Stress is harmful in numerous ways.  This post focuses on one of the worst mediators of the negative effects of stress, but it’s not the only culprit.

If you have one or more of the following, you might have a CRH issue (the more you have the more likely): leaky gut, leaky brain barrier, mast cell/histamine issues, skin problems, sleep issues, SIBO, gut inflammation and general inflammation, IBS-Constipation, gut pain, Diarrhea, problems gaining weight, anxiety/fear, depression, emotional instability, cognitive dysfunction, arthritis, Hashimoto’s, uveitis, IBD, disrupted circadian rhythm, oxidative stress, low Testosterone and high estrogen, low libido and problems with fertility?

If you’re reading this blog, you likely ticked off at least 5 of those.  CRH is a common thread in all of these.  Put your science hat and get ready for a technical read 🙂

SelfDecode has some SNPs on the CRH gene.  If you want to interpret your genes, you can use SelfDecode.

CRH

Intro

Corticotropin Releasing Hormone (CRH) is the first hormone of the HPA axis, and it’s released by the hypothalamus.  CRH->ACTH->Cortisol.

I suspect that CRH is playing the largest role in gut permeability, which is a significant cause of stress-induced food sensitivities.

CRH production takes place in the cerebral cortex, limbic system, cerebellum, locus coeruleus of the brain stem, and dorsal root neurons of the spinal cord. It is also present in the adrenal medulla, T-lymphocytes of the immune system and the gastrointestinal tract (R).

The Stress Response and CRH

The stress-response is classically divided into three categories: behavioral, autonomic, and hormonal responses.

CRH is believed to be involved in all three stress-responses, involving different brain regions (R).

Behavioral responses include muscle readiness, fear, anxiety, heightened vigilance, clarity of thought, decreased appetite, and decreased libido (R).

The behavioral response is initiated in part by the amygdala, which mediates fear-associated behavior.

The amygdalar CRH system is more sensitive to the psychological stressor than the hypothalamic CRH system given that psychological (R).

The amygdalar CRH system causes wakefulness and arousal (R).

Autonomic responses are controlled by the hypothalamus and are responsible for the automated effects of sympathetic activation/fight or flight activation.  These include increased heart rate, breathing rate, blood flow to brain and muscle, activation of innate immunity, decreased blood flow to the skin, gut and penis, activation of innate immunity, vasodilation and pupil dilation (R). Other Autonomic functions include certain reflex actions such as coughing, sneezing, swallowing and vomiting.

CRH neurons connect to the brainstem, which is responsible for autonomic responses (R).

The hypothalamus is just above the brain stem and acts as an integrator for autonomic functions (receiving input from the limbic system to do so) (R).

The hormonal response provides fuel for such activities (R).

Read: Why stress is badA full list of stress response activators

CRH: The Bad

CRH Induced Anxiety, Depression and Cognitive Dysfunction

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My clients with an overactive nervous system tend to have issues tolerating stressful situations.  They are more likely to have anxiety, depression, emotional instability and poor memory function.  These symptoms are caused – to one degree or another – by CRH.

CRH causes fear and anxiety (RR2) (via CRHR1(R)) and major depression (R).

CRH promotes anxiety in part by reducing cannabinoids in our amygdala.

This happens when CRH (CRHR1) increases FAAH in the amygdala, which causes a reduction in the endocannabinoid anandamide (AEA) (R).

Endocannabinoids balance the stress and anxiety responses (R).

CRH causes enhanced emotionality i.e. emotional instability (R).

CRH causes structural changes in hippocampal neurons, including reduced dendritic branching (R).  This likely worsens memory.

CRH accelerates cognitive decline in a mouse model of Alzheimer’s disease (R).

Acute stress can activate brain mast cells, which is dependent on CRH. This causes an increased blood–brain barrier permeability in rodents, particularly in brain areas containing mast cells (via CRHR-1) (R).

CRH receptors are decreased by chronic stress (R).

CRHR2 has been shown to reduce feeding behavior and gastrointestinal motility (R).

