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Optimal Dose Of Pregnenolone For Androgen Synthesis

Discussion in 'Scientific Studies' started by haidut, Dec 1, 2016.

  1. haidut

    haidut Member

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    There was a recent discussion about high dose pregnenolone on the forum and some people sent Peat my comments that high dose pregnenolone can inhibit androgen synthesis. Peat replied that he has not seen such effects, but did not directly speak against the idea. Privately, I got quite a few messages accusing me of making stuff up. Well, I was not making stuff up, I was referring to an actual study and also to reports of people who found pregnenolone beyond 200mg daily killed their sex drive. Doses below 100mg had largely stimulating effect on libido and muscle tone, indicative of an androgen boost. The larger doses, as we know from the schizophrenia studies, converted mainly into progesterone and allopregnanolone.
    So, here is the study suggesting that there is indeed an optimal range of pregnenolone concentration so that it stimulates the conversion of said pregnenolone down the androgen pathways. Higher than the optimal concentration was suppressive of androgen synthesis from pregnenolone. Unfortunately, the optimal pregnenolone concentrations are different for stimulating androstenedione, DHEA, and 17-OH-pregnenolone synthesis so there is no one size fits all. But I think aiming for not exceeding the optimal concentration that simulated DHEA synthesis (about 2uM) maximally would be a good compromise. Also, as you can see, pregnenolone stimulated synthesis of progesterone in any concentration. So, for androgens synthesis pregnenolone seems to have a bi-phasic effect while for progesterone it is stimulating in any dose. The latter part matches well the human studies with large doses pregnenolone.
    While this study concerns mostly oral administration of pregnenolone, application to the scrotum is probably also subject to some restrictions in terms of optimal dose. Some people using the topical approach already noted that higher than 10mg dose of pregnenolone on the scrotum gave them symptoms of progesterone rather than androgen synthesis.
    Finally, the study makes the claim that the further away a derivative of pregnenolone is from pregnenolone in the steroid pathways, the more sensitive it is to inhibition of its synthesis by pregnenolone. You can see this effect in the attached image. Lower concentrations of pregnenolone were needed to inhibit androstenedione synthesis than DHEA, since androstenedione is further away from pregnenolone. The next androgen down the line being testosterone, the pregnenolone concentration for its inhibition may be even lower than the one for androstenedione.
    TLDR: In lower concentrations pregnenolone increases synthesis of both androgens and progesterone. In higher concentrations, it inhibits androgen synthesis but continues to stimulate progesterone synthesis. If the progesterone synthesis pathway becomes too dominant (as was seen with high dose pregnenolone in humans), that can lead to the anti-androgenic side effects associated with progesterone.

    Variation in 3β-hydroxysteroid dehydrogenase activity and in pregnenolone supply rate can paradoxically alter androstenedione synthesis. - PubMed - NCBI
    "...Results of the steady-state analysis in which supply of pregnenolone (P5) is varied between 0.01 and 10 uM/s, a sufficiently wide range to capture of all qualitative results, are shown in Fig. 5. Parameters other than P5 supply are the same as in the simulation example in Section 3.2. The curves illustrate that increasing the P5 supply rate initially increases the synthesis of all the steroids; however, when the P5 supply rate reaches a certain level, further increasing this rate will firstly suppress the synthesis of A4, then DHEA, and lastly, 17OHP4. In contrast, increasing P5 supply rate resulted in a continual increase in P4 production."

    "...By taking into consideration competitive inhibition of the enzymes by substrates and products, the model shows that when the rate of P5 supply reaches a certain level, further increases in P5 supply rate will suppress the synthesis of A4, DHEA, and 17OH-P4, but not the synthesis of P4. Obviously, at low rates of P5 supply, the concentrations of all steroids are low and inhibition of P450c17 by substrates and 3-HSD by both substrates and products is negligible. Increasing the P5 supply rate progressively increases the synthesis of all the steroids to a point when the steroid concentrations reach levels that are sufficient to start inhibiting the activities ofthe both enzymes. The more reaction steps there are between the precursor substrate P5 and the end product, the stronger the effect of competitive inhibition is on its synthesis. Therefore, as the P5 supply rate increases, the suppression of A4 synthesis occurs first, following by that of DHEA and then 17OH-P4. In turn, this increasingly drives P5 flux down the 4 pathway towards the synthesis of P4. The increased flux down the 4 pathway is able to overcome the effect of the inhibition of 3-HSD by its catalytic substrates and products, allowing P4 synthesis to continue to rise with increasing P5 supply rate."
     

