PUFA (linoleic acid) is a true estrogen, similar to estradiol

[haidut]

This is one of those studies that, in my view, largely puts the debate about PUFA to rest. If PUFA, as the study found, is a direct xeno-estrogen at the receptor level, and can cause the same genomic effects as estradiol, then it is a moot point to argue about any "benefits" of that lipid. Why did I say xeno-estrogen? Well, since we cannot endogenously synthesize the "essential" fatty acids such as linoleic acid, this makes PUFA an obligate exogenous estrogen that can only come through the diet, and that is now known as a xeno-estrogen (similar to the ones coming from plastic, pesticides, herbicides, artificial flavors/colors, etc). That means a population-wide avoidance of PUFA intake would dramatically lower the estrogenic load in the population, considering PUFA is consumed at virtually every meal, and in high amounts. Speaking of high amounts, the concentrations at which linoleic acid activated the estrogen receptors in the study are achievable in humans with less than 1g of dietary PUFA daily, which means most people on a Western diet are essentially bathing their entire organism in xeno-estrogens multiple times daily, considering PUFA intakes are in the 10g+ range per meal. The US government already declared estrogen a "known human carcinogen", so the combination of PUFA's now known estrogenicity and estrogen's known carcinogenicity should be enough to convince most people (but probably not doctors) that PUFA is a carcinogen to be avoided at all cost.

Redirecting

"...The methanol extract of chaste-berry bound to both ERα and ERβ with an IC50 value of 46 ± 3 µg/ml and 64 ± 4 µg/ml, respectively. The assay guided isolation resulted in the identification of linoleic acid as the corresponding estrogen receptor ligand. Linoleic acid bound to ERα and ERβ with an IC50 value of 27 ± 2 µM and 30 ± 6 µM, respectively."

"...Upregulation of ERα mRNA expression in T47D:A18 breast cancer cells was found to be constitutive using RT-PCR (data not shown); however, expression of ERβ mRNA was inducible in the presence of estrogen receptor ligands. Both the chaste-berry extract (10 µg/ml) and linoleic acid (3.6 µM) enhanced the expression of ERβ mRNA in T47D:A18 breast cancer cells (Fig. 2). Ishikawa is an ER positive endomentrial adenocarcinoma cell line (Holinka et al. 1986). The mRNA of the progesterone receptor in Ishikawa cells is expressed in higher amounts in the presence of compounds that bind to the estrogen receptor and activate the estrogen response element found upstream from the DNA encoding the PR. PR mRNA from treated Ishikawa endometrial cells was upregulated by chaste berry extract at 10 µg/ml and by linoleic acid at 3.6 µM (Fig. 3). "

"...In conclusion, bioassay-guided fractionation using estrogen receptor binding as a marker led to the isolation and identification of linoleic acid as an estrogenlike compound found in V. agnus-castus berries. Both the chaste-berry methanol extract and linoleic acid showed significant up-regulation of mRNA expression of PR in Ishikawa cells and ERβ in T47D:18A cells."

"...The interaction of linoleic acid with the estrogen receptor did increase the mRNA of estrogen inducible genes in Ishikawa and T47:A18 cells. Previous studies demonstrated the ability of conjugated linoleic acid to bind to PPAR gamma and alter the expression of some genes regulated by an estrogen response element (ERE) (Stoll, 2002). "

Discovery of estrogen receptor α modulators from natural compounds in Si-Wu-Tang series decoctions using estrogen-responsive MCF-7 breast cancer cells - PubMed
"...In other compounds group, all compounds showed strong estrogenic activity (>60% in 20 lg mL1). Linoleic acid (28) with higher estrogenic activity (141.67% in 20 lg mL1) might act as a more potent estrogen agonist. Anisole (29) and aucubin (30) with estrogenic activities (100% in 20 lg mL1) could also be as potent estrogen agonists. Cinnamaldehyde (32) and benzaldehyde (38) possessed biphasic activity, which exhibited high estrogenic activity at low concentration, and the activity was reversed at high concentration. Maybe aldehyde group in the benzene ring was responsible for the biphasic activity."

 

[Peatress]

Ray Peat Right Again!

