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DHEA Enhances Cortisol Degradation

Discussion in 'Scientific Studies' started by haidut, May 22, 2016.

  1. haidut

    haidut Member

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    DHEA is one of the body's primary defense mechanisms against cortisol. Not only does DHEA act like a functional anti-glucocorticoid and protect tissues but as I posted a few month ago, DHEA blocks new cortisol synthesis by inhibiting the enzyme 11β-HSD1 in micromolar concentrations, which is achievable with 5mg-10mg dose of DHEA.
    DHEA, in low doses, directly inhibits cortisol synthesis
    Now, this study shows that DHEA also enhances the actvity of 11β-HSD2, and that is the enzyme responsible for de-activating cortisol by converting it into cortisone. Inhibitors of 11β-HSD1 are a holly grail of Big Pharma as a drug for treating diabetes, depression, obesity, mania, etc and activators of 11β-HSD2 can do the same. As I posted recently, niacinamide seems to be such enhancer of 11β-HSD2 and maybe also even an inhibitor of 11β-HSD1.
    Niacinamide Lowers Cortisol
    So, a drug that does both (DHEA + niaciamide, or emodin + niacinamide combo) would be an absolute gold nugget, so I would not be surprised if DHEA gets expeditiously declared as "anabolic steroid" and banned once FDA realizes what potential it has.

    DHEA induces 11 -HSD2 by acting on CCAAT/enhancer-binding proteins. - PubMed - NCBI

    "...Recently, we reported that DHEA decreases 11β-HSD1 mRNA expression in cultured cells and C57Bl/6J mice.17 Here, we tested the hypothesis that DHEA has antiglucocorticoid effects by inducing a switch from 11β-HSD1–dependent activation to 11β-HSD2–dependent inactivation of glucocorticoids. We investigated the impact of DHEA on 11β-HSD2 expression and activity in RCCD2 rat cortical collecting duct cells.21 Incubation of RCCD2 cells for 24 h with 25 μM DHEA resulted in 2.6-fold higher 11β-HSD2 gene expression (Figure 1A) and 3.5-fold increased reductase activity (Figure 1B). DHEA dosage-dependently enhanced 11β-HSD2 activity, reaching approximately 80% of maximal activation at 25 μM (EC50 approximately 15 μM; data not shown). DHEA up to 100 μM did not affect corticosterone conversion in human embryonic kidney 293 (HEK-293) cells expressing recombinant 11β-HSD2 under the control of a cytomegalovirus promoter, excluding a direct stimulatory effect of DHEA on enzyme activity (Figure 1C). We next examined whether the DHEA-mediated induction of 11β-HSD2 gene expression involves changes in mRNA stability. DHEA treatment increased 11β-HSD2 transcription in RCCD2 cells approximately three-fold (Figure 1D). Addition of the transcription inhibitor actinomycin D (10 μg/ml) after 24 h of incubation with vehicle or 25 μM DHEA resulted in a similar decay of 11β-HSD2 mRNA over the course of 4 h, with estimated half-lives of 138 and 148 min, respectively (Figure 1D). Together, these observations suggest that DHEA stimulates 11β-HSD2 activity in RCCD2 cells primarily through activation of gene transcription. In contrast to renal cortical collecting duct cells, DHEA did not affect 11β-HSD2 expression in Caco-2 and SW620 colon cells (data not shown), suggesting tissue-specific regulation."

    "...To ensure that the DHEA-mediated suppression of glucocorticoid reactivation reported in a previous study with mice17 is not species specific, we measured 11β-HSD1 mRNA expression in liver, white adipose tissue (WAT), and kidney from Sprague-Dawley rats fed standard rodent chow or chow containing 0.2% DHEA. DHEA significantly lowered 11β-HSD1 mRNA expression in liver (19 ± 3% of control; P < 0.001), WAT (28 ± 5%; P < 0.001), and kidney (57 ± 10%; P < 0.01; Figure 4), in line with previous observations in C57BL/6J mice.17 DHEA treatment for a relatively short time (12 d) did not significantly alter food intake or body weight in C57BL/6J mice and Sprague-Dawley rats (data not shown)."