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  2. goodandevil

    goodandevil Member

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    @haidut I've heard of libido problems at higher pregnenolone doses but I've also heard ray say it's the impurities that cause problems. I wonder if the decreased androgens necessarily corresponds to decreased androgenic tone, for lack of a better term. maybe someone retains androgenic characteristics, even with the kncreased pregnenolone, then the side effects are from impurities. what do you think about that?
     
  3. Wagner83

    Wagner83 Member

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    Would there be a connection between androgens levels of an individual and the dose resulting in inhibition?
    Why would inhibiting androstenedione be ok? What is the equivalent in mg of such a dose?

    It actually makes me wonder if supplementing with the steroids at the very end of the chain is not as safe as precursors like dhea and pregnenolone when it comes to inhibition and positive effects , and if a combination of both precursors and end steroids could keep imbalances away while maximizing androgenic effects.
     
  4. OP
    haidut

    haidut Member

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    I think the smoking gun really is the lack of inhibition of progesterone from any dose pregnenolone. This is consistent with the human studies showing oral high dose pregnenolone raised progesterone and allopregnanolone more than anything else. The anti-androgen effects of high levels of progesterone in males are well known. So, to me the more important message is that pregnenolone in higher doses probably has anti-androgenic effects (libido aside). The impurities and such are also important but the clinical trials with humans used pure pregnenolone. I am with Peat that the inhibition of specific enzymes could be due to impurities but the ability of pregnenolone to trigger negative feedback mechanisms on steroids downstream should not be ignored either.
    Bottom line - high dose pregnenolone is definitely pro-progesterone and potentially androgen synthesis inhibiting as well. That may not have a direct effect on serum androgens but the overall tone of the organism will probably shift towards progesterone and as such will be anti-androgenic.
     
  5. OP
    haidut

    haidut Member

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    I don't think inhibiting androstenedione would be OK. That is the point of the study - beyond a certain rate of pregnenolone availability to the steroidogenic enzymes it inhibited androstenedione, DHEA and 17-OH progesterone synthesis, all of which are on the pathway to androgens such as T and DHT. Not sure how the supply rates from the study would convert to doses but basically at any point you probably don't want pregnenolone concentrations to exceed 1-2 uM/L, which means for optimal androgen synthesis, less than 10mg pregnenolone per dose may be optimal to avoid inhibition of androstenedione and DHEA.
    As to your final point - this is exactly what Selye said in the pregnenolone study I posted in the original Pansterone thread - i.e. using pregnenolone with an end-point steroid like T, cortisone, or estrogen allows for a much lower dose of the endpoint steroids to be used and get the same effects, while also likely protecting from the side effects. Check it out, it is good read.
     
  6. Makaveli

    Makaveli Member

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    Slightly off topic but what would the equivalent dose of pregnenolone 100mg orally be to StressNon topically? I assume the routes of administration have different bioavailabilities.
     
  7. goodandevil

    goodandevil Member

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    Ok so what do u think about 300mg/week i single doses? I ask because that'e what I'm taking.
     
  8. acrylic

    acrylic Member

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    Do you think this could result in harm to males? I've experimented with 300mg of pregnenolone a day for months and felt quite good (30 year old male). Never noticed any libido inhibition. Don't want to hurt myself, though...
     
  9. OP
    haidut

    haidut Member

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    It has not been tested on too many people but I have tested on myself. Taking the full 20mg dose StressNon topically in one sitting results in about the same pregnenolone concentration as an oral dose of about 200mg pregnenolone. The blood tests were done 1 and 8 hours post administration. Oral StressNon is similar to oral pregnenolone, so no advantage in taking it orally. But topically, StressNon seems to have about 10:1 effectiveness in raising blood pregnenolone levels. Both oral and topical pregnenolone will undergo a heavy conversion into other steroids. Both liver and skin are very active steroidogenic organs. But the liver likes to accumulate pregnenolone (as does the brain) so if you ingest even a hefty dose, very little of it will end up in the bloodstream as unchanged pregnenolone. The liver will convert maybe 60% to other steroids, keep another 30%-35% for itself and only let about 1%-2% unchanged pregnenolone in the blood. Topical pregnenolone , while also undergoing conversion does not metabolize as extensively unless you apply to a really large skin area. So, topical pregnenolone will deliver more unchanged pregnenolone to the blood, especially when the carrier is DMSO.
     