CRH and CCK: A Bad Synergy

One interesting study mentioned that if your stress response is activated chronically (chronic CRH), that makes the anxiety effects of CCK (released after meals, especially those with lectins) worse and this leads to ‘hypersensitive emotional circuitry.’   This is the case even if CRH isn’t elevated at the time of CCK secretion (R).

Additionally, mild stress causes long-lasting changes in CCK neurons in the prefrontal cortex, which causes glutamate excitation (R).

Other studies show that CCK increases CRH and your stress response (R).

CCK independently of CRH cause anxiety and they potentiate the other (R).

CRH and The Circadian Rhythm

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The master circadian time keeper is in the hypothalamic suprachiasmatic nucleus, which controls your HPA axis.

CRH (via CRHR1) is very important (in hamsters) for having light set your circadian rhythm (phase advance). People with too much CRH at night (from chronic stress or cortisol resistance) or too little in the morning will have problems with setting your circadian rhythm.

Based on this study, it’s believed that blocking CRH will counter the circadian disruption associated with depression and other stress-related disorders (R).

However, having normal CRH levels is also important for the circadian rhythm, as CRH-deficient mice have a very low or absent rhythm in cortisol secretion (R).

CRH and Sleep

My clients have sleep problems, and in particular, they will have less slow wave sleep.

CRH decreases Slow wave sleep and increases REM (R).

CRH and Oxidative Stress

  • CRH causes oxidative stress (R).
  • CRH could enhance superoxide production in certain scenarios (primes macrophages to release superoxide in rabbits) (R).
  • In mice bred to get Alzheimer‘s, blocking CRH (CRHR1) lowered oxidative stress and increased glutathione peroxide activity (R).
  • CRH increases peroxynitrite (ONOO), which is an oxidant (R).

CRH->glutamate excitotoxicity->mitochondrial breakdown->energy problem-> more stress.

CRH, Inflammation and Histamine Intolerance

inflammation_233859859

My clients with an overactive nervous system tend to have inflammatory issues, as well as immunodeficiency.  They also have lower blood pressure and some people have issues with mast cells.

I believe that CRH is at the heart of mast cell activation, while it also contributes to inflammation and lower blood pressure.

CRH increases Th1 dominance, Nf-kB, IL-1b (by 8.5X), IL-6 (7.3X), TNF (13X), MHC-II (HLA-DR) and ICAM-1 expression. Max inflammation was reached in an hour. (R)

CRH also increases TLR-4 (a significant source of inflammation), including in the intestines (R).  I suspect that TLR-4 is a very significant cause of lectin sensitivity.

These effects will contribute to lectin sensitivity, which is one reason why it’s the people with an overactive nervous system who develop lectin sensitivity.

CRH causes mast cell activation, nitric oxide-dependent vasodilatation (which lowers blood pressure), WBC increase and WBC cytokine release (R).

Mast cell activation by CRH explains why stress induces allergic symptoms (R).

CRH is found in the joints of rheumatoid arthritis and uveitis patients.  It’s also found in inflammatory immune cells (presumably, plays an inflammatory role) (R).

In Hashimoto’s and UC, inflamed tissues contained large amounts of CRH (R).  These are common conditions with clients of mine who have an overactive nervous system.

Increased blood levels of CRH levels (and decreased skin CRHR-1) was found in psoriasis and atopic dermatitis (R). These are also common issues in the anxious phenotypical client.

Some studies suggest that CRH inhibits NK cell activity (R), which will make you less capable of fighting viral infections.  This effect is prevented by Benzos (R) and beta-adrenergic antagonists (R). Other studies show that CRH increases natural killer cell activity in mice (via an opioid pathway) (R).  It could be cell type and environment dependent.

CRH and the Gut

gut_270210278

My clients with an overactive nervous system tend to have gut problems. CRH is probably the single most significant cause.

In particular, they have slower small intestinal flow, and sometimes quicker large intestinal flow.  They will also tend to have lower HCL.  This will cause bloating and SIBO.  They also have intestinal inflammation.

Your gut has these motors that move things along at a steady pace. CRH is a direct cause of IBS by increasing the flow or motor speed in the colon and decreasing it in the small intestine (R).

