation is the natural response to that. Inflammation is not all bad. In an acute setting, inflammation is what helps us to heal. The problem happens when inflammation doesn’t get turned off appropriately, and then it just kinda runs wild and you get chronic inflammation, and it’s that chronic inflammation that is a risk factor for disease, not the acute inflammation that helps us to heal. So, in a normal functioning person, what would happen is that you’d get a cold or you’d get some kind of injury or acute condition that causes inflammation, and then the glucocorticoids, like cortisol, are produced and they turn off the inflammatory response by activating the glucocorticoid receptors. So, what these researchers have found is that people who are under chronic stress, that doesn’t work right. The cortisol gets secreted, but it doesn’t activate the receptors, and then you get a runaway inflammatory response. And this has been shown in other studies. They’ve found that cortisol resistance is present in spouses of brain cancer patients, in parents of children with cancer, and in people that are very lonely, and all of those populations are known to be experiencing significant stress.

So, in this study, the researchers used, I think, a pretty ingenious model to demonstrate this effect. I mean, it’s well established that chronic stress increases the susceptibility to the common cold and upper respiratory infections, as I mentioned earlier. So, the researchers actually did two studies in one. The first one was meant to determine whether stress causes cortisol resistance and whether people with cortisol resistance are more likely to develop a common cold in the first place. And then the second one was meant to determine whether cortisol resistance could predict the amount of local inflammation in the nose, for example, in response to a viral infection. So what they did is they actually purposely infected people with a virus, a rhinovirus that causes the common cold and respiratory infection, and as expected in the first study, the results did show that exposure to stress increased cortisol resistance, and in the control group they found that exposure to an acute stressor was associated with white blood cell count, but in the group that was under chronic stress there was no association. So, in other words, what should happen is that when you’re exposed to a stressor, as I mentioned, cortisol should turn off the inflammatory response and reduce the white blood cell count, but that didn’t happen in people that were under chronic stress and had cortisol resistance.

In the second study, they found a correlation between cortisol resistance and the levels of various proinflammatory cytokines locally, like interleukin-6 and TNF-alpha. And then they also saw a decreased sensitivity of white blood cells to the inhibitory effects of cortisol, like we’ve been talking about. So, in other words, when you’re stressed out, the immune system cannot turn off the inflammatory response like it’s supposed to, and then you’re more likely not only to get sick in the first place, but you’re more likely to stay sick for longer because that inflammatory process doesn’t get inhibited. So, the interesting thing also about this study is that there was no correlation between actual cortisol levels, like circulating cortisol levels, and disease risk or inflammation. So, it seems like it’s the cellular receptivity to cortisol, the sensitivity of the receptors to the actions of cortisol, that’s the most important, rather than the circulating levels of cortisol themselves. So, I thought that was pretty interesting, and it may not change things from from an end-user perspective too much because the idea is still that you want to take steps to manage your stress, but for me, every study I see like this is just another affirmation of the importance of stress management, and I see it in my work with my patients, I see it in my own life and my own experience, and people might be getting tired of hearing me talk about it, but I’m gonna keep talking about it because I thinks it’s kinda the elephant in the room in a lot of cases. In my patient population, I think I can pretty safely say that people who are taking active steps to manage their stress have significantly better clinical outcomes than people who don’t, and I just think it’s a much bigger contributor to the whole disease process than most of us really realize.

Steve Wright: That’s pretty insightful, man. And I thinks it’s awesome that we’re getting more data on what the problem is because you do hear a lot about, well, you’re not totally stressed out or you can go do another CrossFit workout as long as your cortisol isn’t over 20 or something like that.

Chris Kresser: Yeah.

Steve Wright: So, this is cool to have a new model. Now, do you know if, for instance, because we’re a little bit better at measuring insulin resistance and leptin resistance, are the three correlated? So, if I’m insulin resistant, I’m likely leptin resistant or I am leptin resistant. Am I also cortisol resistant then?

Chris Kresser: I don’t know what the exact relationship between all of those would be, but I certainly think that HPA axis dysregulation can contribute in some way to leptin and insulin resistance and probably vice versa. I wish there was a way of testing for cortisol resistance in the commercial setting. I don’t think there is. I think it’s only available in research settings. But what’s interesting about this study is that I think, like you said, the idea that we can just run an adrenal stress index or any kind of hormone profile where we measure cortisol, and if the person has normal cortisol we say: OK, you’re clear to do, you know, five CrossFit workouts a week. We can’t really make that assumption because that test is not gonna show cortisol resistance in the white blood cells. I think ultimately just paying attention to symptoms is a pretty good guide because if you have this cortisol resistance pattern, you’re gonna have more difficulty recovering from workouts because that inflammatory response won’t get turned off. I mean, working out, especially lifting weights, but doing any kind of intense workout is basically like a controlled stimulation of inflammation. You’re breaking down tissue when you lift weights. You’re breaking down your muscle tissue, and the idea is that when it builds back, it builds back bigger and more able to deal with the next stressor, in that case, lifting weights. So, that works well if you give the body long enough to recover, if you give the body long enough to turn off that inflammation and then to start the anabolic process rather than the catabolic process of building the tissue back up. And if you’re a healthy person with no significant stress levels and you’re not dealing with any chronic inflammatory condition, that should happen fairly quickly and commensurately with the amount of exercise that you did. But if you’re dealing with chronic stress and you have cortisol resistance, here’s what’s gonna happen: You’ll do the intense workout, you break your tissue down, which is what happens and is the whole point, but the recovery process will be very, very slow, and the inflammation will persist. So, instead of taking one day or maybe two days to get back to baseline and then start building new tissue, stronger tissue, you’ll take several days to get back to baseline, or maybe you really never fully do get back to baseline. And then you do another intense workout, so then you break down more tissue and cause more inflammation, and then it’s a downhill slide from there. And I see this a lot in the CrossFit community, people who come to me who have been doing CrossFit. And this is not all people who do CrossFit. I’m talking about people who are under significant stress and who may be dealing with a chronic health challenge. But the fact is most of us in this modern world are under stress, and some of us are better at managing it than others, and some of us pay more attention to that than others, but I think this is a very real phenomenon and it’s not just affecting people who have kids with cancer or spouses with cancer or people who are socially isolated. It’s affecting all of us to some degree or another.