  10. OP
    haidut

    haidut Member

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    That dose it probably not going to raise progesterone to the point of causing anti-androgenic effects. The physiological doses of pregnenolone are about 30mg - 50mg daily, so that's pretty much what you are taking with that single weekly dose.
     
  11. OP
    haidut

    haidut Member

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    I don't think it will harm them, but it may cause some of progesterone's known side effects, which many people on the forum experienced with high dose pregnenolone and reported them. These included sleepiness, penis numbness, reduced libido, etc. If that dose makes you feel fine then by all means keep doing it. The study was meant to say that in some people the extensive pregnenolone conversion into progesterone and potential inhibition of androgen synthesis MAY result in symptoms consistent with high progesterone. So, something to be aware of when dosing pregnenolone and not just blindly gulp massive doses every day.
     
  12. Wagner83

    Wagner83 Member

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    Would that be 10 mg topical pregnenolone or oral or both? The two different ways of using it seem to yield quite different results (even outside of potency) .
    Thanks I'll check it out more thoroughly .
     
  13. milk_lover

    milk_lover Member

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    so if I want to take pregnenolone orally with food, I should take no more than 10 mg? And can I do that five times a day for a total of 50mg without inhibiting DHEA as long as the doses are seperated reasonably? Lately, I have been taking 50mg per dose and I've noticed too much anti-androgen effect, although I felt good mentally. Sometimes I take 3 doses of 50mg.

    If I take 4 drops of pansterone on my balls, that would translate to 2.5mg pregnenolone but topically it would be effectively 25mg pregnenolone. Will that affect androgens negatively since it's above 10mg or would the DHEA in pansterone help mitigate that issue?
     
  14. OP
    haidut

    haidut Member

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    I think taking 10mg pregnenolone 5-10 times daily orally will have very different effect than taking 50mg - 100mg in a single setting. It would be more balanced in smaller, frequent doses as it would go down both the progesterone and DHEA pathyways. In higher single doses it would be mostly a progesterone and allopregnanolone effect, so not very androgenic for males but maybe perfect for females. Topical pregnenolone (dissolved in DMSO) will to gown along 3 pathways - the 5-AR route (5a-DHP, allopregnanolone), the 3b-HSD route (DHEA) route, and remaining as unchanged pregnenolone. Exactly what percentage of the pregnenolone will go down each route is unknown, but it is known that topical pregnenolone feels more androgenic than oral (at the same dose) and seems to stimulate conversion of DHEA down the androgen pathways and away from estrogen. The scrotal application of pregnenolone/dhea/K is probably the best way for males to raise serum androgens and have most of pregnenolone and DHEA go down the androgen pathway. Oral pregnenolone will give more of a progesterone response, and topical (but not on scrotum) will give some androgenic, some progesterone and some unchanged pregnenolnoe response. Since the optimal way for everybody is different, I suggest experimenting with different doses and routes and sticking with the one that makes you feel best.
     
  15. OP
    haidut

    haidut Member

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    As I explained in my response to Wagner above, the fate of pregnenolone metabolism depends on the route of delivery and the dose and nobody knows for sure how exactly it pans out. The information we do have is that if you want pregnenolone to have a more balance effect and convert down both the progesterone and DHEA pathways then using smaller doses more frequently would be better than taking the same total dose once. So, taking 10mg doses 5 times a day for a total of 50mg will have a more balanced effect than a single dose of 50mg. This is hinted to by some of the human studies, which found benefit from lower doses pregnenolone for specific conditions but not form the higher dose. The dose that was found to work was 30mg - 50mg daily. Higher doses may also work, but the higher the dose the more it is going to favor the progesterone pathway with all of its benefits and side effects. If depression in men is mostly driven by androgen deficiency (which is what happens in hypothyroidism) then smaller doses more regularly would be better. Higher dose pregnenolone, is probably very effective as an anti-cancer strategy and the studies I have seen (mostly in vitro) show that it is the most potent inhibitor of liver, kidney, and skin cancer available, and that effect is dose-dependent. So, you'd need 400mg+ pregnenolone in a single dose to see effects against liver cancer and melanoma, but lower doses are more for optimizing steroid pathways. Thus, it seems the lower doses would be optimizing hormone balance and preventing bad stuff from happening, while the higher doses would be for situations where crap has already hit the fan and males do not care about the progesterone dominance high dose pregnenolone may lead to. See below studies for lower vs. higher dose pregnenolone - i.e. the best effect was reported with doses of 30mg and 50gm daily, 200mg daily was ineffective, and positive effects again begin to emerge beyond 500mg daily.
    Pregnenolone and dehydroepiandrosterone as an adjunctive treatment in schizophrenia and schizoaffective disorder: an 8-week, double-blind, randomiz... - PubMed - NCBI
    "...RESULTS: Compared with subjects who received placebo, those administered PREG-30 had significant reductions in positive symptom scores and extrapyramidal side effects (EPS) and improvement in attention and working memory performance, whereas subjects treated with PREG-200 did not differ on outcome variable scores for the study period. The general psychopathology severity and general functioning of patients receiving placebo and PREG-30 improved more than that of those subjects treated with DHEA, while EPS improved more in subjects treated with DHEA than in patients receiving placebo. Negative symptoms and akathisia were not significantly benefited by any treatment. The administration of PREG and DHEA was well tolerated."