“Sugars, if they are consumed in quantities beyond the ability to metabolize them (and that easily happens in the presence of PUFA) are converted into saturated fatty acids, which have antistress, antiinflammatory effects. Many propaganda experiments are set up, feeding a grossly excessive amount of polyunsaturated fat, causing sugar to form fat, specifically so they can publish their silly diet recommendations, which supposedly explain the obesity epidemic, but the government figures I cited show that vegetable fat consumption has increased, sugar hasn’t. My articles have a lot of information on the mechanisms, such as the so-called ‘Randle cycle,’ in which fatty acids shut down the ability to oxidize sugar. Polyunsaturated fats do many things that increase blood sugar inappropriately, and my articles review several of the major mechanisms. Several years ago, medical people started talking about the harmful effects of insulin, such as stimulating fat production, so ‘insulin resistance’ which keeps a high level of insulin from producing obesity would seem to be a good thing, but the medical obesity culture really isn’t thinking very straight. One factor in the ‘insulin resistance’ created by PUFA involves estrogen—chronic accumulation of PUFA in the tissues increases the production of estrogen, and the polyunsaturated free fatty acids intensify the actions of estrogen, which acts in several ways to interfere with glucose oxidation.” Ray Peat

 

[haidut]

Ray Peat Right Again!

“Sugars, if they are consumed in quantities beyond the ability to metabolize them (and that easily happens in the presence of PUFA) are converted into saturated fatty acids, which have antistress, antiinflammatory effects. Many propaganda experiments are set up, feeding a grossly excessive amount of polyunsaturated fat, causing sugar to form fat, specifically so they can publish their silly diet recommendations, which supposedly explain the obesity epidemic, but the government figures I cited show that vegetable fat consumption has increased, sugar hasn’t. My articles have a lot of information on the mechanisms, such as the so-called ‘Randle cycle,’ in which fatty acids shut down the ability to oxidize sugar. Polyunsaturated fats do many things that increase blood sugar inappropriately, and my articles review several of the major mechanisms. Several years ago, medical people started talking about the harmful effects of insulin, such as stimulating fat production, so ‘insulin resistance’ which keeps a high level of insulin from producing obesity would seem to be a good thing, but the medical obesity culture really isn’t thinking very straight. One factor in the ‘insulin resistance’ created by PUFA involves estrogen—chronic accumulation of PUFA in the tissues increases the production of estrogen, and the polyunsaturated free fatty acids intensify the actions of estrogen, which acts in several ways to interfere with glucose oxidation.” Ray Peat

Yes, but this study goes beyond what Peat said in that quote. He said PUFA increase the production of estrogen and amplify estrogen's effects. The study I posted says PUFA is itself an estrogen and would exert estrogenic effects even if there was no estrogen in the body. PUFA is not just pro-estrogen, it is estrogen (a xeno-estrogen, to be precise).

Xenoestrogen - Wikipedia

en.wikipedia.org

 

[PopSocket]

Ray Peat Right Again!

А true legend. Great find Haidut ! Thanks for posting all those interesting studies.

 

[Peatress]

Yes, but this study goes beyond what Peat said in that quote. He said PUFA increase the production of estrogen and amplify estrogen's effects. The study I posted says PUFA is itself an estrogen and would exert estrogenic effects even if there was no estrogen in the body. PUFA is not just pro-estrogen, it is estrogen (a xeno-estrogen, toe be precise).

Xenoestrogen - Wikipedia

en.wikipedia.org

Good find Haidut. Thank you

 

[Sitaruîm]

This might be semantics, but is it proper to say that PUFAs are not synthesizable?

Desaturase enzymes increasing the degree of unsaturation of a fatty acid could be seen as the endogenous production of PUFAs using a more saturated fatty acid as a building block, AKA endogenous production

 

[haidut]

This might be semantics, but is it proper to say that PUFAs are not synthesizable?

Desaturase enzymes increasing the degree of unsaturation of a fatty acid could be seen as the endogenous production of PUFAs using a more saturated fatty acid as a building block, AKA endogenous production

I think medicine labelled some PUFA as "essential" precisely due to the fact that we cannot synthesize them endogenously. Similar to the essential amino acids. I think omega-6 is considered essential, while omega-3 is not since the former cannot be synthesized endogenously, but the latter can (from the former).

 

[Bioenergy_Space]

Maybe this will give the science community something to think about what "receptors" mean for a cell. If PUFA activates the estrogen receptor, and Stearic Acid antagonizes it, that protein is doing so much more than just growing breasts and cycling ovulation. But they will probably just come out with some omega 6 "menopause relief" cancer-in-a-pill.