Steve Wright: Way to wrap that up. I think it’s important to keep learning about it

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There are now a host of human states associated with tissue-specific changes of GC action. Decreased GC responsiveness is found in patients with chronic obstructive pulmonary disease and acute respiratory distress syndrome, and is also an issue for some patients with asthma, rheumatoid arthritis, inflammatory bowel disease and lymphoproliferative disorders. For example, about 30% of patients with rheumatoid arthritis fail to respond to steroid therapy, whereas 5-10% of asthmatics fall into the category of relative GC insensitivity. In asthmatics, this sub-population is itself divided into smaller subsets which have different underlying mechanisms, ranging from an inherited genetic basis to altered GCs signaling triggered by exposure to environmental stressors such as cigarette smoking or infection.

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The level of expression of the glucocorticoid receptor (GR) is the principal determinant of glucocorticoid sensitivity in most cells. GR levels are permanently ‘set’ in a tissue-specific manner in response to the perinatal environment, an effect we have previously shown to relate to differential expression of tissue-enriched alternative promoters/exons 1 of the GR gene. In adult animals, GR levels are dynamically regulated around the ‘set point’ by glucocorticoids themselves, with glucocorticoids down-regulating GR mRNA in most cells and tissues {the longer the exposure to cortisol the more resistance - the receptors need a break from cortisol in order to reset}. Here we have examined whether autoregulation of GR mRNA by glucocorticoids involves differential promoter regulation. We show that, in contrast to tissue-specific programming of GR mRNA levels, autoregulation of GR mRNA in vivo does not involve differential regulation of variant exon 1-containing GR mRNAs in that the major variants are down-regulated to a similar extent by glucocorticoid treatment. Consistent with this, transfections of reporter constructs showed that the majority of GR promoters, which are contained within a 4.4 kb region upstream of exon 2, are similarly regulated by glucocorticoids, with two regions of the promoter redundantly required for glucocorticoid regulation. Thus transcriptional autoregulation can occur in adult tissues around the set point established by promoter selection in early life.

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Restoring Glucocorticoid Sensitivity with Curcumin

Another paper5 reports that curcumin is able to restore corticosteroid sensitivity in human monocytes by maintaining levels of HDAC2 (histone deacetylase 2) which is known to be deficient in COPD and asthma patients. Deficiency of HDAC2 correlates with the severity of disease. The amount of curcumin required in vitro to restore HDAC2 activity and corticosteroid efficacy in cigarette smoke extract exposed cells is exceptionally small, having an EC(50) of approximately 30 nM (NANOmoles) and 200 nM (NANOmoles) respectively.5 Theophylline, a natural methylxanthine chemically related to caffeine, is also able to restore HDAC2 activity.6

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SEROTONIN AND OTHER MOLECULES INVOLVED IN DEPRESSION
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The adrenal glands secrete glucocorticoids (such as cortisol, in human beings), which interact with the serotonin receptors in the brain.

When someone experiences a stressful event, the level of glucocorticoids in their blood rises. Via specific receptors in the hippocampus, this activates the hypothalamus, which then secretes corticotropin-releasing hormone (CRH). The CRH in turn causes the pituitary gland to release adrenocorticotropic hormone (ACTH) into the bloodstream, from which it enters the adrenal glands and causes them to secrete cortisol.

This process creates a negative feedback loop in which the excess cortisol activates the brain's glucocorticoid receptors and suppresses the production of CRH. In depressed patients, however, this loop no longer works, resulting in excess production of CRH and hence of cortisol.

Many seriously depressed patients have high blood levels of cortisol, caused by chronic stress.

In rats, chronic stress and/or a high level of glucocorticoids alters certain serotonergic receptors (increases the 5-HT2A receptors in the cerebral cortex and reduces the 5-HT1A receptors in the hippocampus). These same changes have been observed in humans who have committed suicide or suffered from diseases that cause hypersecretion of glucocorticoids. The continued administration of antidepressants causes changes in the serotonergic receptors that are the opposite of the changes produced by chronic stress. It also reverses the hypersecretion of stress hormones.

Not incidentally, in humans, many glucocorticoid receptors (GRs) and mineralocorticoid receptors (MRs) (see sidebar) are located in the hypothalamus and the hippocampus, two structures involved in mood control and the ability to experience pleasure. These receptors are sensitive both to the levels of the various corticosteroids in the body and to the length of time that they are active, so their activation mechanisms will have direct impacts on the behavioural response chosen to a given stimulus.

For example, when corticosteroids circulate at low levels they facilitate, via the MR receptors, the reactions associated with fear (momentary paralysis and turning toward the frightening stimulus). But when corticosteroids circulate at high levels (for example, when the organism is exposed to chronic stress), they instead potentiate inhibition of action, via the GR receptors .

