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What Can Cause Excess CRH?

Discussion in 'Cortisol, Serotonin, Histamine' started by farshad, Aug 21, 2018.

  1. farshad

    farshad Member

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    hello, I have battled with anxiety for so long. I have found the cause but not what causes it. My anxiety is caused by excess CRH-CRHR1 signaling. CRHR1 is activated through the binding of CRH (Corticotropin-releasing hormone). Im not sure what causes it but I have narrowed it down to 3 plausible causes:

    1. A hypermorphic mutation causes an increase in normal gene function.[1] Hypermorphic alleles are gain of function alleles. A hypermorph can result from an increase in gene dose (a gene duplication), from increased mRNA or protein expression, or constitutive protein activity.
    Muller's morphs - Wikipedia

    2. CRH tumor
    Ectopic corticotropin-releasing hormone (CRH) syndrome from metastatic small cell carcinoma: a case report and review of the literature

    3. autoimmune disease (least plausible)
    Autoimmune disease - Wikipedia

    Im just looking for ways to decrease CRH. At the moment I have tried all supplements that has an decrease effect on CRH like St johns Wort, ginkgo biloba, lithium and some more but they are weak. I need a man-made drug. I have found one which is called carbamazepine it directly inhibit hypothalamus crh straight from the source. So hopefully this will be the end of my anxiety.
     
  2. lampofred

    lampofred Member

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    Excess serotonin I think directly stimulates ACTH/CRH and excess estrogen prevents cortisol from shutting down CRH through the normal feedback loop. So excess serotonin and estrogen I would guess, relative to low dopamine/progesterone/thyroid.
     
  3. OP
    farshad

    farshad Member

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    constitutive protein activity - "Constitutive" activity means that the regulation of the enzyme's activity is gone, it's been mutated or something to allow it to always be active.

    Consider an enzyme: An mRNA molecule is translated to make a protein, which has enzymatic activity on some substrate, and can be regulated.

    Expression is a readout for the translation of the mRNA into stable protein.



    protein expression - DNA > mRNA > Protein expression(CRH) , it is possible to have low mRNA but high protein expression becuase a single mRNA molecule can stick around and be translated many times. And protein has longer half-life.



    CRH-gene duplication - gene duplication, if the promoter regions (the DNA that communicates with proteins that tells the mRNA synthesis machinery when and for how long to make that particular gene's mRNA) and/or the enhancer regions (the DNA that adds nuances to what the promoters do) are copied along with the gene, you can predict that the expression of the duplicate will mirror that of the original. If not, maybe the duplicate is just turned off, maybe it picks up signals from promoters/enhances in the new region it gets duplicated into? All options.

    Additionally some genes are tightly regulated so that the "dose" of that particular protein doesn't get to high or to low. If this is the case of a gene that gets duplicated, feedback mechanism may kick in and change the total amount of protein that gets made.



    CRH-Secreting tumor - a tumor secreting a certain substance, if that substance is a protein or peptide, then yes, it has to go through transcription (DNA --> RNA), and translation (RNA--> protein) (fortunately CRH is a Peptide hormone). Since cortisol is not a protein, or peptide, it is a steroid hormone, it is synthesized (by proteins in the cell that did have to follow the DNA --> RNA--> Protein route), from other molecules that the cell takes up. The ability to synthesize these molecules is not unique to tumor cells, although the regulation of the synthesis may be drastically altered.
     
  4. broozer

    broozer Member

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    hi man,

    how did you measure your excess CRH-CRHR1 Signaling? im interested because i think i have the same problem. for me there are 3 reasons as root:

    a) prolonged stress
    b) infections/EBV, inflammation in the brain
    c) post finasteride syndrome (leading to a))

    did you try any carbamazepine or clomipramine? in the early 2000s there where some promising results in clinical trails for CRHR1 antagonists (e.g. F.Holsboer). unfortunately they never get the approval as they couldnt beat placebo. but for a subgroup of patients they worked well (the anxious-depressed ones).
    im not sure those CRHR1 antagonists are completely out of interest now, still Holsboer-Maschmeyer holds licenses and consider relicensing.

    R.I.P. my english ;)
     
  5. thomas00

    thomas00 Member

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  6. broozer

    broozer Member

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    absolutelty. i woke up today, not restet, burnt out,desperate. took 5drops of stressnon(topical pregneolone). 1h later i felt relieve, went out shopping,chatting with the girls in the supermarket and got instant and long lasting erections. girls where also more flirty towards me,putting toungue out like fooling around a bit..this happend to me like never?!?
    i believe in it. it also summs up my opinion on libido: its important to have high T/Cortisol ratio. so lowering cortisol works very well too.
     
  7. OP
    farshad

    farshad Member

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    I measure it with my anxiety .. just joking, you can have blood test for CRH levels (I think)? I didn't test my levels but I always knew I had excess CRH which caused a lot of CRHR1 activation. Im taking Clomipramine right now and my anxiety is 100% gone.
    In my case I think my high CRH is caused by a hypermorphic mutation which is increased gene function.
    Muller's morphs - Wikipedia

    finasteride sure could cause high CRH becuase I think it lowers your GABA right? so it is possible. But increased CRH to the extend that a mutation would? probably not.

    Here are some drugs that reduce CRH:

    -Prochloraz (By using correlation analyses, it was found that the decrease in E2 plasma concentrations caused by PCZ was correlated with the down-regulation of CRH mRNA expression.)
    -Pentobarbital (Furthermore, blocking the neuroexcitant effects of CRH (using pentobarbital) abolished the alterations in CRF1 binding and expression)
    -Propylthiouracil (Propylthiouracil (PTU)-induced hypothyroidism caused a significant reduction in CRH gene transcripts in the paraventricular nucleus of male rats)
    -Clomipramine (It was found that clomipramine lowers CRH mRNA expression in the PVN by 74%, regardless of stressor conditions)
    -Pivagabine (pivagabine is now believed to act somehow via modulation of corticotropin-releasing factor (CRF).)
    -Imipramine (As assessed by in situ hybridization, 8 wk of daily imipramine treatment (5 mg/kg, i.p.) in rats decreased corticotropin-releasing hormone (CRH) mRNA levels by 37% in the paraventricular nucleus (PVN) of the hypothalamus)
    -Valproic acid (Moreover, CRF mRNA expression was decreased in the central nucleus of the amygdala (CeA) and paraventricular nucleus (PVN) of the hypothalamus.)
    -Carbamazepine (Although CBZ has been shown to inhibit hypothalamic CRH secretion in vitro)
    -Tiagabine (blockade induced a setpoint-shift of the stress hormone system toward lower levels as indicated by decreased plasma corticosterone concentrations and attenuated gene expression levels of corticotropin-releasing factor in the paraventricular nucleus of the hypothalamus)
     
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