Iron Metabolism And Liver Health

[michael94]

I was writing a response to gbolduev's post here: IP6 For Iron Chelation My response was getting a bit long and unrelated to IP6 so I just decided to make a new thread.

Retention of iron in the liver is due to low estrogen. Peat is super wrong on this. Women after menopause start retaining iron in their livers also, since their estrogen levels fall.

Basically if you are stressed you will use a lot of pregnenolone to make progesterone for cortisol and aldo pathway and will have very little DHEA. That will put your testosterone and estradiol into the lower part of the range. And you will start accumulating iron and copper in the liver. The mechanism how it works is this.

To release iron from the liver you need xanthine oxidase which runs on vitamin B2 and molybdenum, then you need ceruloplasmin to oxidize iron and put it on transferrin.

SO here we can possibly have 2 problems , lack of B2 or molybdenum , and lack of DHEA from stress so there is very little estrogen made.LOW estrogen equals low ceruloplasmin which equals no iron on transferrin and tons of it in ferritin.

Another problem is suppressing estrogen)))) like Peat advices, and then you run low on zinc no matter what you do and you wear glasses as thick as a windshield in your car)). Estrogen is needed to make zinc bioavailable since without bioavailable copper that estrogen provides your zinc levels will be suppressed. And when you run low on bioavailable zinc your protein synthesis goes down the drain and what suffers first. Yes you got it, the tiny muscles around your eyes. NOW we look at the thickness of PEATs glasses))) Cant see his eyes behind those. It is funny that I had exactly the same when I got sick before I got into all this medical crap. I remember I was driving a car and I could not see the signs on the road and my eyes constantly got tired .



SO the good idea would be to test your DHEA,Pregnenolone and also B2 and molybdenum status. IF you have low pregnenolone, that is most likely you have SIBO in the gut, since prenenolone is made from cholesterol and koenzym A which requires B5 in its active form --pantethine and acetic acid( vinegar).
B5 recycling depends on the gut.

That is why so many people are helped with simple vinegar plus brewest yeast.

Also iron chelation is good, but dont forget we have low iron in tissues but some free iron in the organs and also tons of iron in the liver. SO I think proper iron chelation would be by making iron bioavailable so it does not spill from the liver and making sure you have proper ceruloplasmin levels to make iron work.

I hope this makes sense


Serum estradiol associates with blood hemoglobin in elderly men: the MrOS Sweden study. - PubMed - NCBI

Estrogen regulates iron homeostasis through governing hepatic hepcidin expression via an estrogen response element. - PubMed - NCBI

I usually dont look at these, but the first study was Swedish , so may be not as bull**** as FDA controlled crap on pubmed)))

1. Xanthine Oxidase

Let's start with xanthine oxidase. I was doing research and it seems like xanthine dehydrogenase is the enzyme for exporting non-heme iron. There are three xanthine oxioreductase forms and xanthine oxidase is generally the most problematic unless tightly controlled but I won't get too much into those details because it's beyond my chemistry/biology abilities. Suffice it to say all of them play an important role in the body and it's probably inaccurate to say xanthine oxidase is "bad". Both XDH and XO are inhibited by nitric oxide and in addition the radical formation associated with XO is greatly attenuated by methyelene blue. Alcohol inhibits XDH too so we can start to see the connection between alcohol liver damage and iron accumulation. This obviously points to the benefits of MB as a therapeutic agent along raising the NAD/NADH in general. Of course MB acts in more ways than just restoring XDH activity but that's definitely one of the main mechanisms. Google MB + liver damage and see for yourself. I really doubt molybdenum/B2 levels are the limiting factors in people not eating weird super-restrictive diets although that may be wrong, open to being convinced otherwise.

2. Low Estrogen

Gbolduev covered everything on that issue pretty well. Low estrogen lowers ceruloplasmin as well as raises hepcidin which blocks the export of iron from the liver, see image below. Low vitamin D and inflammation in general also raises hepcidin.