Prolonged chronic stress also seems to alter the response of the MR and GR receptors and to have very harmful effects on people's mental equilibrium, especially when social or family supports are absent. Under these conditions, the glucocorticoid response, which was originally highly adaptive, becomes clearly maladaptive.
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Here's another example: people with Cushing's syndrome, a disease in which the body produces excess cortisol, display a high incidence of depression, and their depression lifts when they are given treatments that bring their cortisol levels back to normal.

Thus, all indications are that the end products of the HPA axis—glucocorticoids— play a role in depression by influencing several neurotransmitter systems, including those for serotonin, norepinephrine, and dopamine, all three of which are involved in depression.

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Drea said:

It might help to slow down on the smoking when stressed. I remember the C's mentioning smoking only when in the right mindset. I've noticed that when I have that extra cigarette to try and take the edge off it kind of back fires and makes things worse so it's something to keep in mind. If the only answer here is to reset those receptors then that may take some strategy especially seeing as how we're probably wired that way now. Thanks for digging this up RedFox, and thanks for the summary in layman's terms Carl.

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Carl said:

Interesting question: Would it be useful for those of us suffering from this to quit smoking? Or have I fallen for some junk science regarding the nicotine->cortisol relationship?

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Foxx said:

Do you have the quote from the session where they said that? I ran some searches but didn't find it and am interested in their comments.

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Primal Health: Understanding the Critical Period Between Conception and the First Birthday said:

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Prostaglandins have been well known since the Nobel Prize was awarded in 1982 to scientist working in this field. Like hypothalamus, T lymphocytes and DNA, prostaglandins is a word not to be ignored, even if you are not a scientist. Prostaglandins are local regulators of cell activity. They have a very short life indeed, working on a second to second basis. They are just about everywhere, in every cell and body tissue.

Prostaglandins are classified as belonging to series 1, 2, or 3, depending on which family of fatty acid they are derived from. At this point it is impossible to study in detail all the possible effects of all the known prostaglandins; the subject is too new and too complex. Nevertheless, we can see ho extraordinarily diverse their actions are by taking as an example what we know about prostaglandins series 2.

Prostaglandins 1 are able to dilate the small blood vessels, thus lowering blood pressure. They inhibit the proliferation of cells of the smooth muscles which are in the vessel walls, so having an action on their calibre. Prostaglandins 1 inhibit the aggregation of the type of white blood cells called platelets; when the platelets bunch up togother and clog the blood vessels there is a risk of thrombosis. They inhibit the synthesis of cholesterol, and help to halt the inflammatory process. They lay an important role in the thymus, and their action on the maturation of T lymphocytes is comparable of thymic hormones.

It is not hard to imagine therefore that problems with the synthesis of prostaglandins 1 can have several consequences. In fact this is what is happening to the newborn baby who is separated from its mother; the high level of cortisol blocks the synthesis of protaglandins, particularly series 1, and the low level of melatonin cannot compensate for this. It is precisely the imbalance between different prostaglandins which characterizes mos of the diseases of civilization. Usually the synthesis of prostaglandins 1 is too low the synthesis of prostaglandis 2 tends to be relative high. Prostaglandins 2 exaggerate the inflammatory process when their synthesis and action is not modulated by prostaglandins 1. When you know how pervasive prostaglandis are, you can see how imbalance between them can be responsible for a wide range of disparate symptoms.What we know about prostaglandins reveals the uniformity behind the apparent plurality masking the diseases of civilization. A review of the main aspects of the disease of civilization will throw light on some hidden facts.
Depression
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The hormonal disturbances which go with depression are now better understood. Indeed, much has been written about the depletion of hormones such as noradrenalin and serotonin in depression.

But it is the high level of cortisol, and the consequent low level of certain prostaglandins which links depression to other aspects of the disease of civilization. This rise in the level of cortisol has a greater or lesser effect depending on the person's age. In a baby or young child a raised level of cortisol has a spectacular effect in reducing the size of the thymus. This organ is big only in babies and children, when the thymus is at its most active. The thymus is set to have limited number of cell divisions during a lifetime. A high level of cortisol in babies has the effect of accelerating the aeging process of the thymus, and thus of the individual.

Some aspects of depression seem to be more and more common, perhaps because they are becoming better known. Seasonal depression start in autumn and last up to the end of winter. It seems that patients with seasonal depression are not properly adapted to darkness, and light might be the best treatment. It is likely that an irregularity of the pineal gland plays a role in this type of depression.

Regardless of age or of the function of the pineal gland, however, a high level of cortisol disturbs the synthesis of porstaglandins.
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Alcoholism
When your level of prostaglandins 1 is rather low, you feel unhappy. The chances are that you will then search for a drug to boost your spirits ---alcohol. A small amount of alcohol boosts the level of prostaglandins 1. It makes you feel better straightaway. The trouble is that the release of prostaglandins can only take place by depleting the stock of a particular fatty acid, which is the precursor of prostaglandins.
The name of the precursor deserves recognition. The fact that human breast milk is one of the only natural sources of this fatty acid suggest its paramount importance. Its name is gamma-linolenic acid or GLA for short. An adult must able to synthesize GLA, because there are almost no foods that contain it. GLA is synthesized from linoleic acid, found mainly in seeds and seed oils, like sunflower seed. Any deficit of GLA reduces the synthesis of prostaglandis and also upsets the balance between the different kinds of prostaglandis. Alcohol has the effect of depleting the stock of GLA, so the level of prostaglandins 1 drops.