CRH causes your gut to be ‘hypersensitive,’ and you experience gut pain more. When given a drug that blocks CRH, the pain goes away (R).

CRH (via CRHR2) slows small intestinal transit (R).  CRH also quickens large intestinal transit (R). This will cause both IBS-C and IBS-D, but usually IBS-C.  IBS-D will occur if you have certain genes that push you in that direction.

CRH induces intestinal barrier injury (Leaky gut) via the release of mast cell proteases and TNF-α (R).

The stimulatory effect on the colon is mediated by the vagus nerve, 5-ht3 receptors, nicotinic receptors, muscarinic receptors, and CRF receptors of the brain stem (which GLP-1 activates (R)) (R).

CRH inhibits stomach acid/HCL secretion and stomach emptying (R).

CRH (CRHR1) causes intestinal inflammation and increases VEGF, which cause IBD (R). S boulardii inhibits intestinal inflammation and VEGF (R). Norepinephrine also increases VEGF in the gut (R).

CRH can also cause nausea through activating the 5-HT3 receptors (via serotonin (R, R2).

It is possible that one of the CRH-related peptides (urocortin I or III) mediates some of the effects via the CRH receptors (R).

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 (R).

CRH and the Skin

shutterstock_297804983

My clients with an overactive nervous system tend to have skin problems.  CRH is probably the most significant cause.  Here are some specifics:

CRH is believed to be an important cause of acne, psoriasis, eczema, alopecia areata, skin tumors and hives (urticaria) (R).

CRH increases sebum (oily secretion) production (R, R2).  One mechanism is by CRH increasing testosterone in the skin (R).

CRH causes less VEGF in the skin (R).  VEGF promotes hair growth and can, therefore, result in reduced hair growth or baldness.

CRH causes the release of IL-4, IL-6, IL-10, and IL-13 from skin cells and mast cells.  All these have the effect of reducing the skin immune system (R).

CRH activates mast cells in the skin, which makes you feel more flush. Mast cell activation plays a central role in skin issues such as eczema, itching, and hives (R).

In people, CRH was increased in the skin in Alopecia Areata.  However, they had insufficient cortisol.  The effect of CRH on mast cells contributes to less hair growth (R).

CRH and mast cell activation from it play an important role in contact dermatitis, which is a rash you develop from a foreign substance.  CRH increases the immune response to foreign substances and also increases inflammation (Nf-kB) in hair cells (R).

CRH enhanced tumor cell growth and angiogenesis and can cause or contribute to melanoma (R).

CRH and Appetite

shutterstock_284988062

CRH (CRHR2) is an appetite suppressant (RR2, R3) and reduces body weight (R).

CRH is a causal factor in Anorexics having a lower appetite.  Depression and Anorexia both have an elevated HPA axis, but with anorexia, this is driver by CRH (RR2).

CRH dose-dependently reduced Ensure food intake in rats, and these food reducing effects were potentiated by insulin (R).

In most people, CRH will cause the production of NPY both directly (R) and indirectly by raising cortisol, which increases NPY (R).  NPY stimulates appetite, but CRH is overall an appetite suppressant.

When cortisol increases, blood sugar goes up, and that causes insulin to be secreted (R).

CRH and Hormones

My clients with an overactive nervous system tend to have hormonal issues. Some of these effects are likely mediated by CRH.

What’s interesting is that the effects of CRH tend to mimic what I see is imbalanced in clients.  I previously thought that this was the main mechanism, but I have learned that other mechanisms also play a role.

  • CRH increases ACTH, Cortisol, and cortisol is most often elevated.
  • CRH inhibits GnRH and therefore LH+FSH (by increasing opioids) (R). GnRH (releases LH, FSH) can’t make its way to the pituitary to release LH and FSH if there’s increased CRH (R).
  • CRH inhibits GHRH in males, but not in females (R).  GHRH is needed to produce growth hormone, and it increases slow wave sleep. More significantly, stress increases GnIH, which directly inhibits GnRH (R).
  • In monkeys, CRH injection lowers Testosterone (R).
  • CRH decreases progesterone (R),
  • CRH decreases Growth Hormone (R), 
  • CRH increases estrogen (R)
  • CRH increases prolactin (R
  • Higher CRH levels in mothers causes higher adiponectin in offspring (R).
  • CRH increases NPY (R)
  • CRH inhibits estrogen and progesterone production in female reproductive cells, presumably having a negative impact on fertility (R)

CRH and Decreased Libido and Fertility

There is considerable evidence that stress has a major negative effect on reproduction (R).