This is all a very individual thing.Some people have high estrogen or normal estrogen and may still have iron metabolism problems but in people with too low estrogen it IS contributing to the problem no doubt about it. Pregnenolone/DHEA supplementation may be in order because low pregnenolone/DHEA/Estrogen etc can be a vicious cycle to get out of especially if you have gut problems. Temporary raising of steroids back to healthy levels can re-allow the egress of unnecessary non-heme iron and excess copper and lead to good long term endogenous production by reducing excess iron and copper related oxidative stress. If zinc is not being utilized properly due to low estrogen then you are fighting an uphill battle against poor liver function. Zinc is necessary for vitamin A to work and both contribute to the breakdown of fibrotic tissue. That stuff won't show up in your liver ALT/AST levels and your clown doctor will say liver is fine. Dipshits. Pregnenolone itself also has important anti-fibrotic actions. I know @haidut mentioned pregnenolone alone having a important role in liver toxin management so there's another benefit although I had a hard time finding info on that specifically.

3. L-Carnitine

L-carnitine is very important, thanks to @kineticz for turning me onto this substance. In my experience it has a very good stabilizing effect on energy levels and blood flow. I could write a lot but I'll just spam some studies and you can come to your own conclusions.

- Neuroprotective Effects of Pre-Treament with l-Carnitine and Acetyl-l-Carnitine on Ischemic Injury In Vivo and In Vitro -----> Role of xanthine oxidase in ischemia/reperfusion injury. - PubMed - NCBI ( tying back into XO/XDH connection )
- Plasma carnitine concentrations after chronic alcohol intoxication. - PubMed - NCBI
- https://sci-hub.io/10.1016/0024-3205(96)00343-8
- L-carnitine ameliorated fatty liver in high-calorie diet/STZ-induced type 2 diabetic mice by improving mitochondrial function
- L-Carnitine Prevents Progression of Non-Alcoholic Steatohepatitis in a Mouse Model with Upregulation of Mitochondrial Pathway
- L-carnitine ameliorated fasting-induced fatigue, hunger, and metabolic abnormalities in patients with metabolic syndrome: a randomized controlled study
- Effect of acetyl-L-carnitine on lipid peroxidation and xanthine oxidase activity in rat skeletal muscle. - PubMed - NCBI

inb4 carnitine lowers thyroid, discussed on this page: PUFA Depletion Can (probably) Be Accomplished In 30 Days!

 

[michael94]

So, for proper iron metabolism and liver health these are some suggestions :)

1. Good diet. Eat to instinct. Gelatinous and fatty beef cuts will be especially protective ( high carnitine high zinc high glycine high sat fat ).
2. Address gut issues, fermented foods are very helpful here as well as avoiding things that give bad reactions. Carrot salad helps some people but did little for me compared to foods like sauerkraut. Worth a try as it's incredibly easy/inexpensive.
3. Raise Vitamin D levels if deficient. Estroban or sunshine is common. I like cod liver oil because it hits a lot of things in one go and it's a whole food product. It's also very good for gut inflammation on my experiences and this is confirmed in literature. "Understanding intestinal lipopolysaccharide permeability and associate" by Venkatesh Mani Antiulcer activity of cod liver oil in rats Some of you want to avoid because it will give you PUFA cancer which I understand. I don't consider CLO as supplement but a food.
4. L-carnitine, seems to have the least ( basically 0 ) complications in supplementation and is probably the best place to start.
5. Pregenolone + DHEA, follow up the carnitine with preg + DHEA if you suspect low estrogen and androgens.
6. Methylene blue inhibits aromatase which may be contraindicated if you already have low estrogen so I would use this last or start with just 1 drop ( 500 mcg or less ). If you think you have very high estrogen you can move MB up the list.

This is not necessarily in order of what will benefit people most. I think Preg/DHEA will be by far the most dramatic boost in the people that need it. You're just going to want to get the other things in order first ( avoid complications ).

Honorable mention

-Curcumin, based on whom I've talked to the curcumin is helpful but I think the quality can vary A LOT. Would recommend for cooking with or supplementing if you have money to blow. I won't get into curcumin benefits but turmeric has a long history of being a healing substance.

Any criticisms or changes to recommendations are welcome.