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Carl said:

This is very interesting. So from what I gather so far:

0) Cortisol receptor sensitivity is screwed up by a bad perinatal environment. I'd wager that this is exacerbated through early childhood, school life etc.
1) During early life, more cortisol is pumped out in response to stressful events than would be the case if we were healthy to begin with.
2) All this cortisol dampens our cortisol receptors even more, leading to increased resistance.
2b) In addition to this, we suffer the effects of chronically elevated cortisol: It causes anxiety, suppresses serotonin (depression/low self-esteem), etc.
3) We are constantly inflamed so we actually seek to increase our cortisol (now the whole "addiction to stress" begins to make some sense).
4) This continues until we develop CFS, crippling mental health issues, chronic illness etc.

What makes sense now is the strange paradox that my habitual way of dealing with external life stress and remain happy and focused is to increase my level of stress hormones artificially: I.E. caffeine, nicotine, other stimulants, alcohol etc. This works temporarily, overcoming the receptor insensitivity through brute force, but only furthers the problem in the long term (and screws up a lot of other things).

So as Kresser says, the solution is still the same: Stress management, cutting out artificial sources of cortisol, giving the receptors time to heal. But this puts it all in a new light. Thanks for posting this RedFox.

Interesting question: Would it be useful for those of us suffering from this to quit smoking? Or have I fallen for some junk science regarding the nicotine->cortisol relationship?

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Main functions in the body[edit]
Metabolic response[edit]
In the early fasting state, cortisol stimulates gluconeogenesis (the formation of glucose), and activates anti-stress and anti-inflammatory pathways.[5] Cortisol also plays an important, but indirect, role in liver and muscle glycogenolysis, the breaking down of glycogen to glucose-1-phosphate and glucose. This is done through its passive influence on glucagon.[clarification needed] Additionally, Cortisol facilitates the activation of glycogen phosphorylase, which is necessary for epinephrine to have an effect on glycogenolysis.[6][7]

In the late fasting state, the function of cortisol changes slightly and increases glycogenesis. This response allows the liver to take up glucose that is not being used by the peripheral tissue and turn it into liver glycogen stores to be used if the body moves into the starvation state.[citation needed]

Elevated levels of cortisol, if prolonged, can lead to proteolysis (breakdown of proteins) and muscle wasting.[8] Several studies have shown that cortisol can have a lipolytic effect (promote the breakdown of fat). Under some conditions, however, cortisol may somewhat suppress lipolysis.[9] {so things to look out for to indicate cortisol problems: inability to gain/keep muscle, or muscle loss at times of stress. Inability to gain body fat (assuming you're eating enough), or an inability to body loose fat - these two tend to be genetic it seems. Both super skinny/'over weight' probably have problems with cortisol}

Immune response[edit]
Cortisol prevents the release of substances in the body that cause inflammation. It is used to treat conditions resulting from over activity of the B-cell-mediated antibody response. Examples include inflammatory and rheumatoid diseases, as well as allergies. Low-potency hydrocortisone, available as a non-prescription medicine in some countries, is used to treat skin problems such as rashes, and eczema. {therefore when cortisol resistant you may suffer from chronic versions of any of those things}

It inhibits production of interleukin (IL)-12, interferon (IFN)-gamma, IFN-alpha and tumor-necrosis-factor (TNF)-alpha by antigen-presenting cells (APCs) and T helper (Th)1 cells, but upregulates IL-4, IL-10, and IL-13 by Th2 cells. This results in a shift toward a Th2 immune response rather than general immunosuppression. The activation of the stress system (and resulting increase in cortisol and Th2 shift) seen during an infection is believed to be a protective mechanism which prevents an over activation of the inflammatory response.[10]

Cortisol can weaken the activity of the immune system. Cortisol prevents proliferation of T-cells by rendering the interleukin-2 producer T-cells unresponsive to interleukin-1 (IL-1), and unable to produce the T-cell growth factor (IL-2).[11] Cortisol also has a negative-feedback effect on interleukin-1.[12]

Though IL-1 is useful in combating some diseases; however, endotoxic bacteria have gained an advantage by forcing the hypothalamus to increase cortisol levels (forcing the secretion of CRH hormone, thus antagonizing IL-1). {something to investigate!!} The suppressor cells are not affected by glucosteroid response-modifying factor (GRMF),[13] so the effective setpoint for the immune cells may be even higher than the setpoint for physiological processes (reflecting leukocyte redistribution to lymph nodes, bone marrow, and skin). Rapid administration of corticosterone (the endogenous Type I and Type II receptor agonist) or RU28362 (a specific Type II receptor agonist) to adrenalectomized animals induced changes in leukocyte distribution. Natural killer cells are affected by cortisol.[14]

Cortisol stimulates many copper enzymes (often to 50% of their total potential), probably to increase copper availability for immune purposes.[15]:337 This includes lysyl oxidase, an enzyme that cross-links collagen and elastin. {if you have collagen (skin/bone/tissue) healing problems this is something to consider} [15]:334 Especially valuable for immune response is cortisol's stimulation of the superoxide dismutase,[16] since this copper enzyme is almost certainly used by the body to permit superoxides to poison bacteria.

Other effects[edit]

Metabolism[edit]

Glucose[edit]

Cortisol counteracts insulin {Insulin resistance! Could diabetes be related, as it raises blood sugar and blocks insulin from moving sugar out of the blood? Having blood sugar spikes/crashes despite being keto? Brain fog until you eat something?}, contributes to hyperglycemia-causing hepatic gluconeogenesis[17] and inhibits the peripheral utilization of glucose (insulin resistance)[17] by decreasing the translocation of glucose transporters (especially GLUT4) to the cell membrane.[18] However, cortisol increases glycogen synthesis (glycogenesis) in the liver.[19] The permissive effect of cortisol on insulin action in liver glycogenesis is observed in hepatocyte culture in the laboratory, although the mechanism for this is unknown.

