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Pregnenolone Is The Most Potent Inhibitor Of The Stress Signal (CRH)

Discussion in 'Scientific Studies' started by haidut, Mar 15, 2016.

  1. haidut

    haidut Member

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    I think this study should finally put to rest the arguments and debates of whether pregnenolone raises or lowers cortisol, and how it affects the stress response overall. I posted a similar study, which showed that the pregnenolone metabolites progesterone and allopregannolone potently inhibited ACTH release and thus cortisol synthesis.
    Pregnenolone Does Not Boost Cortisol, It Lowers It By 60%

    CRH (CRF) is the first step in the manifestation of the stress response. It is a hormone produced in the hypothalamus whenever the organism is under stress, and elevations of CRF/CRH signal the pituitary to produce ACTH, and ACTH signals the adrenals to produce cortisol. Elevated levels of CRF/CRH are found in many diseases, especially "mood" disorders like depression, schizophrenia, PTSD, anxiety, etc. It is well-known that the GABA-ergic system in the brain is one of the natural inhibitors of CRH release and this principle is currently applied in using GABA agonist drugs for treating stress conditions and diseases like Cushing that are characterized by high levels of cortisol.
    This study looked at the effect of several steroids on the levels of CRF/CRH. The steroids under study included pregnenolone, allopregnanolone, THDOC, DHEA, and the sulfated derivatives pregnenolone sulfate, and dhea sulfate.
    It is already well-known that allopregnanolone and THDOC, both being potent GABA agonists, inhbit CRF/CRH release. What the study found surprising was that pregnenolone itself was the most potent inhibitor of CRF/CRH and it has those effects in relatively low concentrations of 1uM - 30uM range. For the purposes of estimating effects in humans, it is brain levels of pregnenolone that would matter given that CRF/CRH is produced in the brain. Brain levels of pregnenolone are on the order of 100-fold higher than serum levels. I posted a human study in the Pansterone thread showing that a single oral dose of 175mg pregnenolone produced serum levels of 0.5uM in humans and it kept those levels for up to 24 hours. This suggests that the 175mg dose produced brain concentrations of about 50uM. So, to achieve the 30uM concentration found to be most effective for lowering CRF/CRH in the study, one would need about 100mg pregnolone (assuming linear scaling). As many of you here know, Ray has consistently recommended 100mg - 150mg of pregnenolone as a good dose for inhibiting stress, and improving overall health. Given the almost complete absense of studies on pregnenolone bioavailability and pharmacokinetics in humans, the ability of Ray to predict proper dosages of these substances (often decades in advance) is simply astounding!!
    One last thing of note is that the steroid allopregnanolone investigated in the study as well is a metabolite of pregnenolone through the progesterone pathways and the activity of the enzyme 5-AR. The scientists suspected that pregnenolone may be inhibiting CRF/CRH through its conversion into allopregnanolone, so they also used the drug finasteride in combination with pregnenolone in order to block its conversion into allopreganolone. Pregnenolone still has the same strong inhibitory effect on CRF/CRH, which means its anti-stress action is intrinsic. That being said, by converting into allopregnanolone as well, pregnenolone may have double anti-stress action - once as an intrinsic effect of pregnenolone, and a second one through the GABA-ergic system activated by its metabolite allopreganolone.
    So, pregnenolone is accumulating more and more evidence as one of the primary tools for lowering stress and improving overall health, especially in the brain. Ray recommended to one person over email to combine aspirin and pregnenolone as a potent method to lower cortisol and increase testosterone. I already posted on the ability of aspirin to lower cortisol and increase testosterone on its own, so once again Ray is right on the money.
    Aspirin Decreases Cortisol And Increases Testosterone In Humans

    Finally, the stress-inhibiting effect of pregnenolone, combined with its ability to raise metabolism, and lower estrogen/cortisol, make it a prime candidate for treating not only mental conditions but also the so-called metabolic syndrome and especially obesity. Both of the latter are conditions almost entirely driven by the CRF/CRH-ACTH-cortisol-estrogen cascade.
    Pregnenolone For Obesity And Insulin Resistance
    How Pregnenolone And Progesterone Raise Metabolism
    Pregnenolone (should) lower estrogen levels

    OK, enough of my rant:) Here is the actual study.

