Random, interesting studies

[Mauritio]

Vitex Agnus castus:

TLDR:

• very strong evidence on pro-progesterone effect
• strong evidence on anti-prolactin effect, esp. In high doses
• few studies on estrogen and testosterone, effects ranging from low antagonism to slight agonism in both

PROGESTERONE:

In this human study on women with hyperprolactinemia it increased progesterone by almost 4-fold ,while increasing estrogen 1.13 fold.
So there's a very strong increase in progesterone and a comparably insignificant increase in estrogen.

"...and eliminated deficits in luteal
progesterone synthesis (placebo: 1.99±0.65→2.34±0.59 ng/ml; verum: 2.46±0.70→9.69±6.34) in
the verum group. The changes were significant. All other examined hormonal parameters did not change with the exception of 17ß-estradiol which increased significantly in the luteal phase in patients receiving verum (placebo: 119.5±26.0 pg/ml→131.1±33.2; verum: 131.6±25.0 pg/ml→151.6±25)"

PROLACTIN:

Here's a lot of info on it from the RPF ,with OP claiming it removed his premature ejaculation. Dosage seems to be important.
https://lowtoxinforum.com/threads/vitex-for-men.11538/

[Mauritio]

"Result showed 5-HT released from platelet decreased..."
https://pubmed.ncbi.nlm.nih.gov/8043997/

[Mauritio]

Another very impressive study about A. Melegueta a.k.a. Grains of Paradise.

Not only did rats on a high fat diet not gain weight they actually lost weight while on GoP. Rarely ever saw that.

It also increased UCP1 by more than 100% and PGC1a several fold.

https://journals.sagepub.com/doi/full/10.1177/1934578X211033744#sec-2

It can also quadruple rats testosterone , reduce prolactin and estrogen ,while not touching progesterone. For more info look at my posts on it on the former RPF.

[Mauritio]

The Acute Effects of a Commercially Available Caffeinated and Caffeine-Free Thermogenic Dietary Supplement on Resting Energy Expenditure, Hunger, and Hemodynamic Responses
https://www.mdpi.com/1661-3821/4/1/6

[cs3000]

@Mauritio nice one on the syringic acid thanks, agonises the trB receptor. so could be helpful for people with chronic inflammation having their t3 eaten up by immune cells / deiodinase 3 getting around this by hitting the receptor direct .
1,25 vit D up in poor health also has much more potent affinity for that receptor than t3 but as a blocking effect instead

Looking around at sources because of the dose i dont think u'd get enough from foods right, (they said 50mg/kg was better than 25mg/kg so wouldnt get the effect from lower by the sounds of it) ,
its reasonably priced but only seeing it on the sites not selling to individuals

so its a hydroxybenzoic acid like aspirin

wonder if ferulic or vanilic acid could be alternatives?

ferulic acid also stimulates t3 activates TPO so maybe binds thyroid receptor too ? but by other effects not as potently as syringic
https://pmc.ncbi.nlm.nih.gov/articles/PMC8151655/

https://www.researchgate.net/figure/Structures-of-aromatic-compounds_fig8_226981671

or vanillin from vanilla extract but less similar

ferulic acid can be bought as a cosmetic , not very bioavailable in cereals because its bound in polysaccharides but given to mammals by itself its very bioavailable
here in vivo it reversed hypo too
https://link.springer.com/article/10.1007/s12020-024-03818-z
50mg/kg t3 levels
(not as effective as syringic)

very liver protective in cadmium toxicity when given after established (but like most of these polyphenols dosing high could deplete too many needed metals too over time)
10.1007/s11356-019-05420-7

,
curious what the differences are agonising trA vs trB thyroid receptors

[cs3000]

@cs3000 also ferulic acid is a partial 5ht1a agonist without effecting 5ht2a. not active at 10mg/kg in mice orally but is 50mg/kg ~250mg-300mg human , and 250mg/kg started losing effect. maybe 150mg - 500mg