 

[haidut]

I think gbolduev has some very good points, but where I disagree with him is the cortiol/estrogen pathways. I do agree that under stress the steroids will be diverted into the cortisol pathway. And since the 11b-HSD enzymes are present in virtually every cell, your entire organism can become a cortisol synthesizing machine. However, I don't agree with gbolduev that estrogen in such situations will be low. It will also be high as cortisol is one of the most potent inducers of the aromatase enzyme. And since aromatase is also present in virtually every cell, your entire organism will also become an estrogen synthesizing machine if cortisol is high. The reasons for this interplay are very good. Cortisol is the main signal of stress response. That stress response includes the cell switching from glucose oxidation to fat oxidation, retaining water (swells) and even starting dividing. Estrogen is needed for all of these events to occur, and can be thought of as the main conductor of the of stress. There is really no other way, they both work together. Estrogen is needed to upregulate carnitine synthesis for fat oxidation, and estrogen turns off the enzyme PDH. Without PDH there can be no efficient use of glucose so the alternative is fat. Estrogen also stimulates lipolysis, and the FFA if they are PUFA antagonize insulin and stimulate even more the cortisol/estrogen synthesis, while inhibiting PDH even more. Estrogen turns off the negative feedback on cortisol production and this vicious circle goes on and on for as long as there is stress applied to the organism strong enough to warrant these changes. Sometimes, things like niacinamide, pregnenolone, vitamin E, thyroid, progesterone, etc can turn off the stress response pretty quickly (alone or in combination). But if this has been going on for some time, then the cells and tissues have memory of past events and will take some time to re-arrange in a proper anti-stress metabolic field. How long, it depends on each person and the circumstances they experienced as well as on continued stress, nutrition, drugs they take, time of year, etc.
Ultimately, the issues about iron accumulation and storage in the liver are moot if iron is not high in diet and thyroid is good. Remember, everything is controlled by thyroid and the metabolites it influences. So, if thyroid is going well and there is proper synthesis of CO2, pregnenolone and all steroids downstream from it then mineral balance is not much of an issue. That, and good nutrition of course, which brings us back to diet as being at least as important as astrophysics (as Peat says).
If stress is under control or absent, thyroid is working well, and pulse/temps are good and the person is still not feeling well then there is something else continuing to bother the organism. Chronic infection, bad environment, or crappy food can be some such latent stressors that most people and doctors do not think twice about.

 

[Tarmander]

I always thought it was interesting that gbolduev talked about Ray's vision. He is near sighted correct?

About a year ago I looked into near sighted rates among populations and found an older study that strongly correlated it with your occupation. So farmers had rates in the single digits, craftsmen were a bit higher, scribes were even higher, and so on.

What I took away from it was that the most important matter in deciding your vision was how much close up work you were doing. The more you had your head in books and wrote the worse your vision became. I imagine as a PH.D, and what we know of Ray's life, he's done an extraordinary amount of close up work.

One thing I do to mitigate this is wear reading glasses when I am doing close up work and push the print a bit farther away to simulate reading something farther away.

 

[michael94]

Yes well I think Peat is right about excess estrogen and nitric oxide in the right context, but they play an important therapeutic role in maintaining cell function. Estrogen/NO are crucial for us to not dissolve into puddles of flesh from free radical formation. Your body does not hate you. Aromatase up-regulation during stress is adaptive and lowering it artificially will probably lead to big problems. Reducing stress and things like MB are much different than synthetic aromatase/estrogen blockers of course because they treat the root cause. Dopamine agonists can be contraindicated with excessive use for the same reasons.

See:
An Error Occurred Setting Your User Cookie
Estrogen and oxidative stress: A novel mechanism that may increase the risk for cardiovascular disease in women

As for low estrogen not being an issue, I do not agree. I think low estrogen, low test, low DHEA are all problematic in themselves and tied to low pregnenolone. Like I said, aromatase upregulation is adaptive.

Running on fat is not an issue either and the move to fat oxidation under stress is probably a result of fat oxidation being a much cleaner and simpler process than proper glucose oxidation ( which requires A LOT more things to go right ). There is a reason people stay "stuck in glycloysis" for so long. Mitochondria need to be very healthy for oxidative glucose metabolism and fat oxidation can side-step that problem.

The thing with PUFA is it's more inhibitive of glucose metabolism than fat metabolism ( linoleic acid will **** up your mitochondria ) so you can get away with PUFA running on fat but with glucose good luck. Also, good quality milk is nothing like starches. Starches are much more glycolysis promoting. You don't want 0 glucose to function optimally but you can't just rush into being a lean mean carb burning machine when you've been treating your mitochondria and liver like ***t for so long ( i.e. most people on this forum ).

