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Nitrates / Nitrites Inhibit Androgen Synthesis By Raising NO

Discussion in 'Scientific Studies' started by haidut, Nov 4, 2016.

  1. haidut

    haidut Member

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    Ray had a separate newsletter and a radio show on the dangers of NO precursors like dietary nitrates / nitrites and supplements like arginine. It is a bit ironic that quite a few bodybuilders out there pay a lot of money for the so-called NO boosters and in reality get the exact opposite effect due to the decreased androgen synthesis.

    https://www.ncbi.nlm.nih.gov/pubmed/11133344

    "...Nitrites and nitrates are consumed nonchalantly in diet. Organic nitrates are also used as vasodilators in angina pectoris, but the therapy is associated with tolerance whose mechanism remains elusive. Previously, we found inorganic nitrate inhibited steroidogenesis in vitro. Because adrenocorticoids regulate water and electrolyte metabolism, tolerance may ensue from steroid deficiency. We have studied the effects of nitrite and nitrate on in vitro synthesis and in vivo blood levels of steroid hormones. In vitro, nitrite was more potent than nitrate in inhibiting human chorionic gonadotropin (hCG)-stimulated androgen synthesis by Mouse Leydig Tumor cells. At concentrations above 42 mM, nitrite completely inhibited androgen synthesis, and, unlike nitrate, the inhibition was irreversible by increasing hCG concentration. The cAMP production remained intact but reduced with both ions. The nitric oxide (NO) scavenger, 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxy-3-oxide (c-PTIO) significantly increased hCG- or cAMP-stimulated androgen synthesis in all buffers, suggesting that NO is a chemical species directly involved in the nitrite/nitrate-induced inhibition. This is further supported by c-PTIO countering the inhibitory action of methylene blue on androgen synthesis. Rats given distilled water containing 50 mg/L NaNO(2) or NaNO(3) for 4 weeks drank significantly less daily. At the end, their blood corticosterone and testosterone levels were significantly decreased. The adrenocortical histology showed bigger lipid droplets, which are pathogonomic of impaired steroidogenesis. Nitrite and nitrate are metabolized to NO, which binds heme in cytochrome P450 enzymes, thereby inhibiting steroidogenesis. Therapeutic nitrates likewise may decrease adrenal (and gonadal) steroidogenesis. Cortisol deficiency would impair water excretion causing volume expansion, and aldosterone deficiency would cause sodium loss and raised renin. Paradoxically, volume expansion without sodium retention and raised renin has all been reported in tolerance."
     
  2. BobbyDukes

    BobbyDukes Member

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    I watched a documentary recently on meat, and they were talking about the potential cancerous effects of nitrates that you get in packs of ham/processed meats (that are everyday staples for some folk).

    I know from taking viagra a few times some years back, that it deceased the pleasure of orgasm quite a lot (for myself). Certainly different from a Peat inspired orgasm.
     
  3. High_Prob

    High_Prob Member

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    Haidut - There is a sentence in the above study that states:

    >>This is further supported by c-PTIO countering the inhibitory action of methylene blue on androgen synthesis.<<

    Does Methylene Blue inhibit androgen synthesis as well?
     
  4. High_Prob

    High_Prob Member

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    Come to think of it, it would make sense if that was actually a typo. It just doesn't make any sense within the context of the study since c-PTIO is an NO scavenger and Methylene Blue inhibits NO synthesis. It would make more sense if the sentence read: This is further supported by c-PTIO enhancing the positive action of methylene blue on androgen synthesis...
     
  5. High_Prob

    High_Prob Member

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  6. Koveras

    Koveras Member

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    "...methylene blue (an inhibitor of guanylate cyclase) to prevent the synthesis of cGMP."

    "Methylene blue also blocks accumulation of cyclic guanosine monophosphate (cGMP) by inhibiting the enzyme guanylate cyclase: this action results in reduced responsiveness of vessels to cGMP-dependent vasodilators like nitric oxide"

    "cGMP is a signal molecule – or a second messenger – that transfers messages in the pituitary cells from other messenger hormones to the DNA. More cGMP means more LH."