    Effects of neurosteroids on the human corticotropin-releasing hormone gene. - PubMed - NCBI
    "...Corticotropin-releasing hormone (CRH), a peptide synthesized mainly in the paraventricular nuclei (PVN) of the hypothalamus, is a key regulator of hypothalamic-pituitary-adrenal (HPA) axis activity during stress. CRH via pituitary adrenocorticotropic hormone (ACTH) stimulates glucocorticoid synthesis and release from adrenal glands. In turn, glucocorticoids inhibit production of CRH in PVN and ACTH in pituitary by a feedback mechanism. CRH hypersecretion in the central nervous system (CNS) is thought to be an important factor in pathogenesis of some stress-related diseases, such as major depressive disorders, post-traumatic stress disorder (PTSD) or panic disorder [34, 39, 42, 55]. The elevated CRH concentrations in the cerebrospinal fluid and the increased number of CRH-expressing neurons in the hypothalamus have been found in depressed patients [29, 37]. Similarly, the increased CRH concentration or dysregulation of cortisol secretion has been observed in patients with PTSD and panic disorders [11,42]. Also in experimental animals, central administration of CRH or overproduction of this peptide in transgenic mice evoked anxiety, depression, and schizophrenia-like behavior [3, 12, 47]. A large number of preclinical studies have indicated that anxiety-like behavior results from the action of CRH through CRH1 receptor."

    "...Apart from CRH1 receptor blockade, another possibility of limiting CRH effect could involve repression of the synthesis of this peptide. Interestingly, although CRH synthesis is augmented by many neurotransmitters and neuropeptides, only two major mechanisms are known to inhibit the HPA axis activity, namely the glucocorticoid negative feedback and the gaminobutyric acid (GABA) [17]. Among compounds acting on GABA receptors, neurosteroids deserve the special attention. Neurosteroids are precursors or metabolites of steroid hormones, which do not show affinities for intracellular steroid hormone receptors, but modulate the action of some membrane receptors, such as GABA, NMDA and sigma-1 [24, 45]. Steroid metabolites with hydroxyl group in the position 3 and with reduced ring A, i.e., allopregnanolone (3a-hydroxy-5a-pregnan20-one, ALLO) and allotetrahydrodeoxycorticosterone (THDOC) are among the most potent allosteric positive modulators of the GABA receptors and exert anxiolytic and antiepileptic activity [7, 9]. Concentrations of ALLO and THDOC are increased in plasma and CNS in response to acute stress and that leads to effect HPA axis activity [14, 36]. Moreover, ALLO and THDOC attenuate the anxiogenic activity of CRH and the methoxamine-stimulated CRH release [33]. Contrary to acute stress, chronic stress decreases brain ALLO concentration and disturbs negative feedback mechanism of HPA regulation."

    "...The excitatory neurosteroid, PGL [pregnenolone] potently and in a concentration-dependent manner (0.3–30 μM) inhibited CRH-CAT activity, whereas its sulfate form was active only at high (30 μM) concentration (Fig. 2A and 2B). Similarly as basal activity, also forskolin-stimulated gene transcription was potently inhibited by PGL (1–30 μM), while PGL-S was inactive in these concentrations (Fig. 2C and 2B)."

    "...The 5a-reductase inhibitor – finasteride, at 0.1 and 1 μM did not change the basal CAT activity and had no effect on PGL (1 μM) inhibition of CRH gene promoter activity (Fig. 5)."