Bone and collagen[edit]
Cortisol reduces bone formation, {problems with bone/skin healing?}[3] favoring long-term development of osteoporosis (progressive bone disease). It transports potassium out of cells in exchange for an equal number of sodium ions (see above).[20] This can trigger the hyperkalemia of metabolic shock from surgery. Cortisol also reduces calcium absorption in the intestine.[21]

Collagen is an important component of connective tissue. It is vital for structural support and is found in muscles, tendons, and joints, as well as throughout the entire body. Cortisol down regulates the synthesis of collagen.[22]

Amino acid[edit]
Cortisol raises the free amino acids in the serum. It does this by inhibiting collagen formation, decreasing amino acid uptake by muscle, and inhibiting protein synthesis.[23] Cortisol (as opticortinol) may inversely inhibit IgA precursor cells in the intestines of calves.[24] Cortisol also inhibits IgA in serum, as it does IgM; however, it is not shown to inhibit IgE.[25]

Wound healing[edit]
Cortisol and the stress response have known deleterious effects on the immune system. 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 a 4 mm punch biopsy had the fastest healing time.[26] In dental students, wounds from punch biopsies took an average of 40% longer to heal when performed three days before an examination as opposed to biopsies performed on the same students during summer vacation.[27]

Electrolyte and water balance[edit]
Cortisol acts as a diuretic, increasing water diuresis, glomerular filtration rate, and renal plasma flow from the kidneys, as well as increasing sodium retention and potassium excretion. It also increases sodium and water absorption and potassium excretion in the intestines.[28] {Got re-occurring leg cramps that only potassium fixes?}

Sodium[edit]
Cortisol inhibits sodium loss through the small intestine of mammals.[29] Sodium depletion, however, does not affect cortisol levels[30] so cortisol cannot be used to regulate serum sodium. Cortisol's original purpose may have been sodium transport. This hypothesis is supported by the fact that freshwater fish utilize cortisol to stimulate sodium inward, while saltwater fish have a cortisol-based system for expelling excess sodium.[31] {Water retention?}

Potassium[edit]
A sodium load augments the intense potassium excretion by cortisol. Corticosterone is comparable to cortisol in this case.[19] For potassium to move out of the cell, cortisol moves an equal number of sodium ions into the cell.[20] This should make pH regulation much easier (unlike the normal potassium-deficiency situation, in which two sodium ions move in for each three potassium ions that move out—closer to the deoxycorticosterone effect).

Gastric and renal secretion[edit]
Cortisol stimulates gastric-acid secretion.[32] Cortisol's only direct effect on the hydrogen ion excretion of the kidneys is to stimulate the excretion of ammonium ions by deactivating the renal glutaminase enzyme.[33]

Memory[edit]
Cortisol works with epinephrine (adrenaline) to create memories of short-term emotional events; this is the proposed mechanism for storage of flash bulb memories, and may originate as a means to remember what to avoid in the future.[34] However, long-term exposure to cortisol damages cells in the hippocampus;[35] this damage results in impaired learning. Furthermore, it has been shown that cortisol inhibits memory retrieval of already stored information.[36][37]

Sleep, stress, and depression[edit]
Diurnal cycles of cortisol levels are found in humans.[6] In humans, the amount of cortisol present in the blood undergoes diurnal variation; the level peaks in the early morning (approximately 8 a.m.) and reaches its lowest level at about midnight-4 a.m., or three to five hours after the onset of sleep. Information about the light/dark cycle is transmitted from the retina to the paired suprachiasmatic nuclei in the hypothalamus. This pattern is not present at birth; estimates of when it begins vary from two weeks to nine months of age.[38]

Changed patterns of serum cortisol levels have been observed in connection with abnormal ACTH levels, clinical depression, psychological stress, and physiological stressors such as hypoglycemia, illness, fever, trauma, surgery, fear, pain, physical exertion, or temperature extremes. Cortisol levels may also differ for individuals with autism or Asperger's syndrome.[39] There is also significant individual variation, although a given person tends to have consistent rhythms.[40]

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Factors reducing cortisol levels[edit]
Magnesium supplementation decreases serum cortisol levels after aerobic exercise,[65][66] but not after resistance training.[67]
Omega-3 fatty acids have a dose-dependent effect[68] in slightly reducing cortisol release influenced by mental stress,[69] suppressing the synthesis of interleukin-1 and -6 and enhancing the synthesis of interleukin-2; the former promotes higher CRH release. Omega-6 fatty acids, on the other hand, have an inverse effect on interleukin synthesis.[70]
Music therapy can reduce cortisol levels in certain situations.[71]
Massage therapy can reduce cortisol.[72]
Laughing, and the experience of humour, can lower cortisol levels.[73]
Soy-derived phosphatidylserine interacts with cortisol; the correct dose, however, is unclear.[74][75]
Black tea may hasten recovery from a high-cortisol condition.[76][77][78]
Regular dancing has been shown to lead to significant decreases in salivary cortisol concentrations.[79]