So could give a relaxing / anti anxiety effect
but maybe a short effect time / half life
(lowered the amount they moved around frantically in new environment or around new mouse, and lowered the heightened aggression, given acutely
all of the effect went when they gave them a 5ht1a antagonist
https://pubmed.ncbi.nlm.nih.gov/33829309/

50mg/kg orally in mice = enhanced exercise endurance, and prevented fatigue from consecutive days exercise
https://www.jstage.jst.go.jp/article/bbb/73/6/73_90062/_pdf/-char/en

&
fully restored brain performance in Alzheimers model by restoring brain blood flow
https://pmc.ncbi.nlm.nih.gov/articles/PMC8423929/#Sec20
cool imaging

1 way to get a better idea if ferulic acid is legit, should smell like "metallic meat" or hot dogs

[CrumblingCookie]

@cs3000
It's bizarre that ferulic acid hasn't been getting much more attention on these forums already long ago. In cosmetics/skin care it's a "secret" niche ingredient. It's comparatively cheap to buy and mostly extracted from rice bran.
Taken orally, ferulic acid is super powerful with noticably effects already after a few hours / half a day. For me it gives a remarkably clear head/mind. As you've brought up it has this very rare anti-serotonin profile on the specific receptors. But it's also very antiinflammatory. I.e. it may have powerful effects on lowering immunity. I can't say which effect weighs stronger and therefore stopped to take it after only a few days (+-250mg twice a day) because the effects were uncannily good.

[cs3000]

@CrumblingCookie cool, so did you stop alltogether or you take it a few days a week? im thinking if i notice benefits will go for 150mg - 250mg and 1 day between uses
just had a look at ant inflammatory effects yeah looks very good in the intestines at least

[CrumblingCookie]

@cs3000
I've looked into my notes (glad I had made some!): I was taking 250mg (not 500mg) once to twice a day. I had stopped it altogether because my reasoning told me that such a strong effect could only be ascribed to strong antiinflammatory effects which I am very wary of with regard to maintaining immunity.
Some more of my notes on FA:

FA is a presynaptic 5-HT1A agonist, alleviates neuroinflammation. 
May also improve skin tone and marks long-term. 
Compared to agmatine FA felt calmly stimulating. Maybe because it also 
agonises β2-receptors and inhibits MAOs, increases ghrelin and peristalsis. 
No increases in CRH, ACTH and cortisol.
Modulation of Nurr1 expression as well as immunotoxicity by inhibiting TRAF/TAK1/NF-κB, 
Nrf2 and p53 pathways.
(Antiviral, antibacterial), antiinflammatory, promoting angiogenesis 
and activating the energy-regulating AMPK.
The increased mental clarity by FA began half a day after the first intake
and further increased over the course of three days.

AFAIK 
TRAF and TAK1 are far up the cascade of intracellular signalling from pathogen sensing.
Inhibition of those not only decrease NF-κB 
but also the pathway down AP1 essential for innate immunity.
Inhibition of Nrf2 decreases bacterial phagocytosis (less bacteria getting eaten by macrophages).

[Mauritio]

@cs3000 @CrumblingCookie

Ferulic and vanillic acid seem to have some estrogenic properties. Maybe gigantol and Geranylgeraniol are some alternatives.

---

Quercetin and Ferulic Acid Elicit Estrogenic Activities In Vivo and In Silico
https://pubmed.ncbi.nlm.nih.gov/37446770/

The authors' conclude that FA causes human breast cancer cell proliferation by up-regulation of HER2 and ERalpha expression.
https://pubmed.ncbi.nlm.nih.gov/16893382/

Ferulic acid possessed phytoestrogenic effect by up-regulating pS2 gene expression and the receptor subtype of ERalpha.
https://pubmed.ncbi.nlm.nih.gov/21246834/

Although this one says it Inhibits estrogen.
https://pubmed.ncbi.nlm.nih.gov/33987364/

---

I've found less evidence of vanillic acid being estrogenic so I'd be more willing to experiment with that one.