IF you are running on a high glucose diet you absolutely need high thyroid. High thyroid production is a very involved process and not easily resolved by switching to a good diet which comes back to side-stepping this issue via fat oxidation. Hell even Danny Roddy still takes thyroid lol ( Danny is great btw I mean no offense )! Carnitine is like thyroid hormone for fats ( not a perfect analogy but it fits pretty well ) and much easier to have in adequate amounts.

I'm rambling here but the main points are:

Quality diet, lower stress, MB, pregnenolone, dhea, etc = GOOD
synthetic aromatase blockers and dopamine agonists = BAD ( most of the time )

As far as carb intake it depends on how your mitochondria and liver are, in addition to the right sources. Blaming fat metabolism because it's associated with stress is completely missing the fact that it's ADAPTIVE TO STRESS. Omega-6 pufas **** everything but glucose metabolism moreso than fat.

 

[PakPik]

Any criticisms or changes to recommendations are welcome.

Hello Icecreamlover,
I'd recommend you reconsider your instance on the CLO. I am sure you are being honest, that it helped you; indeed fish oils can powerfully lower inflammation. But this is not a kind of benign inflammation, this is in fact a direct lowering of immunity. Fish oils are frequently compared in power to cyclosporin, the immunosuppresant, awesome for organ transplant. That's not something one strives for, that's pretty dangerous and can even lead a person more easily to things like sepsis. The septic effect has been shown in lab animals. Yep, even worse than the seed oils. Fish oil powers work mainly through their decomposition in free radicals like acrolein, which is like a hundred times more powerful than the radicals produced by the O-6. And many more radicals. And as you say, very carcinogenic.


"What about fish oils?

It's worse. The good thing about fish oil is that it's so unstable that most of it doesn't survive to reach your bloodstream there it would inhibit your thyroid function; so it breaks down into other compounds which are actually toxic, and the first thing you see affected is the immune system. The breakdown products of the spontaneously oxidizing fish oil include acrolein, which is a carcinogen, and ethane which you can measure on the breath after people eat fish oil. But several of these toxic breakdown products are immunosuppressive, so they have an antiinflammatory effect that in the short run makes them seem beneficial."[1]

“Acrolein is known as a ubiquitous pollutant in the environment. Here we show that this notorious aldehyde is not just a pollutant, but also a lipid peroxidation product that could be ubiquitously generated in biological systems.” “…polyunsaturated fatty acids are sources of acrolein that cause the production of protein-bound acrolein. These data suggest that the protein-bound acrolein represents potential markers of oxidative stress and long-term damage to protein in aging, atherosclerosis, and diabetes.”[2]

“Acrolein is a major cytotoxic product of lipid peroxidation and its adduction to neuronal proteins has been demonstrated in diseased brain regions from patients with Alzheimer’s disease.” “Our data show that acrolein primarily inhibits mitochondrial respiration at several levels…”[3]

“Acrolein, which is increased in Alzheimer’s disease brain, may be partially responsible for the dysfunction of mitochondria and loss of energy found in Alzheimer’s disease brain by inhibition of pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase activities, potentially contributing to the neurodegeneration in this disorder.”[4]

1. Thyroid and Polyunsaturated Fatty Acids Interview with Raymond Peat (2008)
2. Protein-bound acrolein: potential markers for oxidative stress (1998)
3. Acrolein inhibits respiration in isolated brain mitochondria (2001)
4. Acrolein inhibits NADH-linked mitochondrial enzyme activity: implications for Alzheimer’s disease (2003)

(Got this quotes from Danny Roddy's facebook)

I also agree with Haidut's instance on hormones, particularly, that a person typically piles up estrogen with chronic stress and degeneration; estrogen accumulation in tissues, not necessarily high in serum, Peat explains that in his articles.

Thank you.

 

[Tarmander]

B6 is a dopamine agonist...

 

[michael94]

B6 is a dopamine agonist...

Yes I'm talking about synthetic ones. B6 plays an important bio-chemical role in methylation and protecting against oxidative stress.

Hello Icecreamlover,
I'd recommend you reconsider your instance on the CLO.

Omega-3s are unnecessary in a context of "PUFA depletion" because your body very efficiently converts the DHA and EPA it needs. Omega-6s inhibit this conversion and even after avoiding them you will probably be deficient in DHA/EPA for a while. Cod liver oil isn't just my experience but literally that of millions of people spanning many generations. In basically every study I have read it has led to increase markers of health not decreased. But if you still think CLO is harmful I can't force it. Do what works for you.