    "...In the present study, we found that some neurosteroids in a concentration-dependent manner inhibited CRH gene promoter activity in the differentiated Neuro-2A cells. Among investigated neurosteroids, PGL [pregnenolone], the main precursor of steroid hormones, exerted the most potent effect. ALLO and THDOC, two potent endogenous positive modulators of the GABA receptors had only a little weaker inhibitory effect than PGL on CRH activity. It is likely that the inhibitory effect of ALLO and THDOC on CRH gene transcription may be implicated in the mechanism of their anxiolytic action."
     
  2. Makrosky

    Makrosky Member

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    Thank you very much haidut! Very interesting as always!

    By the way.... You have mentioned in other posts and in this one that depressed patients have hypercortisolemia, high CRH levels, etc. I was thinking... What if depression is an inflammatory disease and the cortisol is there to protect from the inflammation ? Does it make any sense to you ?

    Also, I want to add that the study you linked is IN VITRO, not in vivo. Just to put things in context.
     
  3. Kasper

    Kasper Member

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    I think this could be. I have also heard theories that cortisol is like insulin, and that you could speak about cortisol sensitivity. You want your body to work so that only very little cortisol is needed to get rid of the inflammation.
     
  4. Makrosky

    Makrosky Member

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    This could be with normal day to day inflammation but in a disease the inflammation is supposed to be very high, hence a higher need of cortisol. I don't know I'm just wondering.
     
  5. Drareg

    Drareg Member

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    Does pregneolone not have the attribute of lowering inflammation on its own?
    Doesn't Peat mention pregnenolone going down the pathway needed? SHould pregnenolone work for low cortisol by increasing cortisol also?

    How much of stressnon is needed to get this effect compared to regular ?
     
  6. Orion

    Orion Member

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    This is per week and not 100-150mg/day? This needs clarification.
     
  7. Makrosky

    Makrosky Member

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    Sorry I'm not sure I get your point. I was talking strictly about the relation between high cortisol/CRH in depression and it's possible action as a defensive mechanism against excessive inflammation in depressed patients.

    @Orion I would go by feeling ;-) If one weekly dose works for you, so be it. If one dose every two days works, so be it. Ray has taken up to about 1gram of PREG. Anyway it's effects should be cumulative.

    In my personal experience taking PREG once the stress response is set isn't as good as taking it before the stress response. After all, PREG can be converted to cortisol. Remember to take it with enough fuel.
     
  8. Drareg

    Drareg Member

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    Sorry, I get what your saying now. It's an interesting theory.
    Theanine lowers cortisol ,can alleviate depression. Theanine also alleviates histamine and serotonin issues that could be causing the inflammation,cortisol might go back to normal at that point.
    Pregnenolone acts on serotonin also, I'm not sure it deals with histamine like theanine or cyproheptadine etc.
    If pregnenolone lowers cortisol but histamine still there causing inflammation might explain strange reaction to it?
     
  9. OP
    haidut

    haidut Member

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    Ray said written that taking 1 grain pregnenolone weekly (325mg) is good for general health preventive purposes. However, when asked directly, especially by males who want to take progesterone, he said also said that daily doses of 100mg - 150mg is a good long term dose. I guess it would depend on context. To inhibit the stress response, you probably need the daily dose and to maintain optimal steroid balance (assuming otherwise good health) 325mg weekly may be enough.
     
  10. Kasper

    Kasper Member

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    @haidut Your products seem to contain much less than that right? Pansterone 5 mg and StressNon 10 mg.
     
  11. OP
    haidut

    haidut Member

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    Well, yes, inflammation's role in depression is widely recognized but up until very recently it has been considered localized, brain-specific inflammation.
    Yet Again, Brain Inflammation Linked To Depression
    https://www.sciencedaily.com/releases/2015/11/151120182942.htm

    Now, since we know that inflammation stems primarily from PUFA metabolites, it would be sensible to propose that may be PUFA is involved in the pathogenesis of depression. Also, given their effects on the entire body, depression would be a systemic disease. This is exactly what a recent study I posted found.
    Depression Is A Systemic Disease Linked To Pufa Oxidation