 

[haidut]

But they will probably just come out with some omega 6 "menopause relief" cancer-in-a-pill.

Plenty of "studies" making that pernicious claim already. When the WHI studies destroyed estrogen's reputation, medicine turned to estrogenic surrogates and PUFA was the natural one to pick up and run with.

https://www.sciencedirect.com/science/article/abs/pii/S0378512204003627

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9100978/

Omega-3 Fatty Acids Ease Depressive Symptoms Related To Menopause

Omega-3 fatty acids ease psychological distress and depressive symptoms often suffered by menopausal and perimenopausal women, according to new research. The study presents the first evidence that omega-3 supplements are effective for treating common menopause-related mental health problems.

www.sciencedaily.com

https://www.semanticscholar.org/paper/n-3-PUFA-Improve-Emotion-and-Cognition-during-A-Decandia-Landolfo/d7d3e864669400976e90aa85f559a94bef83a7b3

Balance of essential fats may prevent bone loss after menopause

So, medicine knows PUFA is estrogenic. It just refuses to admit estrogen is bad, despite the government officially labeling estrogen a "known carcinogen" way back in 2002.

 

[Regina]

This is one of those studies that, in my view, largely puts the debate about PUFA to rest. If PUFA, as the study found, is a direct xeno-estrogen at the receptor level, and can cause the same genomic effects as estradiol, then it is a moot point to argue about any "benefits" of that lipid. Why did I say xeno-estrogen? Well, since we cannot endogenously synthesize the "essential" fatty acids such as linoleic acid, this makes PUFA an obligate exogenous estrogen that can only come through the diet, and that is now known as a xeno-estrogen (similar to the ones coming from plastic, pesticides, herbicides, artificial flavors/colors, etc). That means a population-wide avoidance of PUFA intake would dramatically lower the estrogenic load in the population, considering PUFA is consumed at virtually every meal, and in high amounts. Speaking of high amounts, the concentrations at which linoleic acid activated the estrogen receptors in the study are achievable in humans with less than 1g of dietary PUFA daily, which means most people on a Western diet are essentially bathing their entire organism in xeno-estrogens multiple times daily, considering PUFA intakes are in the 10g+ range per meal. The US government already declared estrogen a "known human carcinogen", so the combination of PUFA's now known estrogenicity and estrogen's known carcinogenicity should be enough to convince most people (but probably not doctors) that PUFA is a carcinogen to be avoided at all cost.

Redirecting

"...The methanol extract of chaste-berry bound to both ERα and ERβ with an IC50 value of 46 ± 3 µg/ml and 64 ± 4 µg/ml, respectively. The assay guided isolation resulted in the identification of linoleic acid as the corresponding estrogen receptor ligand. Linoleic acid bound to ERα and ERβ with an IC50 value of 27 ± 2 µM and 30 ± 6 µM, respectively."

"...Upregulation of ERα mRNA expression in T47D:A18 breast cancer cells was found to be constitutive using RT-PCR (data not shown); however, expression of ERβ mRNA was inducible in the presence of estrogen receptor ligands. Both the chaste-berry extract (10 µg/ml) and linoleic acid (3.6 µM) enhanced the expression of ERβ mRNA in T47D:A18 breast cancer cells (Fig. 2). Ishikawa is an ER positive endomentrial adenocarcinoma cell line (Holinka et al. 1986). The mRNA of the progesterone receptor in Ishikawa cells is expressed in higher amounts in the presence of compounds that bind to the estrogen receptor and activate the estrogen response element found upstream from the DNA encoding the PR. PR mRNA from treated Ishikawa endometrial cells was upregulated by chaste berry extract at 10 µg/ml and by linoleic acid at 3.6 µM (Fig. 3). "

"...In conclusion, bioassay-guided fractionation using estrogen receptor binding as a marker led to the isolation and identification of linoleic acid as an estrogenlike compound found in V. agnus-castus berries. Both the chaste-berry methanol extract and linoleic acid showed significant up-regulation of mRNA expression of PR in Ishikawa cells and ERβ in T47D:18A cells."

"...The interaction of linoleic acid with the estrogen receptor did increase the mRNA of estrogen inducible genes in Ishikawa and T47:A18 cells. Previous studies demonstrated the ability of conjugated linoleic acid to bind to PPAR gamma and alter the expression of some genes regulated by an estrogen response element (ERE) (Stoll, 2002). "

:haidutrightagain

 

[David PS]

Thanks, this ups the ante for people who eat 'cheat meals' every week.

