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The Anti-cortisol Mechanism Of Pregnenolone

Discussion in 'Scientific Studies' started by haidut, Dec 31, 2016.

  1. haidut

    haidut Member

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    One of the recurring arguments on this forum is whether pregnenolone and progesterone (being technically precursor to the glucocorticoids) raise or lower cortisol levels, and whether they have effects opposing or promoting those of the glucocorticoids. The argument advanced by a few people here is that since pregnenolone and progesterone are direct precursors, when administered in higher doses they must raise cortisol levels. Other people argue that pregnenolone is a "stress" hormone and supplementing with it can have negative effects. The first argument is very similar to the whole "pregnenolone steal" theory, which is biochemically impossible. What these arguments forget is that a valid analogy would be to propose the so-called "testosterone steal" theory - i.e. during lack of stress, supplementing with pregnenolone and/or progesterone should raise testosterone levels since technically both steroids are precursors to T as well. Well, I am not aware of any evidence showing "testosterone steal" occurs, and in my mind both cortisol and testosterone "steal" are bunk ideas. In reality, pregnenolone and progesterone both oppose the glucocorticoids and I hope that the studies below will shed some light on how pregnenolone does it. I will post about progesterone in a separate thread.
    While I have posted evidence before showing that pregnenolone and progesterone metabolites like allopregnanolone lower ATCH and consequently cortisol synthesis by the adrenal gland. These studies below are different as they demonstrate direct effects of pregnenolone itself, in opposition to cortisol. The mechanism of action is prevention of cortisol (bound to the GR receptor) from moving into the cell nucleus. This so-called "translocation" of the cortisol-GR bound peptide is necessary for cortisol to exert its systemic effects. By inhibiting the translocation of the cortisol-bound GR to the nucleus pregnenolone largely eliminates cortisol's effects on the organism. So, while pregnenolone is not a direct cortisol antagonist in the sense that it binds to the GR receptor as antagonist, it has indirect antagonist effect in the sense that it prevent cortisol from exerting any of its typical effects through activation of transcription factors in the cell nucleus/DNA. Similar inhibitory effects on cortisol accumulation in the cell nucleus were also noted with progesterone and DHEA. However, progesterone and DHEA were not nearly as potent as pregnenolone and also the high micromolar concentrations required to observe the inhibitor effects make DHEA inconvenient as it would result in estrogen elevation.
    While the first study showed dose-dependent reduction by pregnenolone of cortisol accumulation in the nucleus, the second study showed that there is an optimal concentration for this effect and it is relatively low (500nM/L). This concentration can be achieved in a human with a dose of <50mg daily.
    Finally, the last study in the list below shows that metabolites of pregnenolone like 7-keto-pregnenolone, 7-OH-pregnenolone, as well as downstream pregnenolone metabolites along the DHEA pathway (e.g. 7-keto-DHEA) are capable of inhibiting the enzyme 11b-HSD1, which is responsible for cortisol synthesis. As such, pregnenolone not only acts as a cortisol antagonist by blocking GR translocation but also directly inhibits de-novo cortisol synthesis. Aside from progesterone, I don't know of any other steroid that can do both.

    "...In the past years, a rather conclusive amount of information has accumulated supporting a direct interaction of steroid hormones with the cell nucleus of the target organs as one of the initial steps in hormone action [for review see 17, 351. When administered in vivo steroid hormones can be found in the nucleus of the target cells [1o, 11, 15, 16, 20, 21, 28] where they enhance RNA synthesis [ll, 12, 19, 26, 27, 32, 33, 38]. In some cases a direct interaction between the hormone and the chromatin has been demonstrated, also leading to a stimulation of RNA synthesis [l, 341. Thirty minutes after the administration of 3H-cortisone to rats a considerable amount of the radioactivity could be recovered in the nuclear fraction of the liver in the form of active corticosteroid [28]. Using an in vitro system composed of isolated rat liver nuclei, we could demonstrate that cortisol rapidly stimulates RNA polymerase activity [2, 231. This stimulation requires very specific ion concentrations [2, 231, can be blocked by actinomycin D [ 14, 231 and is, at least partly, due to an increased template activity of the chromatin [2]."

    "...Preincubation with progesterone and 17 a-hydroxyprogesterone, which like the hormonally active corticosteroids, have a keto group in 3C and a similar side chain in 17C, also results in a lower rate of 3H-cortisol uptake by the nuclei. Pregnandiol which instead of a keto group possesses a hydroxyl in 3C, has no inhibitory effect on the uptake of labelled cortisol by the nuclei. Androgens like testosterone, androstendione and methylandrostendiol, which lack a side chain at 17C, also do not have an inhibitory effect on the uptake of 3H-cortisol by the nuclei, although a keto group in 3C is present in two of them. A particular case among the steroids tested is represented by pregnenolone and dehydroepiandrosterone, which have a double bond in ring B; both compounds show an inhibitory effect on the uptake of 3H-cortisol by the nuclei."

    Mifepristone promotes adiponectin production and improves insulin sensitivity in a mouse model of diet-induced-obesity. - PubMed - NCBI
    "...We tested several other pharmacological agents chemically or pharmacologically related to mifepristone: GR antagonists, pregnenolone and DHEA; synthetic progestin causing abortion, levonorgestrel; MR antagonist, spironolactone [8,3134]."