Intense or prolonged stress has been shown to inhibit gonadotropin (LH, FSH, hCG) secretion (R).

CRH has been implicated as a major inhibitor of reproductive function in both sexes. CRH also decreases libido, which is commonly an issue in my clients (R).

Low Blood Pressure

CRH might cause lower blood pressure, which is common in the anxious and fatigued phenotypical client of mine.

Experimental evidence suggests that the CRH Receptor 2 may be involved in vasodilation and blood pressure control (urocortin with over 20-fold higher affinity, compared with CRH) (R).

The Good

CRH activates orexin, causing wakefulness. This is one reason why we feel more awake at first when stressed (RR2).

CRH increases endorphins (R), which can improve our mood.

CRH increases ACTH, Vasopressin (R) and Cortisol, which can be beneficial in certain situations.

Lack of the hormone CRH results in the feelings of extreme tiredness common to people suffering from chronic fatigue syndrome. Lack of CRH is also central to seasonal affective disorder (SAD), the feelings of fatigue and depression that plague some patients during winter months. (R)

CRH Increases DHEA-s (37%), DHEA (doubled), Androstenedione (tripled) in humans (R). (CRH increases DHEA-S in human fetal cells (R).)

CRH could enhance superoxide production in certain scenarios (primes macrophages to release superoxide in rabbits) (R).  This can help fight infections.

CRH inhibits Nf-kB in some situations (via POMC) (R) – but it increases it in other ways.

CRH stimulates insulin release and can be anti-diabetic (R).

CRH induces TSH in nonmammalian vertebrate (R), which can stimulate thyroid hormones.

CRH and Bad Signaling

I’ve made a full list of HPA axis triggers.

Chronic stress increases CRH by decreasing negative feedback. CRH will not be inhibited by cortisol like it normally should (R).

Normally, after CRH is released, there’s also a spike in ACTH and cortisol, which feeds back to to reduce CRH if you aren’t ‘resistant’ or ‘insensitive’ to the negative feedback from cortisol.

But if this negative feedback isn’t solid because of chronic stress and genetics then cortisol won’t reduce CRH by as much as it should.

This will occur when the cortisol (glucocorticoid) receptors aren’t functioning right.  The result is too much CRH.

The other problem people have is when CRH doesn’t produce enough cortisol, so more CRH has to be produced for a given amount of cortisol (R).

In both cases, excess CRH is produced.

In people with major depression, CRH doesn’t produce enough ACTH (and cortisol) (R).

Chronic mild stress (in mice) causes cortisol resistance by increasing nitric oxide in the hippocampus (via activating mineralocorticoid receptor), which decreases the cortisol/glucocorticoid receptors (via cGMP and peroxynitrite). This elevates CRH (R).

What Increases CRH

See this post for a full list.  This is only a partial list.  Most of the time, anything that raises cortisol, raises CRH.

Cortisol/Glucocorticoids inhibit CRH production in the hypothalamus (R). However, in the amygdala – a brain region involved in the behavioral stress response – cortisol increases CRH (R), leading to anxiety and fear.

Acetylcholine, norepinephrine, histamine, and serotonin increase hypothalamic CRH release, while GABA inhibits it. Angiotensin, vasopressin, neuropeptide-Y, substance P, atrial natriuretic peptide, activin, melaninconcentrating hormone and b-endorphin increase CRH (R).

Hypoxia increases CRH in rats and doesn’t let CRH stimulate insulin (because of reduced ATP and cAMP and coincident loss of intracellular calcium oscillations) (R).

cAMP is needed produce CRH (R), so forskolin likely increases CRH.