    "...Our results from experiments with RCCD2 cells suggest that the effects of DHEA are not due to its metabolism to 17β-estradiol or testosterone with subsequent activation of estrogen receptor and androgen receptor, because neither antagonists of these receptors (Figure 7A) nor the aromatase inhibitor formestane (data not shown) had any influence. Instead, inhibition of Akt kinase prevented the DHEA-induced increase of C/EBP-β protein expression and its phosphorylation on Ser105 as well as stimulation of 11β-HSD2 activity. Recent evidence suggested that DHEA might act through G-protein–coupled membrane receptors and subsequent activation of PI3K/Akt.23 Phosphorylation of Ser105 on rat C/EBP-β has been shown to enhance its transactivation potency.24,38"

    "...Impaired intracellular metabolism of glucocorticoids contributes to the development of various pathologic conditions. Here, we investigated the counteracting effects of DHEA on local glucocorticoid metabolism by 11β-HSD enzymes, a mechanism originally proposed by Homma et al.,15 who observed reduced ratios of corticosterone to 11-dehydrocorticosterone and decreased BP in spontaneously hypertensive rats. We previously reported that DHEA downregulated 11β-HSD1–dependent glucocorticoid regeneration in liver, adipose tissue, and kidneys of C57BL/6J mice.17 DHEA had the same effects in Sprague-Dawley rats in this study. Moreover, 11β-HSD2–dependent glucocorticoid inactivation was enhanced in kidneys of DHEA-treated mice and rats. The sum of the locally altered glucocorticoid metabolism (i.e., enhanced renal 11β-HSD2 activity and reduced 11β-HSD1 activity in liver and adipose tissue; Table 1) led to decreased ratios of urinary free corticosterone to 11-dehydrocorticosterone in DHEA-treated Sprague-Dawley rats, in line with Homma et al.15 Because DHEA does not compete with glucocorticoids for binding to glucocorticoid receptors,25 it may protect from excessive glucocorticoid action by means of altered glucocorticoid metabolism."
     
  2. aguilaroja

    aguilaroja Member

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    DHEA came very near to being classified as a controlled drug in 2005. Only intense negotiating led to an exemption for DHEA. Here is one account:

    http://www.nytimes.com/2005/04/17/us/how-one-pill-escaped-the-list-of-controlled-steroids.html?_r=0

    DHEA does come under scrutiny for athletes. Here is a sad account of an amateur athlete sanctioned by the United States Anti-Doping Agency:

    USADA Doping Ban for Trail-Loving “Middle-Aged Mom”
    "Rather than...a...penalty of two years, officials apparently reviewed the case—and Anderson’s...using DHEA ..with a prescription received from her MD—and offered her a 12-month ban....

    " 'I’m not an elite runner,” she told Masterstrack.com. “I’m a middle-aged mom and business owner who loves to run in the mountains.'...'Despite taking the dose recommended, my levels remain low; there is no competitive advantage from my perspective.'

    "Anderson admitted that she was puzzled as to why USADA was at the Pike Peak Marathon and equally confused why they would be interested in a runner who is not a member of USA Track and Field."
     
  3. OP
    haidut

    haidut Member

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    Have you heard anything about pregnenolone and progesterone in that regard (legal)?
     
  4. DaveFoster

    DaveFoster Member

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    Awesome. Very good to know, thank you haidut.

    With Pansterone, are there conversion advantages to applying the product on the testes or any other place on the body?
     
  5. OP
    haidut

    haidut Member

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    Given that the testes need both pregnenolone and DHEA to manufacture testosterone, application on testes or penis may stimulate endogenous steroidogenesis by the testicles more so than what peripheral application to arms, legs, torso, etc would do.
    Just an educated guess though. I have not measured this myself but the studies using direct application of pregnenolone/DHEA to monkey scrotum found increased testicle steroidogenesis.
     
  6. DaveFoster

    DaveFoster Member

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    Alright, thanks for the info. Once I get back to where I was, I'll try this out with your product.
     
  7. DocHolliday

    DocHolliday Member

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    I've been applying 4 drops of pansterone and one drop of Kuinone for a week now. The only noticeable effect I've gotten are more vivid dreams and a few pimples on my face. I'm thinking the latter is a sign of the Pansterone converting into androgens.
     
  8. OP
    haidut

    haidut Member

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    Yep, the pimples are a sign of local increase in DHT. Increase in body hair may also be noted if DHT continues to rise.
     
  9. DocHolliday

    DocHolliday Member

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    How do you make the distinction between local and systemic increase in DHT? I mean since I been applying it around the genital area, wouldn't acne in the face be a sign of a systemic effect?
     
  10. Pointless

    Pointless Member

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    As someone with bipolar tendencies, dhea makes me giddy and aggressive. Pregnenolone more so. I wouldn't call either a wonder drug in the allopathic sense. I can name 3 things that can instantly lower cortisol no problem, but I get eczema because cortisol blocks inflammation in a stressed person. Really thyroid is the way to go...

    If anything gets dhea banned, it's gonna be the bodybuilders that lather themselves in it. Mainstream medicine doesn't want anything to do with a drug that improves long term health and gets at the roots of disease. I could write more, but I think I'll take it to my journal so I don't derail your thread.
     