Factors increasing cortisol levels[edit]
Viral infections increase cortisol levels through activation of the HPA axis by cytokines.[80]
Caffeine may increase cortisol levels.[81]
Sleep deprivation[82]
Intense (high VO2 max) or prolonged aerobic exercise transiently increases cortisol levels to increase gluconeogenesis and maintain blood glucose;[83] however, cortisol declines to normal levels after eating (i.e., restoring a neutral energy balance)[84]{Poor posture (see below), damage connective tissue (from excess cortisol) and nerve damage can all trigger muscles to be in a state of 'prolonged aerobic exercise' - i.e. chronic muscle tension. Stress makes you tense, tension makes you stressed}
The Val/Val variation of the BDNF gene in men and the Val/Met variation in women are associated with increased salivary cortisol in a stressful situation.[85]
Hypoestrogenism and melatonin supplementation increase cortisol levels in postmenopausal women.[86]
Severe trauma or stressful events can elevate cortisol levels in the blood for prolonged periods.{As cortisol/adrenaline create 'flash bulb' memories, the recall of them in things like PTSD will again raise cortisol}[87]
Subcutaneous adipose tissue regenerates cortisol from cortisone.[88]
Anorexia nervosa may be associated with increased cortisol levels.[89]
The serotonin receptor gene 5HTR2C is associated with increased cortisol production in men.[90]
Severe calorie restriction causes elevated baseline levels of cortisol.[91]
Posing in low-power nonverbal displays through close, contractive postures can increase cortisol levels.{Your body posture effects cortisol levels!}[92]
Smelling androstadienone has been found in one study to raise cortisol levels in women; as well as, in other studies, to affect mood (see androstadienone article for details and citations).

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The Role of Cortisol in Sleep

THE CORTISOL-SLEEP CONNECTION
Adaptation to extrinsic and intrinsic forces is a survival necessity for all living organisms. The hypothalamic-pituitary-adrenal (HPA) axis is an adaptive system with the purpose of maintaining a dynamic equilibrium or homeostasis in a constantly changing environment. Sleep is regulated by the HPA axis in multiple ways, and a growing body of research suggests reciprocal associations between sleep and the activity of the HPA axis.

The HPA axis
Corticotropin-releasing hormone (CRH) is secreted by a hypothalamic region called the paraventricular nucleus (PVN) and acts on CRH receptors in the anterior pituitary to cause the release of adrenocorticotropic hormone (ACTH) into the blood. ACTH acts on the adrenal cortex, which produces and releases cortisol into the blood and participates in maintaining homeostasis throughout the body. CRH also activates the locus ceruleus (LC) which utilizes norepinephrine (NE) and causes further stimulation of the PVN and subsequent release of CRH. It also stimulates the amygdala {danger/anxiety}, which is part of the limbic system.1,2 Elevated brain NE levels and CRH have been implicated in sleep disturbances, including primary insomnia.3,4 NE levels have also been shown to directly correlate to CRH levels, whereby elevated NE results in elevated CRH and low NE results in low CRH.5,6
Along with its numerous actions in the body, cortisol has feedback inhibition on the PVN and anterior pituitary to decrease CRH and ACTH production and release, respectively. Many areas of the brainstem, including the LC, are rich in cortisol receptors, indicating additional negative feedback mechanisms mediated by the cortisol- HPA axis.7,8 Furthermore, the PVN receives GABAergic innervations, which can also inhibit the release of CRH.9
These GABAergic neurons are chiefly opposed by the excitatory neurotransmitter glutamate.7 Therefore, in addition to negative feedback signaling by cortisol, HPA axis regulation also includes NE, GABA, and glutamate modulation. {that is, if things like GABA help a bit cortisol and the HPA is an area to investigate}
[..]
Sleep/HPA Axis and Cortisol Rhythm
The initiation of sleep occurs when HPA axis activity is lowest, and sleep deprivation is association with HPA activation. Nighttime awakening is associated with pulsatile cortisol, NE, and CRH release and is followed by a temporary inhibition of cortisol secretion. Cortisol begins to have a rapid rise upon the first morning awakening and continues to rise for about 60 minutes. This phenomenon is called the awakening response.
Dysfunctional HPA axis activity may play a role in some sleep disorders, but in other cases the HPA axis dysfunction is actually the result of a sleep disorder, as seen in obstructive sleep apnea. HPA axis hyperactivity can lead to fragmentation
of sleep, decreased slow-wave sleep, and shortened sleep time. To complicate matters, sleep disturbances can worsen HPA axis dysfunction, thereby worsening the cycle. Both insomnia and obstructive sleep apnea are specific sleep disorders that are
associated with HPA dysfunction.
Depression and other stress-related disorders are also associated with sleep disturbances, elevated cortisol,11 altered NE levels,12 and HPA axis dysfunction.13 Interestingly, chronic insomnia without depression occurs with elevated cortisol levels, particularly in the evening and the first part of the nighttime sleep period.14,15,16,17 This elevation in cortisol may be a primary cause of the sleep disturbance. In addition, the elevated cortisol may be a marker for increased CRH activity
and CNS norepinephrine.18,19,20
In summary, HPA axis hyperactivity can have a negative impact on sleep, leading to sleep fragmentation, decreased deep slow-wave sleep, and shortened sleep time. In turn, sleep problems including insomnia and obstructive sleep apnea can further propagate HPA axis dysfunction.
Interventions to normalize HPA axis abnormalities, decrease nocturnal CRH hyperactivity, and decrease cortisol may be beneficial in treating insomnia and other sleep disorders.