Chronic cold stress increases CRH production (R) and CRH receptors (via dopamine) (R). However, acute cold stress decreases CRH production (R).

Hypothyroidism increases CRH and AVP production in the hypothalamus of rats (R).  So hypothyroidism can stimulate your HPA axis.  A lot of my clients have low T3.

Orexin stimulates CRH via OX2R (R)

MSH (prevents fasting-induced decrease in CRH) (R)

VIP (raises CRH) (R),

Substance P (CRHR1) (R, R2)

Estrogen (alpha, beta – CRH) (R)

NGF (R),

BDNF (R)

Noradrenaline (R),

Glutamate (R), 

Dopamine (D1/D2) (CRH in PVN) (R) – contradictory (R),

Serotonin (specifically 5-HT2CRs): Serotonin increased CRH and its neuronal activity and CRH (and corticosterone release). (RR2) 

Acetylcholine (R). Chronic SSRI usage increases CRH, but decreases ACTH and therefore cortisol (R), but fluoxetine decreases CRH (R).

AngiotensinII (R)

Activation of the vagus nerve increases Il-1b in the hypothalamus and CRH release (R).

Β-Amyloid levels directly activate CRH neurons to exacerbate stress responses (R).

Aspirin (R),

What Decreases CRH

CRH Genes

CRHR2

  1. RS255125
  2. RS7793837
  3. RS2284220
  4. RS2267716
  5. RS2267715
  6. RS2014663
  7. RS2284219
  8. RS2284218
  9. RS2267712
  10. RS2284216
  11. RS2190242
  12. RS3779250

CRHR1

  1. RS11657992
  2. RS4792825
  3. RS1876828
  4. RS16940674
  5. RS17763104
  6. RS173365
  7. RS242939
  8. RS171440
  9. RS242941
  10. RS3785877
  11. RS242924
  12. RS4792888
  13. RS4458044
  14. RS4076452
  15. RS12938031
  16. RS393152

CRHBP

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18 COMMENTS

  • CM

    Hi Joseph,
    So I think a lot of us are wondering would reducing CRH be as simple as reducing stress?
    Thanks!
    Cara

    1. Nattha Wannissorn

      Sometimes there are other causes, like inflammation and CRH/cortisol resistance.

  • AP

    Great article!

    How would you suggest to lower CRH, besides taking benzos?

  • Charles

    Have you heard of CRH-R antagonists? If you could block CRH release, you could, in theory, stop Mast Cell activation. Let me know your thoughts.

  • Andrea D'Rozario

    Hi Joseph,
    My son has had eczema since he was 2 years old. It was only concentrated in a two small patches behind the knee. When I stopped giving him milk (Enfalac), his eczema disappeared. He used to get itchy every now and then if his sugar content increased, so I reduced that and he was well on his way until he turned 10 when it came back. He’s 12 now and just last year it started spreading upwards towards the thigh.
    I put him on a hydrogenated water treatment (Izumio by Naturally Plus – orp of -700mV) and within 3 months, he had broken up in very itchy skin all over his body. It is at its worst on his ankles (dry, flaky and broken with scratching). Till today, I haven’t been able to rectify his intense itching. I have put him on a redox routine which has helped improve his skin condition but not the itching.
    Reading your piece on CRH, makes me more curious as to how the hydrogenated water could have played a role in his system.

    Any thoughts on this?

    He hasn’t had any blood tests taken.
    We live in Malaysia.
    Thanks,
    Andrea

    1. Joseph M. Cohen

      I think it’s just a coincidence and hydrogen water wasn’t the cause

  • AT

    Joseph,

    Thanks for the enlightening details regarding CRH.

    I’m in the process of getting my blood work done prior to booking a consult with you and I suspect I may also have a CRH problem.

    Question is, how do you test for it? And if tests point to CRH how can one fix the underlying root cause? My primary prescribed an SSRI as part of whats going on with me (not helping so far) but in your post you indicate serotonin can increase CRH. Granted I’ve only recently begun an SSRI but if that feeds the CRH beast and it turns out I have a CRH problem how do you address the problem?