Linoleic acid is difficult to avoid and it is found in much higher amounts in industrial processed foods (including 'conventionally' raised animals). If the dose makes the poison, then the antidotes must be increased to keep the omega-6 levels in check.

 

[FitnessMike]

sorry if that was already answered somewhere in the depth of this forum, but is there any logical explanation as to why there is a small amount of PUFA in butter/coconut oil and other animal sources? could there be a small amount that our body actually wants?

great study mr Haidut.

 

[aliml]

Some fatty acids have been reported to bind noncompetitively or with mixed-competition to a variety of receptors most likely based on hypodrophobic interactions (Ingkaninan et al. 1999; Kang and Leaf, 1994; Kato, 1989; Vallette et al. 1991). Arachidonic acid, palmitic acid, stearic acid, oleic acid, and docosahexaenoic acid have been reported to bind to the estrogen, progesterone, androgen, and glucocorticoid receptors at weak binding sites different from the endogenous steroid binding site (Kato, 1989). Linoleic acid demonstrated the ability to interact with the opioid receptor and the nucleoside transport protein (Ingkaninan et al. 1999). Here we report the identification of linoleic acid as an estrogen receptor ligand capable of displacing estradiol from the ER and binding to the ligand binding domain of the protein using competitive binding assays and pulsed ultrafiltration. Several other fatty acids were evaluated for binding to the estrogen receptor. Amoung the 20 fatty acids tested, 13 bound to ERα and six bound to ERβ (Table 1). In general, fatty acids shorter than 16 carbons did not bind to the receptor; however, saturated acids had no obvious selectivity for the receptor compared with unsaturated acids.

 

[maillol]

As @aliml has posted above, does this study not also show that linoleic acid binds competitively to the estrogen receptors and therefore displaces biological estradiol which would be a much more potent ligand? This would result in less total estrogenic activity.

 

[GTW]

As @aliml has posted above, does this study not also show that linoleic acid binds competitively to the estrogen receptors and therefore displaces biological estradiol which would be a much more potent ligand? This would result in less total estrogenic activity.

Exactly. Substances with estrogen receptor binding do not produce the same downstream effects.
Similarly, PUFA are not categorically equivalent.
EPA, DHA, and arachidonic acid are, at a minimum, required in cell membranes for their functionality. Elongase and desaturate enzymes can convert linoleic and linolenic fatty acids to EPA and AA, for example, but can't convert omega 3 to omega 6 or vice versa. Linoleic acid was the first identified essential fatty acid. Deficiency was found to cause pathology.

 

[Elie]

This is one of those studies that, in my view, largely puts the debate about PUFA to rest. If PUFA, as the study found, is a direct xeno-estrogen at the receptor level, and can cause the same genomic effects as estradiol, then it is a moot point to argue about any "benefits" of that lipid. Why did I say xeno-estrogen? Well, since we cannot endogenously synthesize the "essential" fatty acids such as linoleic acid, this makes PUFA an obligate exogenous estrogen that can only come through the diet, and that is now known as a xeno-estrogen (similar to the ones coming from plastic, pesticides, herbicides, artificial flavors/colors, etc). That means a population-wide avoidance of PUFA intake would dramatically lower the estrogenic load in the population, considering PUFA is consumed at virtually every meal, and in high amounts. Speaking of high amounts, the concentrations at which linoleic acid activated the estrogen receptors in the study are achievable in humans with less than 1g of dietary PUFA daily, which means most people on a Western diet are essentially bathing their entire organism in xeno-estrogens multiple times daily, considering PUFA intakes are in the 10g+ range per meal. The US government already declared estrogen a "known human carcinogen", so the combination of PUFA's now known estrogenicity and estrogen's known carcinogenicity should be enough to convince most people (but probably not doctors) that PUFA is a carcinogen to be avoided at all cost.

Redirecting

"...The methanol extract of chaste-berry bound to both ERα and ERβ with an IC50 value of 46 ± 3 µg/ml and 64 ± 4 µg/ml, respectively. The assay guided isolation resulted in the identification of linoleic acid as the corresponding estrogen receptor ligand. Linoleic acid bound to ERα and ERβ with an IC50 value of 27 ± 2 µM and 30 ± 6 µM, respectively."