    Adjunctive pregnenolone ameliorates the cognitive deficits in recent-onset schizophrenia. - PubMed - NCBI
    Add-on Pregnenolone with L-Theanine to Antipsychotic Therapy Relieves Negative and Anxiety Symptoms of Schizophrenia: An 8-week, randomized, double... - PubMed - NCBI
    Pregnenolone treatment reduces severity of negative symptoms in recent-onset schizophrenia: an 8-week, double-blind, randomized add-on two-center t... - PubMed - NCBI
    Proof-of-concept randomized controlled trial of pregnenolone in schizophrenia. - PubMed - NCBI
     
  16. Makrosky

    Makrosky Member

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    Wow haidut, thanks a lot for your time explaining all these things. I think it's worth linking this thread in the StressNon product page or something like that ? Or just posting a comment on the StressNon thread pointing here so this thread doesn't get lost. I can make the post if you want. It's very important to keep in mind all these things.
     
  17. OP
    haidut

    haidut Member

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    Yes, please make the post. I will try to edit the original post as well, but it helps when others mention it in the actual thread as most people go directly to the last post and start from there.
     
  18. Wagner83

    Wagner83 Member

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    As Makrovsky said, thanks a lot for the thorough explanation.

    From what I remember they tried intranasal pregnenolone on mice and a greater percentage of it reached the brain (in terms of ratio ) compared to intravenous administration, perhaps this would be a way to treat certain conditions while minimizing side effects.

    Brain distribution and behavioral effects of progesterone and pregnenolone after intranasal or intravenous administration

    Abstract
    Neurosteroids hold great promise for the treatment of diseases of the central nervous system (CNS). We compared the uptake by 11 brain regions and appearance in blood of tritium-labeled pregnenolone and progesterone after intranasal and intravenous (IV) injection. Both neurosteroids appeared in blood and brain after either method of administration, but with important differences in uptake. Bioavailability based on appearance in arterial serum showed that about 23% and 14% of the intranasal administered doses of pregnenolone and progesterone, respectively, entered the blood. Brain levels were about two fold lower after intranasal administration for the two neurosteroids. With intranasal administration, brain levels of the two steroids did not vary over time (2–120 min), whereas brain levels were higher early (10 min or less) after i.v. administration. With i.v. administration, uptake by brain regions did not vary, whereas the olfactory bulb, hippocampus, and hypothalamus had high uptake rates after intranasal administration. Intranasal administration of prenenolone improved memory, whereas progesterone decreased anxiety, thus demonstrating that therapeutic levels of neurosteroids can be delivered to the brain by intranasal administration. The neurosteroids were rapidly degraded after i.v. or intranasal delivery, but pregnenolone was more resistant to degradation in brain after intranasal administration and in serum after i.v. administration. These results show that either the i.v. or intranasal routes of administration can deliver neurosteroids to blood and brain, but that the two routes have significant differences with intranasal administration favoring some brain regions.
     
  19. Makrosky

    Makrosky Member

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    OMG. Really ? I never thought about using pregnenolone intranasally.

    @haidut do you think is there any big risk on snorting a line of pregnenolone powder ? I'm 100% serious. I have some Healthnatura pure preg powder here and I'm willing to use it myself as a resus monkey for the sake of science... Do you think it's dangerous ? After all, the olfactory bulb is part of the brain, so anything going there would bypass the BBB protective mechanisms, if I'm not wrong.
     
  20. Regina

    Regina Member

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    :smokingcrack
     
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