    Look forward to consulting with you in the next few weeks.

  • Graeme

    What makes you think that methylation decreases CRH? Do you have a reference for this?

    1. Joseph M. Cohen
  • Drew

    The question is: How does one normalize / reset their CRH? Is long term, daily meditation the answer?

  • Robin

    Thanks for the heads up about the interview and the link to ices-questions. I will send it over soon. FYI…I keep alienating both my allopathic and integrative/functional medicine physicians with my desire for them to diagnose and prescribe medication or supplements according to the snp variation patterns that I believe are expressing. Sometimes they pay attention to CYP 450 data. Sometimes they are curious and they may dialogue a bit about the blend of genes and the snp points that I think could be contributing to my forms of dysregulation.. But ultimately, they indicate they were not trained to practice medicine in this fashion. It is lamentable that we live during a time that many who have the power to diagnose do not know the meaning of the word: to know something (nosis), through, thoroughly and entirely (dia). Thanks for helping this reader know something with a bit more depth and discrimination.

  • lordilol is dead(?)

    ah i should add that i had psoriasis 2 months ago, for a month and it went away.
    either it was the stress , the viral infection to my throat(severe) which maybe wouldnt appear if i didnt have the stress.or the anitbiotics meant to treat this shit(should maybe use silver?), but got that under control.

  • lordilol is dead(?)

    oh no.
    i was bullied at seventh grade to 9 th needles to say i felt like crap from 7-12 grade(social phobia?)
    how much did my height fell off? what if went to a different school? how much would the damage go down otherwise?
    fuck. why did i insist to keep going to that school?
    lol. also the sentence about long lasting changes is worrying.
    holyshit. i should just optimize my supplements to reduce stress and neuro inflammation.

  • Robin

    Thank you for this post. As someone with systemic mast cell disease, Hashimotos disease and homozygous variations at CRHR1, your synthesis is illuminating. I wish clinical medicine had half of your zeal. Those of us with neuroinflammation seem to confound too many healers, which necessitates finding our own ways to mending/healing.

    I’ve been trying to figure out, can ICES help with T4-T3 conversion (without over stimulating the extra mast cells….my mast cells degranulate with vibration)? If so, hypothetically, where might the best place be to place the coils (thyroid or liver) if you are on a T4 only medication? I’m trying to figure out how to further increase free T3 and reduce reverse T3.

    Again, much gratitude. I’m hoping to be able to consult soon.

    1. Joseph M. Cohen

      Thanks. You’re a good fit for a CRH problem.

      I have an interview that I will release soon with a top mainstream (not into health) researcher from Stanford and he agreed that medicine should work more the way I approach it – from fundamental biology rather than symptoms.

      If you have anxiety, you shouldn’t automatically be given an SSRI. The question should be is CRH causing your anxiety or is some other factor or both? And then you address the underlying cause. This approach requires problem solving, not strict formulas, as medicine currently works.

      Functional medicine is also broken, btw. They talk about the root cause, but I haven’t heard a single person even mention CRH.

      This is where you should ask your ICES Q: http://www.selfhacked.com/forum/index.php?threads/ices-questions.19/

      1. Jamie

        Joseph, why are the only comments you offer meaningful replies to related to ICES? Is it because you get a lot of money from every ICES unit sold?

        1. Joseph M. Cohen

          No money from this, which is my longest comment:

          http://selfhacked.com/2015/05/01/living-more-skillfully-by-realizing-the-myth-of-human-rationality/#comment-13129

          I don’t get significantly more for ICES than I do other products, but given that it’s more expensive, I make more money from it.

          So some of the incentive for a longer response is monetary, sure. But I don’t give long response on anything now.

    2. Sherry

      Robin,

      My twin sister, Bev was diagnosed with Mast Cell, we should talk. Just started taking T3 Cytomel along with a few others and the results have been phenomenal. Bev is one that can only try one thing at one time because of the mast cell, fibro, etc. etc. sherryps91@gmail.com. On a mission to tell the world with that complicated thyroid. Been over 13 yrs. suffering. Sherry

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