    This view is further bolstered by the finding that reversing PUFA-derived inflammation reverses brain aging. The depressed and aged brain are almost indistinguishable from each other on MRI scans.
    Blocking inflammation from PUFA reverses brain aging

    So, elevated cortisol to battle this PUFA-incuded inflammation certainly seems like a natural adaptive response in depressed patients. However, PUFA has a direct cortisol promoting effect of its own, so it probably elevates cortisol more than is needed and also keeps it high even in the absense of inflammation.
    Pufa Stimulates Cortisol Production Even In The Absense Of Acth


    So, if we assume PUFA is the real cause of depression it would be logical to propose treating depression with anti-inflammatory drugs like aspirin and anti-PUFA agents like vitamin E, right? Well, once again, this is what the evidence points to.
    Aspirin is an anti-depressant as effective as pharma drugs
    Vitamin E (alpha tocopherol) is effective anti-depressant

    So, you see, things make perfect sense once we connect the dots. Keep in mind that all of these studies were done by independent teams, across more than a decade. As far as I can see they did not even know about each others work. When such diverse group of people independently confirms various points of a hypothesis that they are not even aware of, it is very likely that the hypothesis is true.
     
  12. OP
    haidut

    haidut Member

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    The pregnenolone in Pansterone is to keep DHEA from converting into estrogen and potentiating its effects. The StressNon is dissolved in DMSO and as such goes to the blood almost directly. As I mentioned in he StressNon thread, the new formulation is equivalent to about 100mg oral pregnenolone, so it is spot on with the doses needed in this study.
     
  13. Kasper

    Kasper Member

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    Cool, thanks.
     
  14. Makrosky

    Makrosky Member

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    Wow, haidut. Dropped jaw. I never connected the dots!!!!!! though the information is already on the forum. Thank you SO MUCH for writing this and taking the time to answer in depth.

    I fantasize about you publishing something like a practical handbook for health. I would gladly buy it. Your knowledge is spread across a myriad of different posts and not everyone is so smart to remember all the practical details. Just a quick and stupid example : I just read your answer and imagine I want to start taking aspirin daily. Now I have to go to check how much vit K I have to take with it in god knows which thread. And then again look for the thread where you post a study stating that a certain supplement (can't remember if it was niacinamide or glycine) prevented digestive problems created by aspirin. And so on and on. I have some of the info on my evernote but still it's not easy to catalog everything.
     
  15. tca300

    tca300 Member

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  16. OP
    haidut

    haidut Member

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    Thanks, I am actually getting some of my posts and noted together to write a pratical guidebook on Peatarian substances. I just have to be careful in how much I can say without getting in legal trouble. The substances you mention that protect from aspirin damage are glycine, theanine, caffeine, magnesium, and baking soda. If you search the forum for each of these and aspirin combined you will find the relevant threads.
     
  17. bzmazu

    bzmazu Member

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    Is this why this old guy is suddenly sleeping a good 6 hours? Was takeing 10mg PREG/5mg DHEA daily in the morning. Somewhere Haidut mentioned he took it before sleep and it helped his sleep...constantly looking for ways to increase/improve my sleep....so I immediately jumped on it and now take it at night...and bingo!...does this say anything about cortisol?
     
  18. OP
    haidut

    haidut Member

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    Yes, the lower the cortisol at night the deeper your sleep will be. Lower doses pregnenolone have been found to improve sleep in humans. Even doses as low as 1mg, taken an hour before bed.
    Neurosteroid pregnenolone induces sleep-EEG changes in man compatible with inverse agonistic GABAA-receptor modulation. - PubMed - NCBI
     
  19. Makrosky

    Makrosky Member

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    Because of the FDA? Can't you write it under a seudonim or publish it on an online platform out of the reach of FDA? There must be a way to bypass that stupid legislation.
     
  20. cantstoppeating

    cantstoppeating Member

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    Brilliant. To avoid their material from becoming watered-down, some people put the standard "this is for entertainment purposes only" disclaimer on their work, and prefix their advice with "some people have done x" when giving their suggestions to do x.
     
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