    "Luteinizing hormone (LH, also known as lutropin and sometimes lutrophin[1]) is a hormone produced by gonadotropic cells in the anterior pituitary gland. it stimulates Leydig cell production of testosterone."

    "Methylene blue inhibited the erectile response in all treatment groups, showing that cyclic GMP is critical to the NO-independent pathway as well as the NO-dependent pathway. "

    " These data show that (1) NO exerts a biphasic effect on testosterone secretion, which is stimulatory at low and inhibitory at high concentrations; (2) the stimulatory effect of NO is mediated by cGMP, the classic second messenger for NO action."

    Androgenic maintenance of the rat erectile response via a non-nitric-oxide-dependent pathway. - PubMed - NCBI

    Biphasic effect of nitric oxide on testosterone and cyclic GMP production by purified rat Leydig cells cultured in vitro. - PubMed - NCBI

    Luteinizing hormone - Wikipedia
     
  7. OP
    haidut

    haidut Member

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    Methylene blue also inhibits the release of pretty much all pituitary hormones, including LH, FSH, prolactin, ACTH, GH, etc. I posted some studies about that. The in vivo studies I have seen did not show any negative effects of MB on androgens synthesis and the above studies only used MB in vitro. The human studies using MB in very high doses for Alzheimer, etc measured hormones and also did not find suppression. MB oxidizes NADH back to NAD and NAD is a required cofactor for androgen synthesis. MB also speeds up metabolism, which is also good for steroid synthesis. So, the net effect in vivo for MB is at most neutral and maybe even positive as far as androgens are concerned. Especially when used in lower doses which affect mostly NAD/NADH ratio.
     
  8. High_Prob

    High_Prob Member

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    Koveras, Haidut - Thanks!
     
  9. Koveras

    Koveras Member

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    The first study was an in vivo study on the effect of methylene blue on erection in rats. I'm sure there are a lot of individuals that may be concerned about the effect of methylene blue on erections, regardless of whether or not their androgens increase, decrease, or stay the same.

    In fact methylene blue is used as a treatment for priapism.

    From methylene blue (methylthionine chloride) to Al-Ghorab procedure: the therapy of priapism (our experience). - PubMed - NCBI

    Priapism - etiology, pathophysiology and management. - PubMed - NCBI

    [Methylene blue: an effective therapeutic alternative for priapism induced by intracavernous injection of vasoactive agents]. - PubMed - NCBI

    Methylene blue as a successful treatment alternative for pharmacologically induced priapism. - PubMed - NCBI

    Nitric oxide donors induce penile erection and yawning when injected in the central nervous system of male rats. - PubMed - NCBI

    Prevention by NG-nitro-L-arginine methyl ester of apomorphine- and oxytocin-induced penile erection and yawning: site of action in the brain. - PubMed - NCBI

    Intracellular mechanism of penile erection in monkeys. - PubMed - NCBI
     
  10. OP
    haidut

    haidut Member

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    Right, I meant that in vivo studies on MB androgens did not show negative effects on androgens. I would absolutely expect MB to help with priapism since it is caused by excess NO. Bottom line - human studies with MB did not find issues with hormones or erection otherwise this would have been quickly noted. A side effect like that is usually considered a buzzkill and clinical trials won't proceed unless a reversal solution is found.
     
  11. paymanz

    paymanz Member

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  12. OP
    haidut

    haidut Member

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    The fact that it raises BP strongly suggests inhibition of NO. That is why it is used to revive people in shock - their NO levels are through the roof, BP is down and heart rate is down. I think the inhibition of NO synthesis only happens at high doses given IV. But in lower doses MB should be able to directly scavenge NO and also it is one of the very few things that can knock NO out of its association with cytochrome C (which is mostly how NO inhibits metabolism).
     
  13. Pointless

    Pointless Member

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    Peat inspires orgasms in you too?
     
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