  11. aguilaroja

    aguilaroja Member

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    The notable thing I recall about regulation recently has been California's mandatory warning about DHEA & Pregnenolone since 2002:

    ftp://www.lhc.ca.gov/pub/01-02/bill/sen/sb_1701-1750/sb_1750_bill_20020418_amended_sen.html

    Since the California market is large, some vendors have included warnings for all markets.

    Pregnenolone often is included in "authority's" discussions of PED's. There are mentions of including it among banned substances but it remains largely exempt from ban. Classifying substance bans is different among sports, organizations, & nations, so it is difficult to track every substance list.
     
  12. docall18

    docall18 Member

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    So 7-Keto Dhea has apparently similar effects on 11β-HSD1 and 11β-HSD2 as regular Dhea. Also, it doesnt convert to estrogens (or androgens) as regular Dhea will, so you can try higher doses.

    I have tried it with good effects. My testosterone is already high, so it doesnt need the androgen boost.

    Is there any reason not to take 7-keto instead of regular Dhea? It doesn't seem to get much mention, either here or by Ray Peat.
     
  13. OP
    haidut

    haidut Member

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    If these are indeed the only effects it has then it would be good to try. I am not sure that it does not affect steroid balance though, keto DHEA can convert into ketotestosterone and even keto DHT. Some human studies found it lowered T, progesterone, and even DHT. I am not sure these are good effects, so I would like to see more human studies before deciding one way or the other.
     
  14. d1d2

    d1d2 Member

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    I'm curious about the low cortisol comment and eczema.

    I've taken Pansterone for about five months and recently stopped it, along with aspirin, niacinamide and cypro. I developed eczema on the front of my shins and a bit on the inside of my arms. It's started to subside and a hydrocortisone gel was helpful. I've had some very small eczema spots in the past but nothing like this. I put some Lapodin on my shin, as there was some thickening skin there. The breakout became quite a bit worse and that could coincidental.

    It's started to clear up although my leg is still a bit itchy and scaly-looking. My arm is almost 100% clear. I've since gotten back onto cypro to test it as I'm quite fond of it. I sleep like a teenager with it and some gelatin with OJ before bed.

    Back to cortisol, inflammation and eczema--what's the connection there? If low cortisol is beneficial, and I'm feeling quite non-stressed/not anxious at all, what might be happening? Should I try to avoid cortisol lowering too much? That wasn't one of my goals... Many thanks.
     
  15. Pointless

    Pointless Member

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    Lapodin powerfully lowers cortisol, and I break out in eczema whenever I use more than 1 drop. Same thing with silicic acid, holy basil, and 7-keto, all of which lower cortisol. At some point I hope to be able to have lower overall inflammation without cortisol, but I'm still working on getting my temps up and clearing out my liver.
     
  16. d1d2

    d1d2 Member

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    Fascinating--are there some resources available to learn about this and such a strategy? I've been poking around to learn more about cortisol and eczema from a Peat management perspective but haven't found much substantial yet.

    BTW, speaking of increasing temps, I tried some powdered egg shell recently a few times and I'm pretty sure that it make me hotter than normal. Since I'm trying not to try too many things at the same time, I've avoided a quick re-test but I'll give that a shot soon.

    Thanks again.
     
  17. Pointless

    Pointless Member

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    I don't have any resources, just personal experimentation. I'm not trying to sound like an expert, but it's just something I've noticed. Maybe it's something different, because I don't have any blood tests to back it up.
     
  18. d1d2

    d1d2 Member

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    Thanks for your feedback, Pointless--much appreciated. I'll keep looking around and post if I find anything.
     
  19. Pointless

    Pointless Member

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    Another possibility is that the DMSO is causing it. If I rub DMSO on the parts where I'm prone to eczema, it gets worse.
     
  20. d1d2

    d1d2 Member

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    I've used a number of Haidut's supplements with the older, more odor-ey DMSO and the newer stuff too. I was curious if it could be an influence as well and will see if I can narrow this down.

    I have a bit of Pansterone with both versions and that would be my main source of DMSO. I have Lapodin but never got too much into a routine with it. I tried to use it on the ticker skin on my shin to see if it would shrink it, if it was more fibrous. As the eczema wasn't going away with different things, the Lapodin made it angry.

    I've taken cypro now for two or three nights with no worsening of the spot that was on my arm (I'm not putting anything on it, so it's a bit of a control). It's nearly gone now. My shins don't seem as itchy today as well, so maybe it's going away too. It could be too soon to tell with cypro as I was taking it for about 5 months or so and it didn't happen until the few weeks. I'll keep with the cyrpo and a bit of aspirin through next week and try Pansterone again the following week.

    BTW, I think it's Pansterone that's helped me to grow a bit more facial hair. I've always been a bit patchy and maybe that's the DHEA. I've definitely had more pimples these last months than years before and the patches are growing together.
     
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