Effects are abolished by anti-estrogenic substance , which doesn't prove it to be directly estrogenic, sometimes they use weird substances with a lot of different effects.
https://pubmed.ncbi.nlm.nih.gov/25106917/
This study says that the Anti-osteoporosis effects of syringic acid and vanillic acid are not due to estrogen. Possibly even anti-estrogenic ?
https://pubmed.ncbi.nlm.nih.gov/31186185/
vanillin elevated both serotonin and dopamine levels in brain tissue.
https://pubmed.ncbi.nlm.nih.gov/25595338/

---

"Moreover, treatments with 10 μM gigantol increased StAR protein levels and progesterone production from MA-10 Leydig cells. However, neither ferulic acid nor isoferulic acid influenced StAR protein synthesis and progesterone production in MA-10 Leydig cells. "
https://pubmed.ncbi.nlm.nih.gov/35723385

Gigantol seems interesting. Anti-cancer, Inhibits mTOR.
https://pubmed.ncbi.nlm.nih.gov/33737087/

---

Geranylgeraniol is another candidate. Also increases progesterone and testosterone. Probably easier to obtain .
https://pubmed.ncbi.nlm.nih.gov/26757775/

It protects from muscle atrophy in this one.
https://pmc.ncbi.nlm.nih.gov/articles/PMC7652489/

In this human study it slightly increases testosterone in males .
https://www.mdpi.com/1661-3821/3/4/43

[cs3000]

@CrumblingCookie thanks for the info , solidified another thing ive been looking for
oh right, yeah sounds reasonable , better for the tail end i guess if symptoms stick for >7 days or get too wild

its really effective at lowering neutrophils in lungs in viral infections (big part of the damage)
(found neutrophils only really needed to peak early to kickstart the process & attract other cells, unless theres a big lack of lymphocytes,
by the time symptoms are noticed theyre probably already peaking or close)
doi: 10.1055/s-2006-958060

~200mg heq, lowered neutrophil in lungs a lot , and giving it on day 0 the viral count increased only a little. but still probably better holding for a day or 2 of symptoms

should be very effective for people hit hard by symptoms in current breakout

[cs3000]

@Mauritio thanks will have a look through, quercetin definitely feels estrogenic to me even at low dose, and long half life. im trying it rn for a specific effect. the supplement doses are kind of crazy for where it has effects generally

[cs3000]

@Mauritio the 1st one, ferulic acid didnt increase uterus weight where quercetin did, (5mg/kg ferulic lowered it a little fitting with the other study showing anti-estrogenic activity at 5mg/kg, but lose some of the effects here),

had mild non significant effect on increasing estrogen vs quercetin that increased it 22.48%.
but thats at ~100mg - 150mg heq. with the estrogenic potential its probably more significant at higher doses. tho has some of its benefits at 150mg, so i think its probably an ok dose there. though more gained further

so milder estrogenic activity than quercetin , but it still binds receptors.
but the breast cancer 1 you posted is concerning yeh they didnt use crazy high concentrations
and potent effect

was dose dependant coming down from 1uM to 100nM to 10nM.

the other one you posted showing anti estrogen effect was low dose 5mg/kg, ~ 50 - 75mg human.
raised testosterone & estrogen together
lowered the elevated estrogen receptor
https://pmc.ncbi.nlm.nih.gov/articles/PMC8106114/

,
here given to male rats it restored & increased testosterone higher than controls 2.45 -> 3.8 , 50mg/kg rats
https://onlinelibrary.wiley.com/doi/abs/10.1111/and.12798

blood levels of testosterone plummet when u give male rats estrogen. so doesnt seem to be showing estrogenic effect in males for some reason,
but the other = good enough reason for some caution yeh

[Mauritio]

Rosmarinic acid.