"...Upregulation of ERα mRNA expression in T47D:A18 breast cancer cells was found to be constitutive using RT-PCR (data not shown); however, expression of ERβ mRNA was inducible in the presence of estrogen receptor ligands. Both the chaste-berry extract (10 µg/ml) and linoleic acid (3.6 µM) enhanced the expression of ERβ mRNA in T47D:A18 breast cancer cells (Fig. 2). Ishikawa is an ER positive endomentrial adenocarcinoma cell line (Holinka et al. 1986). The mRNA of the progesterone receptor in Ishikawa cells is expressed in higher amounts in the presence of compounds that bind to the estrogen receptor and activate the estrogen response element found upstream from the DNA encoding the PR. PR mRNA from treated Ishikawa endometrial cells was upregulated by chaste berry extract at 10 µg/ml and by linoleic acid at 3.6 µM (Fig. 3). "

"...In conclusion, bioassay-guided fractionation using estrogen receptor binding as a marker led to the isolation and identification of linoleic acid as an estrogenlike compound found in V. agnus-castus berries. Both the chaste-berry methanol extract and linoleic acid showed significant up-regulation of mRNA expression of PR in Ishikawa cells and ERβ in T47D:18A cells."

"...The interaction of linoleic acid with the estrogen receptor did increase the mRNA of estrogen inducible genes in Ishikawa and T47:A18 cells. Previous studies demonstrated the ability of conjugated linoleic acid to bind to PPAR gamma and alter the expression of some genes regulated by an estrogen response element (ERE) (Stoll, 2002).

Below is a table from the study.

I haven't read the study in great detail yet, but based on the "binding" or "inhibition" measurements of various fatty acids presented here, I am not sure if we can single out PUFA and its properties in any particular way.

it also states "Boththe chaste-berry methanol extract and linoleic acid showed significant up-regulation of mRNA expression of PR in Ishikawa cells and ERβ in T47D:18A cells.However, they did not stimulate the AP activity inIshikawa cells."

So they two, chaste berry and PUFA, exert a similar effect in this experiment, and yet in reality, one (PUFA) acts as an estrogenic agent, whereas Chaste berry, confers progestorenic effects.

 

[GTW]

Oleic is monounsatrated, therefore not polyunsaturated.
Palmitoleic is produced in the liver to reduce blood glucose, like a hyperglycemia safety valve.

 

[haidut]

Thanks, something to keep in mind indeed - many fatty acids bind to the estrogen receptor. However, not all of them activate it. This study found that linoleic acid actually activates downstream effects of receptor binding similar to the effects of estrogen. As far as the other fatty acids, we do have evidence that at least stearic acid also binds the estrogen receptor but acts as an antagonist. So, SFA may turn out to be literal antagonist of PUFA at the genomic level.

Stearic acid (SA) is an estrogen receptor antagonist

Over the last year or so I stumbled upon a few studies claiming both SA (C18:0) and its methyl ester are capable of binding the estrogen receptors (ER) and modulate their transcription effects. However, those studies did not evaluate if SA acted as an agonist or antagonist on those receptors...

raypeatforum.com

 

[haidut]

Below is a table from the study.

I haven't read the study in great detail yet, but based on the "binding" or "inhibition" measurements of various fatty acids presented here, I am not sure if we can single out PUFA and its properties in any particular way.

it also states "Boththe chaste-berry methanol extract and linoleic acid showed significant up-regulation of mRNA expression of PR in Ishikawa cells and ERβ in T47D:18A cells.However, they did not stimulate the AP activity inIshikawa cells."

So they two, chaste berry and PUFA, exert a similar effect in this experiment, and yet in reality, one (PUFA) acts as an estrogenic agent, whereas Chaste berry, confers progestorenic effects.

View attachment 56865

The table only shows receptor affinity for those fatty acids. It did not test estrogenicity (activation of said receptors), as it did for linoleic acid. It would be great if they did, but so far we only have limited information about the other fatty acids, and at least stearic acid is an actual antagonist.

PUFA (linoleic acid) is a true estrogen, similar to estradiol

This is one of those studies that, in my view, largely puts the debate about PUFA to rest. If PUFA, as the study found, is a direct xeno-estrogen at the receptor level, and can cause the same genomic effects as estradiol, then it is a moot point to argue about any "benefits" of that lipid. Why...

raypeatforum.com

 

[Ras]

@haidut
You made it to /pol/

/pol/ - Politically Incorrect » Thread #445027060

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