 

[michael94]

B6 is a dopamine agonist...

Also, I didnt mean to say that dopamine agonists are always bad. I think they are good acutely to get yourself out of a rut or fine chronically if you are already healthy. Otherwise an unhealthy person relying on synthetic dopamine agonists to function long-term gets the excruciating adderall-type depression eventually.

Ergot derivatives are much safer DA compared to others...I am a huge fan of LSD these things just need to be used intelligently. I think a big contributing factor to the "bad trip" phenomenon is oxidative stress from artificially raising your metabolism so much.

As for synthetic Aromatase inhibitors I would just say stay away from them altogether because most people taking them for excess estrogen don't really have a firm understanding of what's going on and it can lead to bigger problems. I used to be involved in a few steroid/bodybuilding type forums and managing estrogen was the #1 issue with steroid cycles ( both too high and too low ). People see Peat's warnings against excess estrogen and all the complications associated and decide that aromasin or letro is a good idea. Bad idea. Peat's recommendations are for the most part entirely correct BUT if you just take high estrogen is bad out of context you will do stupid things.


Edit:
Just as an example, healthy libido is one of the first things to go when people become sick and that's because maintaining that function is much less important than protecting against oxidative stress/inflammation in the liver, heart, brain etc. Take a dopamine agonist...you're drawing crucial resources ( zinc, blood etc ) to the testes for semen production, inhibit aromatase so all estrogen mediated functions are limited. That's leaving more essential functions out in the cold and contributing to long term damage. Caution is advised.

Substances like caffeine/nicotine are somewhere in between the synthetic Dopamine Agonists and b6/zinc/magnesium/MB/pregnenolone/etc.

 

[haidut]

Yes well I think Peat is right about excess estrogen and nitric oxide in the right context, but they play an important therapeutic role in maintaining cell function. Estrogen/NO are crucial for us to not dissolve into puddles of flesh from free radical formation. Your body does not hate you. Aromatase up-regulation during stress is adaptive and lowering it artificially will probably lead to big problems. Reducing stress and things like MB are much different than synthetic aromatase/estrogen blockers of course because they treat the root cause. Dopamine agonists can be contraindicated with excessive use for the same reasons.

See:
An Error Occurred Setting Your User Cookie
Estrogen and oxidative stress: A novel mechanism that may increase the risk for cardiovascular disease in women

As for low estrogen not being an issue, I do not agree. I think low estrogen, low test, low DHEA are all problematic in themselves and tied to low pregnenolone. Like I said, aromatase upregulation is adaptive.

Running on fat is not an issue either and the move to fat oxidation under stress is probably a result of fat oxidation being a much cleaner and simpler process than proper glucose oxidation ( which requires A LOT more things to go right ). There is a reason people stay "stuck in glycloysis" for so long. Mitochondria need to be very healthy for oxidative glucose metabolism and fat oxidation can side-step that problem.

The thing with PUFA is it's more inhibitive of glucose metabolism than fat metabolism ( linoleic acid will **** up your mitochondria ) so you can get away with PUFA running on fat but with glucose good luck. Also, good quality milk is nothing like starches. Starches are much more glycolysis promoting. You don't want 0 glucose to function optimally but you can't just rush into being a lean mean carb burning machine when you've been treating your mitochondria and liver like **** for so long ( i.e. most people on this forum ).

IF you are running on a high glucose diet you absolutely need high thyroid. High thyroid production is a very involved process and not easily resolved by switching to a good diet which comes back to side-stepping this issue via fat oxidation. Hell even Danny Roddy still takes thyroid lol ( Danny is great btw I mean no offense )! Carnitine is like thyroid hormone for fats ( not a perfect analogy but it fits pretty well ) and much easier to have in adequate amounts.

I'm rambling here but the main points are:

Quality diet, lower stress, MB, pregnenolone, dhea, etc = GOOD
synthetic aromatase blockers and dopamine agonists = BAD ( most of the time )

As far as carb intake it depends on how your mitochondria and liver are, in addition to the right sources. Blaming fat metabolism because it's associated with stress is completely missing the fact that it's ADAPTIVE TO STRESS. Omega-6 pufas **** everything but glucose metabolism moreso than fat.