Alternative Approach to Hypercortisol-Induced Sleep Problems
An effective way to manage chronically elevated cortisol levels is to ensure that the adrenal glands are supported by proper nutrition. Vitamin B6, vitamin B5 (pantothenic acid), and vitamin C often become depleted with prolonged hyperactivity
of adrenal gland activity and increased production of cortisol.21
These nutrients play a critical role in the optimal functioning of the adrenal gland and in the optimal manufacturing of adrenal hormones. Levels of these nutrients can be diminished during times of stress. For instance, urinary excretion of vitamin C
is increased during stress, which is evidence of vitamin C “dumping.” Consequently, additional symptoms may develop with these nutritional deficiencies. Observations and a rich tradition of anecdotal writings and reports supporting this
claim have shown that deficiencies in pantothenic acid results in fatigue, headaches, and insomnia. L-tyrosine and L-theanine support the adrenal glands by supporting NE production and are beneficial in combating fatigue and anxiety symptoms related
to stress.22,23 In addition, the cortisol feedback mechanisms are dependent on adequate amounts of calcium, magnesium, potassium, manganese, and zinc.24 Therefore, supplementation of these nutrients along with other supporting agents, such as
L-tyrosine and L-theanine, may help ameliorate some symptoms as well as assist in proper HPA axis functioning.

Ashwagandha (Withania somnifera), also known as Indian ginseng, has been shown to reduce corticosterone, a glucocorticoid hormone present in amphibians, reptiles, rodents, and birds that is structurally similar to cortisol.25,26 An array of clinical trials and laboratory research also support the use of ashwagandha in enhancing mood, reducing anxiety, and increasing energy.27,28,29,30

Magnolia (Magnolia officinalis), was studied in a randomized, parallel, placebo-controlled study in overweight premenopausal women and resulted in a decrease in transitory anxiety, although salivary cortisol levels were not significantly reduced.31 Magnolia
has been demonstrated to improve mood, increase relaxation, induce a restful sleep, and enhance stress reduction.32
In an unpublished study conducted at the Living Longer clinic, Cincinnati, Ohio, a proprietary blend of Magnolia officinalis and Phellodendron amurense was shown clinically to normalize the hormone levels associated with stress-induced obesity. It was demonstrated that this combination lowered cortisol levels by 37 percent and increased DHEA by 227 percent.

Phosphatidylserine (PS), also known as lecithin phosphatidylserine, is known to blunt the rise in cortisol and ACTH following strenuous training and significantly reduce both ACTH and cortisol levels after exposure to physical stress.33,24 Phosphatidylserine also has been shown to improve mood.35,36

Another approach to improving sleep is targeting GABA activity. Increasing GABA activity will decrease LC, PVN, and resultant HPA axis activity. One method to support GABA functioning is to decrease glutamate signaling. Glutamate
and GABA activity oppose each other; therefore, decreasing glutamate activity will support healthy HPA axis activity.
L-theanine is a glutamate receptor antagonist and has been shown to decrease brain NE levels secondarily to increasing GABA levels.37,38 Interestingly, N-acetylcysteine (NAC) is a known precursor for cysteine, necessary for the synthesis of glutathione,39,40 but also has been shown to decrease glutamate levels. NAC decreases glutamate by enhancing the activity of a cystine/glutamate antiporter. Glutamate is regulated by a cystine/glutamate antiporter that exchanges extraceullular
cystine for intracellular glutamate.41 Ultimately, the actions of this antiporter serve to lessen synaptic glutamate levels. Furthermore, glutamate is involved in immune-cell signaling to increase dendritic cell maturation following the exposure to
antigens. To address elevated glutamate at its source, evaluation of intestinal permeabilities, food sensitivities/allergies, and bacterial and/or viral infections need to be considered due their relationship to dendritic cell maturation via increase antigen
presence.42

4-amino-3-phenylbutyric acid is a synthetic amino acid sold as a nutritional supplement that crosses the blood-brain barrier and is a GABA agonist.43 Like many other GABA agonists, 4-amino-3-phenylbutyric acid can promote sleep by stimulating
sleep-promoting centers in the brain. It also supports healthy cortisol levels by inhibiting the LC release of NE into the PVN.

Rhodiola rosea is an adaptogenic herb that modulates cortisol.44 It reduces catecholamine release and prevents catecholamine depletion from the adrenal glands. In addition, research that was conducted in Russia indicates that it may stimulate opioid receptors,45 which in turn can reduce NE excitability in the PVN and HPA axis activity.46

Many traditional botanicals (eg, American ginseng, ashwagandha, Asian ginseng, astragalus, cordyceps, reishi, eleutherococcus, holy basil, rhodiola, schisandra, maca, licorice) and common nutritional supplements (eg, phosphatidylserine,
L-theanine, 4-amino-3-phenylbutyric acid, NAC) have been utilized for their stabilizing effects on the HPA axis. Combination/multi-ingredient formulations are common in a whole-system approach to restoring HPA axis dysfunction, whether to increase or decrease cortisol levels.

Conclusion
Reducing cortisol levels and stabilizing HPA axis dysfunction can be a very effective approach to addressing sleep disturbances, while also reducing the long-term risks associated with elevated cortisol levels.

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Hypoestrogenism and melatonin supplementation increase cortisol levels in postmenopausal women.[86]

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Carl said:

Moving onto breath. Pipe breathing does not work for me the way other people report, and when I'm in a stressful situation, it doesn't seem to help me relax. It only works when I am already feeling relaxed and safe. What does work is just really deep breathing. I have begun to develop a habit whereby when a typical trigger of anxiety for me arises (e.g. talking in front of a group), I take a really deep breath, try to physically move the energy down out of my head and into my lower body, feeling my feet stable on the ground.