Almost doubled testosterone in controls. And strongly protected against EMF damage . https://pmc.ncbi.nlm.nih.gov/articles/PMC3847387/#sec12

It also protected against different types of radiation .
https://pmc.ncbi.nlm.nih.gov/articles/PMC11053252/

[cs3000]

This post is deleted!

[CrumblingCookie]

@Mauritio said:

Rosmarinic acid.

There's a recurring relation of most anabolic substances being really immunoinhibitive since estrogen receptors are essential also in necessary inflammatory responses and the androgen signallings are quite contrary to that.
I.e. at some basic metabolic level it's mutually exclusive to be high androgen and to be sick.
I'd need to take a very, very specific look at rosmarinic acid because the carnosic acid as a diterpene in rosemary and sage reportedly locks as an antagonist into the VDR. And with a rather high affinity of Ki=54 nM. Thymoquinon from Nigella sativa (black cumin) is messy about that, too.

[Mauritio]

@CrumblingCookie interesting . Yeah it might have some messy hormonal effects.

[Mauritio]

@cs3000 what do you think about a catalase supplement ?

Given that selegiline, ergothioneine and other successful anti-aging substance all leverage the antioxidant pathway, it seems like something worth trying.
Plus over expression of catalase to mitochondria lead to a 20% increase in life span in mice.

The supplements are very cheap. The only issue I see is that of absorption. Would there be a systemic effect , penetrating into the cells and mitochondria?
If that wasn't the case there wouldn't be douzens of success stories of people reversing grey hair with it , since h2o2 is produced inside the cells and mitochondria .

[cs3000]

@Mauritio was looking to get one a while back maybe didnt find a decent supp, in pigs it works at 2g per kg of diet at least locally in the intestines, probably less
maybe its better mixed into food like the pig studies because of the higher ph making it more stable?
getting it up intracellularly should react with h2o2 creating more oxygen to drive mito respiration if theres an excess, but

this one using catalase injected i.v raised lung catalase, they think it was indirect effect 10.1152/jappl.1992.72.3.858
(they increased it 70x in blood lol, relatively milder increase in lungs so i guess most of it gets used up before hitting cells, unless its intestinal cells which get it direct. with indirect increases elsewhere
normal catalase didnt work in the brain https://pmc.ncbi.nlm.nih.gov/articles/PMC4577289/#F004

theres a unique way to do it with lower dose by conjugating catalase with polyethylene glycol and putting it in the nose .
but idk if it does that spontaneously mixed together, looks like a lab process,
increased catalase activity >2x in lung fluid
https://www.nature.com/articles/s41598-020-60443-2#Sec6

Interestingly though feeding chickens catalase increased catalase in liver well along with the intestine, and some in blood
https://www.frontiersin.org/journals/veterinary-science/articles/10.3389/fvets.2022.802051/full

Something in one of the pig studies fed 660mg or 280 U per kg diet, their calcium in blood went up a lot, https://www.mdpi.com/2076-2615/12/7/828
and catalase should help prevent calcification induced by h2o2

^ calcium in blood vessel cells
https://www.tandfonline.com/doi/full/10.3109/10799893.2012.672994#d1e959 through excess ROS signalling and TRPV https://pmc.ncbi.nlm.nih.gov/articles/PMC7599480/#sec4-antioxidants-09-00963

Seems its helping to prevent calcium go into cells which should be good for calcification issues / excitotoxity

https://journals.asm.org/doi/10.1128/spectrum.00654-21
nice effect on ileum villus height

, ordered some
the units are confusing though, pig / chicken studies theyre using units in the 100s for high mg or gram amounts

and this is insightful, https://www.jbc.org/article/S0021-9258(20)35618-0/fulltext even enzymatically inactive catalase can protect against oxidative stress well (hypochlorus acid which is one the most damaging molecules , reacts with it. produced by neutrophils)

[cs3000]

@Mauritio interesting one, more ROS in adipose stem cells from aging donors. ability to differentiate crashed. and adding catalase restored their ability to differentiate
https://www.sciencedirect.com/science/article/pii/S1873506122000575#s0100