These are all valid points, but still, if fat oxidation is good for us then why do drugs like Mildronate help so much? That drug is now not only (ab)used by every athlete out there but is also used off label in Eastern Europe for every degenerative conditions you can think of. Also, what about aspirin and niacinamide? Aspirin can be thought of a Mildronate-like drug in regards to carnitine:
Involvement of Carnitine in Reye’s and Reye-Like Syndromes - Springer

Obviously you don't want fully depleted carnitine, and like any drug even Mildronate can be abused to some very bad results.
Btw, I never said you want low estrogen. I just said that both cortisol and estrogen rise under stress and are both symptoms of stress and mediators of the stress response. What the optimal levels of estrogen and cortisol are I don't know but judging from studies on healthy children, the optimal levels seem to be in the bottom 15% of the range currently defined as healthy for adults. Fat oxidation when done under stress by tissues other than muscles is an indication of stress. Fat oxidation by muscles at rest is OK, that is their preferred fuel source. But, like you said, do what works best for you.

 

[Sheila]

Dear Icecreamlover

I appreciate your research here and the interesting discussion. If l-carnitine is an inducer of cortisol per this thread and Haidut's posts above

Carnitine Is A Glucocorticoid Agonist, Acts Like Cortisol

why do you think it was helpful to you in your situation?

Thank you for your thoughts.

Sheila

 

[Tarmander]

Also, I didnt mean to say that dopamine agonists are always bad. I think they are good acutely to get yourself out of a rut or fine chronically if you are already healthy. Otherwise an unhealthy person relying on synthetic dopamine agonists to function long-term gets the excruciating adderall-type depression eventually.

Ergot derivatives are much safer DA compared to others...I am a huge fan of LSD these things just need to be used intelligently. I think a big contributing factor to the "bad trip" phenomenon is oxidative stress from artificially raising your metabolism so much.

As for synthetic Aromatase inhibitors I would just say stay away from them altogether because most people taking them for excess estrogen don't really have a firm understanding of what's going on and it can lead to bigger problems. I used to be involved in a few steroid/bodybuilding type forums and managing estrogen was the #1 issue with steroid cycles ( both too high and too low ). People see Peat's warnings against excess estrogen and all the complications associated and decide that aromasin or letro is a good idea. Bad idea. Peat's recommendations are for the most part entirely correct BUT if you just take high estrogen is bad out of context you will do stupid things.


Edit:
Just as an example, healthy libido is one of the first things to go when people become sick and that's because maintaining that function is much less important than protecting against oxidative stress/inflammation in the liver, heart, brain etc. Take a dopamine agonist...you're drawing crucial resources ( zinc, blood etc ) to the testes for semen production, inhibit aromatase so all estrogen mediated functions are limited. That's leaving more essential functions out in the cold and contributing to long term damage. Caution is advised.

Substances like caffeine/nicotine are somewhere in between the synthetic Dopamine Agonists and b6/zinc/magnesium/MB/pregnenolone/etc.

I don't think there is a lot of abuse of synthetic Dopamine agonists and Aromatase inhibitors on this forum. Maybe there is? I am not sure but I definitely do not read about it all that much. I do not know how much you need to caution against it as the list of side effects from those things are usually enough to scare most people off. Are you saying lowering estrogen is a good thing unless you use synthetics? Or are you saying lowering estrogen even with non synthetics like B6 is even not good? It seems from my experience most of the things that feel good also lower estrogen in some way...

 

[FredSonoma]

A lot of these things are ringing true but I have a few questions and points of confusion.

A few things that apply:
1. I have long-standing history of possible SIBO / severe gut bloating / inability to eat starch
2. Both pregnenolone and pregnenolone / DHEA mixed (Pansterone) give me a reaction I don't enjoy - the first makes me feel tired / socially anxious and the 2nd makes me feel extremely Beta / tired / estrogenic / no libido. I would think I would be in huge need of both DHEA and Pregnenolone so shouldn't they immediately make me feel better - or could these reactions still mean that I need them?
3. I think I have too much iron - I was "Paleo" for a while and ate 1.5 pounds of beef organ meat per day for 1 year straight.
4. I drink a lot of caffeine / smoke tobacco / eat a lot of cocoa (all of which are dopamine agonists right?) and sometimes feel like I am using them too much and question whether or not they are helping me long-term.
5. I do notice that MB makes me feel better directly after, but if I take even 5 drops, I feel emotionally reactive (aggressive) but also afraid to be alone
6. I have noticed recently that a fatty steak looks like the most delicious thing in the world
7. Cilantro (which chelates iron) tastes delicious to me

I think my biggest question is - Why TF does pregnenolone and DHEA make me feel weird?