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Memory[edit]
Cortisol works with epinephrine (adrenaline) to create memories of short-term emotional events; this is the proposed mechanism for storage of flash bulb memories, and may originate as a means to remember what to avoid in the future.[34] However, long-term exposure to cortisol damages cells in the hippocampus;[35] this damage results in impaired learning. Furthermore, it has been shown that cortisol inhibits memory retrieval of already stored information.[36][37]

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These nutrients play a critical role in the optimal functioning of the adrenal gland and in the optimal manufacturing of adrenal hormones. Levels of these nutrients can be diminished during times of stress. For instance, urinary excretion of vitamin C
is increased during stress, which is evidence of vitamin C “dumping.” Consequently, additional symptoms may develop with these nutritional deficiencies. Observations and a rich tradition of anecdotal writings and reports supporting this
claim have shown that deficiencies in pantothenic acid results in fatigue, headaches, and insomnia. L-tyrosine and L-theanine support the adrenal glands by supporting NE production and are beneficial in combating fatigue and anxiety symptoms related
to stress.22,23 In addition, the cortisol feedback mechanisms are dependent on adequate amounts of calcium, magnesium, potassium, manganese, and zinc.24 Therefore, supplementation of these nutrients along with other supporting agents, such as
L-tyrosine and L-theanine, may help ameliorate some symptoms as well as assist in proper HPA axis functioning.

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3) Chronic stress will deplete resources (vitamins/minerals) which will cause further problems - the dis-regulation in stress may not be correctable without replacing these.

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Regular dancing has been shown to lead to significant decreases in salivary cortisol concentrations.[79][/b]

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The structure and properties of a new immunomodulatory peptide isolated from ovine colostrum are described. PRP acts both in vivo and in vitro, and is not species specific. PRP increases permeability of skin vessels, and causes differentiation of murine thymocytes into functionally active T cells. It can simultaneously change surface markers and function of cells. The polypeptide is able to reduce binding of peanut agglutinin (PNA) to PNA+ thymocytes and to increase the binding of PNA to PNA- cells. PRP is also able to transform cortisone-resistant thymocytes into cortisone-sensitive, and vice versa. The observed changes occurred concomitantly, i.e. changes in binding of PNA were accompanied by changes in resistance to cortisone and in expression of helper or suppressor activity. The fact that changes induced by PRP are reversible after the second exposure of the cells to the polypeptide makes it unique among known immunomodulators. An active nonapeptide fragment: Val-Glu-Ser-Tyr-Val-Pro-Leu-Phe-Pro was isolated from the products of PRP digestion. It shows full spectrum of biological activities of PRP. The sequence-Pro-Leu-Phe- is responsible for the immunological effect of the peptide.

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Beta-sitosterol
Beta-sitosterol has a structural similarity to cholesterol, but none of the artery-clogging effects. In the diet, plant oils contain the highest concentration of beta-sitosterol, nuts and seeds contain fairly high levels, and all fruits and vegetables generally contain some amount of beta-sitosterol. Perhaps the best way to obtain beta-sitosterol is to eat a diet rich in fruits, vegetables, nuts, and seeds.
Beta-sitosterol appears to help modulate immune function, inflammation, and pain levels through effects on controlling the production of inflammatory cytokines. In athletes competing in marathons and other endurance events, beta-sitosterol is known to reduce cortisol levels, maintain DHEA levels, and prevent the typical suppression of immune-system function seen after endurance events. From test-tube and animal studies, it appears that beta-sitosterol can influence the structure and function of cell membranes in both healthy and cancerous tissue. This effect is known to alter cellular signaling pathways that regulate tumor growth and apoptosis (cell death) and provide a possible explanation for the stimulation of immune function observed following beta-sitosterol supplementation.

In terms of general immune function, beta-sitosterol has been shown in humans to normalize the function of T-helper lymphocytes and natural killer cells following stressful events, such as marathon running, that normally suppress immune-system function. In addition to alleviating much of the postexercise immune suppression that occurs following endurance competitions, beta-sitosterol has also been shown to normalize the ratio of catabolic stress hormones (i.e., those that break down tissue, such as cortisol) to anabolic (rebuilding) hormones such as DHEA. In one study, seventeen endurance runners completed a sixty-eightkilometer run (about forty miles) and afterward received either 60 mg of beta-sitosterol (nine runners) or a placebo (eight runners) for four weeks. Those runners receiving the beta-sitosterol supplements showed a significant drop in their cortisol-to-DHEA ratio (indicating less stress) as well as reduced inflammation and a markedly lower immunosuppression. Using the ultramarathon as a model for overall stress, researchers concluded that beta-sitosterol is effective in modulating the stress response by managing cortisol levels within a more normal range.

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Excessive Endurance Exercise Causes Hyper-Cortisol State​

• Cortisol, known as a stress hormone, plays a vital role in our health but can lead to severe health issues like muscle breakdown, inflammation, and impaired immune function when chronically elevated. Understanding cortisol's dual feedback mechanisms in the brain and body is essential
• Long-duration, high-intensity exercises like long-distance running can inadvertently increase the body's cortisol levels, pushing the body into a chronic stress state
• An enzyme called 11β-HSD1, present in most body tissues, is central to producing cortisol and becomes the focus for understanding and potentially treating elevated cortisol levels linked to metabolic diseases
• While drug companies explore inhibitors of the 11β-HSD1 enzyme to manage conditions caused by high cortisol, alternatives like aspirin, emodin, and progesterone offer potential natural solutions, as all three inhibit the activity of 11β-HSD1
• To address elevated tissue cortisol, consider reducing the amount of endurance exercise you do, make sure you’re getting enough healthy carbs, and supplement with progesterone