    Pregnenolone protects mouse hippocampal (HT-22) cells against glutamate and amyloid beta protein toxicity. - PubMed - NCBI
    "...Immunofluorescence profiles of glucocorticoid receptors presented in Fig. 3A-C revealed that control, untreated cells, have less GR nuclear localization as judged from the intensity of immunofluorescence. Cells treated with pregnenolone for 24 hours alone showed a similar GR localization profile as observed for control untreated cells (data not shown). Interestingly, HT-22 cells treated for 20 hours with 5 mM glutamate showed very intense visualization of GR (Fig. 3B), 500 nM pregnenolone treatment for 24 hours, followed by 5 mM glutamate treatment for 20 hours remarkably decreased the nuclear localization of GR (Fig. 3C). We have calculated the relative nuclear to cytoplasmic fluorescence ratio to be 0.07, 0.08, 1.52, and 0.14 in control, pregnenolone alone treated, glutamate treated and pregnenolone followed by glutamate treated cells respectively."

    "...Glutamate is a major activator of the hypothal-amo-pituitary-adrenal (HPA) axis and is known to increase plasma levels of corticosterone via involvement of type II glucocorticoid receptor (GR) availability (17,18). Pertinent to this we observed that treatment of HT-22 cells with 5 mM glutamate for 20 hr resulted in intense nuclear localization of glucocorticoid receptor as detected by immunofluorescence technique. Pre-treatment with 500 nM pregnenolone for 24 hr followed by administration of 5 mM glutamate for 20 hr, dramatically decreased GR nuclear localization. It is of interest that like DHEA, pregnenolone directly modulates nuclear localization of GR (3). Since glucocorticoids are known to exacerbate neuronal cell death and damage (11,15), and pregnenolone exerts consistent neuroprotective effects; it is logical to assume that the neuroprotective effects of pregnenolone, are at least in part, mediated by decreasing GR nuclear localization induced by glutamate neurotoxicity. Our postulate is that pregnenolone exerts its protective action via a nuclear GR down modulation. The neuroprotective effects of pregnenolone are further supported by the recent report showing that the glucocorticoid receptor antagonist RU486 also protects against glutamate neurotoxicity in HT-22 cells."

    Hexose-6-phosphate Dehydrogenase Modulates 11β-Hydroxysteroid Dehydrogenase Type 1-Dependent Metabolism of 7-keto- and 7β-hydroxy-neurosteroids

    11β-hydroxysteroid dehydrogenases: intracellular gate-keepers of tissue glucocorticoid action. - PubMed - NCBI
    steroids_11b-HSD1_inhbition.png
     

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  2. raypeatclips

    raypeatclips Member

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    Fascinating, thank you for posting.
     
  3. tca300

    tca300 Member

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    Thank you!
     
  4. Regina

    Regina Member

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    Good to hear. But no surprise for me. I love pregnenolone.
     
  5. docall18

    docall18 Member

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    A lot of people dont get the positive effects from pregnenolone. I suspect that to benefit from pregnenolone you need a healthy liver.
     
  6. ecstatichamster

    ecstatichamster Member

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    It turns into progesterone for me I think in dosages of maybe 30mg or more. Has the same effects as taking progesterone.

    Small amounts seem fine.

    Thanks much @haidut this is excellent.
     
  7. raypeatclips

    raypeatclips Member

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    What are the things you noticed from progesterone/preg turning into progesterone?
     
  8. Dante

    Dante Member

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    @haidut, could you please point to the reading resource/research paper for the 'biochemical impossibility' of pregnenelone steal theory?
    Thanks.
     
  9. mayweatherking

    mayweatherking Member

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    @haidut if pregenenlone is so powerful, also progseterone, what do you think about increasing your cholesterol as high as possible by eating things like butter and coconut oil with meals and outside of meals to keep cholesterol in the blood stream high, while simultaneously making sure to increase lots of fructose with "peat aprpoved" proteins, wouldn't that hypothetically keep these high? i'm starting to think that butter and coconut oil, are as powerful as progesterone and preg since they are what really keep the true root as high as possible, it seems like the higher the cholesterol, and the more thyroid used, the more of these hormones that would be made?
     
  10. OP
    haidut

    haidut Member

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    I think eating a lot of cholesterol through diet may work. There are a few human studies where eating massive amounts of cholesterol through the diet results in LOWER total blood cholesterol levels, so it must have converted downstream. But the studies did not check if the people were hypothyroid or not so it may not work in all people. Still, Ray's usual recommendation is to raise cholesterol and it is best done through diet.
     
  11. OP
    haidut

    haidut Member

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    Here is one:
    The Myth Of Pregnenolone Steal

    But more importantly, the cortisol synthesized by adrenals and peripheral tissues is rate limited by the available pregnenolone inside those cells. So, an adrenal cell cannot tell a brain cell something along the lines of "give me your pregnenolone as I need it to synthesize cortisol" and thus deprive the brain cell of its pregnenolone. Whatever pregnenolone you have in the blood will probably get distributed to various organs and they will use it accordingly. If the adrenals synthesize cortisol from their pregnenolone, other cells will not spill their pregnenolone back out in the blood to get carried to adrenal cells to synthesize more cortisol. So, if pregnenolone raises cortisol it is because you are under stress and and hypothyroid and cortisol is needed. But if you supply enough pregnenolone, eventually the negative feedback mechanism through ACTH lowering will lower cortisol production. There are rare exceptions like Cushing dieasea and ectopic Cushing syndrome where the negative feedback mechanism may not work but those conditions are rare and most doctors can catch these cases through annual checkups. So, for most people pregnenolone should lower cortisol.
     
  12. Orion

    Orion Member

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    RP Multiple sclerosis, protein, fats, and progesterone article:

    "The excess cortisol of depression, old age, and hyperestrogenism often comes down with use of a thyroid supplement, but pregnenolone has a very direct action (in opposition to serotonin) that can quiet the pituitary, reducing ACTH and cortisol. Progesterone has some similar effects, and is protective against excess cortisol, and is a major factor in nerve and brain restoration. Thyroid, progesterone, and pregnenolone are all involved in the formation of new myelin, and in the prevention of the edema that damages it. "
     
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