Edit: not sure if related at all, but I've recently noticed that my pupils are abnormally small

 

[michael94]

These are all valid points, but still, if fat oxidation is good for us then why do drugs like Mildronate help so much? That drug is now not only (ab)used by every athlete out there but is also used off label in Eastern Europe for every degenerative conditions you can think of. Also, what about aspirin and niacinamide? Aspirin can be thought of a Mildronate-like drug in regards to carnitine:
Involvement of Carnitine in Reye’s and Reye-Like Syndromes - Springer

Obviously you don't want fully depleted carnitine, and like any drug even Mildronate can be abused to some very bad results.
Btw, I never said you want low estrogen. I just said that both cortisol and estrogen rise under stress and are both symptoms of stress and mediators of the stress response. What the optimal levels of estrogen and cortisol are I don't know but judging from studies on healthy children, the optimal levels seem to be in the bottom 15% of the range currently defined as healthy for adults. Fat oxidation when done under stress by tissues other than muscles is an indication of stress. Fat oxidation by muscles at rest is OK, that is their preferred fuel source. But, like you said, do what works best for you.

I think mildronate is fascinating. The thing I wonder about mildronate is what it's entire MOA is. In other words I dont think it is just inhibiting carnitine synthesis. Moreover, glucose is crucial as your body's anti-stress reserve ( you can't make liver and muscle glycogen from fat in sufficient quantities). Athletes by definition are under constant high physical stress and I don't think their glucose metabolism requirements apply as much to average people. I don't know enough to comment further but it's probably hard for unhealthy people or those under high physical stress ( athletes ) to manage glucose and fatty acids at the same time efficiently. Carbohydrate type is also related of course. Full fat unhomogenized milk/yogurt will lead to more efficient energy production than a baked potato with butter ( not that this is necessarily unhealthy ).

I don't think there is a lot of abuse of synthetic Dopamine agonists and Aromatase inhibitors on this forum. Maybe there is? I am not sure but I definitely do not read about it all that much. I do not know how much you need to caution against it as the list of side effects from those things are usually enough to scare most people off. Are you saying lowering estrogen is a good thing unless you use synthetics? Or are you saying lowering estrogen even with non synthetics like B6 is even not good? It seems from my experience most of the things that feel good also lower estrogen in some way...

You are right it is not that common but it does happen you just have to do a forum search. Yes b6 especially as p-5p is good and safe, probably bad in very large amounts but I wouldnt advise to avoid it at all. You'd do more harm avoiding MB/B6/Magnesium/Pregnenolone etc

 

[michael94]

A lot of these things are ringing true but I have a few questions and points of confusion.

A few things that apply:
1. I have long-standing history of possible SIBO / severe gut bloating / inability to eat starch
2. Both pregnenolone and pregnenolone / DHEA mixed (Pansterone) give me a reaction I don't enjoy - the first makes me feel tired / socially anxious and the 2nd makes me feel extremely Beta / tired / estrogenic / no libido. I would think I would be in huge need of both DHEA and Pregnenolone so shouldn't they immediately make me feel better - or could these reactions still mean that I need them?
3. I think I have too much iron - I was "Paleo" for a while and ate 1.5 pounds of beef organ meat per day for 1 year straight.
4. I drink a lot of caffeine / smoke tobacco / eat a lot of cocoa (all of which are dopamine agonists right?) and sometimes feel like I am using them too much and question whether or not they are helping me long-term.
5. I do notice that MB makes me feel better directly after, but if I take even 5 drops, I feel emotionally reactive (aggressive) but also afraid to be alone
6. I have noticed recently that a fatty steak looks like the most delicious thing in the world
7. Cilantro (which chelates iron) tastes delicious to me

I think my biggest question is - Why TF does pregnenolone and DHEA make me feel weird?

I was completely lost until I got my blood tests. This all just happened in the last few days so I am no expert by any means I just wanted to share what I've been learning from others/what has worked for me. Everything is always different depending on the individual so you need to listen to your instincts on how you respond to different substances.

Have you had blood tests?

Estrogen isn't the only factor in iron metabolism you also need good vitamin D levels, low inflammation, zinc/copper. Saturated fat and beef protein is very anti-inflammatory and has lots of zinc/copper. Don't worry about the iron in it, just my 2c.

Gut issues deserves its own thread but what helps me is: cod liver oil, fermented foods ( sauerkraut/yogurt ), not eating starch.

 

[Strongbad]

Niacin limits the release of free fatty acids and l-carnitine burns the rest of remaining free fatty acids into energy. It's literally non-issue anymore. Free fatty acids is not a big deal if you take adequate carnitine and niacin in your diet / supplementation. There's such thing as free fatty acid metabolism, and it's not a bad thing.

The more we drink milk (rich in calcium) the more we deplete vitamin D because it needs to remove free-roaming calcium from our tissues to avoid calcification. Vitamin D works in funny way depending on how much calcium we consume.

 

[PakPik]

Estrogen/NO are crucial for us to not dissolve into puddles of flesh from free radical formation.

I've read exactly the opposite from Peat: Estrogen and NO are two of the main drivers of oxidative stress in the body. Peat never gets tired about stressing that. Estrogen indeed is one of the big causes of the age pigment. Have you read about age pigment? It's a crucially destabilizing factor. Therefore, how can estrogen and nitric oxide be protective according to you?

How do you substantiate those contrary claims?

aromatase upregulation is adaptive

Estrogen acts as a signal for stress, as an S.O.S according to Peat. It should be promptly met by an increase of the protective steroids, and when they appear they act as a signal to stop the estrogen production. That is adaptive. If estrogen isn't stopped that way, aromatase keeps pumping it in a vicious circle. That's MALadaptive.

 

[michael94]

I've read exactly the opposite from Peat: Estrogen and NO are two of the main drivers of oxidative stress in the body. Peat never gets tired about stressing that. Estrogen indeed is one of the big causes of the age pigment. Have you read about age pigment? It's a crucially destabilizing factor. Therefore, how can estrogen and nitric oxide be protective according to you?

How do you substantiate those contrary claims?



Estrogen acts as a signal for stress, as an S.O.S according to Peat. It should be promptly met by an increase of the protective steroids, and when they appear they act as a signal to stop the estrogen production. That is adaptive. If estrogen isn't stopped that way, aromatase keeps pumping it in a vicious circle. That's MALadaptive.

I posted this above: Estrogen and oxidative stress: A novel mechanism that may increase the risk for cardiovascular disease in women

Under normal conditions in younger women, the primary product of estrogen action is NO, which produces a number of beneficial effects on vascular biology. As a woman ages, however, there is evidence for loss of important molecules essential for NO production (e.g., tetrahydrobiopterin, L-arginine). As these molecules are depleted, NOS becomes increasingly “uncoupled” from NO production, and instead produces superoxide, a dangerous reactive oxygen species. We propose that a similar uncoupling and reversal of estrogen response occurs in diabetes. Therefore, we propose that estrogen is neither “good” nor “bad”, but simply stimulates NOS activity. It is the biochemical environment around NOS that will determine whether estrogen produces a beneficial (NO) or deleterious (superoxide) product, and can account for this dual and opposite nature of estrogen pharmacology.

Lowering metabolism is also another way of getting your body to produce less radicals, a function of estrogen. I agree with Haidut we don't need a lot of estrogen but requirements change depending on the context.

I don't think estrogen contributes to a vicious circle UNLESS you are ignoring your body's cues to conserve energy or there are exogeneous substances artificially raising bad estrogen effects while blocking necessary ones ( plastics ). You don't fix that by artificially lowering aromatase. If estrogen is the response to stress and you push through that stress of course it will lead to more estrogen but that doesn't make it maladaptive. You fix these issues by lowering stresses and avoiding toxins. I'm not really arguing against Peat's recommendations it's more of a clarification.

 

[michael94]

Also, lowering estrogen with Pregnenolone/DHEA is not just simply inhibiting aromatase. The youth steroids have important biochemical functions that are restoring order and decreasing the need for a stress response.

 

[FredSonoma]

Also, lowering estrogen with Pregnenolone/DHEA is not just simply inhibiting aromatase. The youth steroids have important biochemical functions that are restoring order and decreasing the need for a stress response.

Could this be why Preg and DHEA make me feel really tired - they are lowering stress hormones?