Estrogen, What Does It Really Do?

Suikerbuik · Jul 4, 2014

Many times I see people mentioning estrogen, but what does estrogen really do? I hope this topic to go beyond standard "oh estrogen is involved you should lower it" if possible. I want to know what it is doing at molecular level. I know this is by far not completely understood but we are in the era that this research is being done and may provide us better insights.

What is the role of estrogen alpha-/ beta receptor? What factors (proteins), so no food components, are involved in the expression of alpha-/beta receptor and aromatase? Is it the ratio between this two that matters? What genes are affected in terms of expression (so how does it change the interactome, casuing symptoms?)? What is the inhibitory capacity of for example progestrone and other natural things that should balanced estrogen?

If there's paper's describing interesting genomic and non-genomic effects of estrogen, you can mention them in this topic.

http://www.cell.com/cell/abstract/S0092-8674(11)00376-X

Suikerbuik · Jul 4, 2014

Estrogen and the estrogen receptors (and aromatase??) do partcicipate in a self regulatory system, somehow. A reduced ER-a/b expression is sometimes seen in disease as is over expression in certain diseases (tissues). So probably reduced estrogen's sensitivity could cause an increase in estrogen by probably increasing aromatase expression in certain tissues, leading to systemic increased estrogen. This may also be the cause for the increase in estrogen in some people supplementing pregnenolone.

Which could also account for the strange effects being obeserved by current medicine. Leading to prescription of E2, not knowing they influence the organism negatively.
http://www.ncbi.nlm.nih.gov/pubmed/16511588

Take the first PDF file (from researchgate) when you search google for:
Expression profile of nuclear receptors upon Epstein -- Barr virus induced B cell transformation.

Genes downregulated in EBV-infected B cells.
Eleven genes were downregulated in LCLs compared with primary B cells (Fig. 2, a, b). We have run Western blotting for the 5 of them: ER-α and -β (Estrogen receptor α (NP_000116) and -β (Q92731)) .... ER-α protein was not detected by Western blotting. ER-β protein level was very low in primary B cells and LCLs.

There's a figure (2a) that shows the downregulation of ER-a and ER-b receptor upon Epstein Barr infection.

Suikerbuik · Jul 4, 2014

Some supporting evidence:

http://www.ncbi.nlm.nih.gov/pubmed/17224934
http://www.ncbi.nlm.nih.gov/pubmed/21372033
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3773840/

But the underlying molecular mechanism, which I actually wanted to target, remains unknown. Still think that at this point in time, the subject is too immature to discuss. Also comparing mouse models with humans is far from reality in my opinion. Mouse models have lots of flaws and certainly in such complex matter where all kind of interactions are involved.

Suikerbuik · Jul 4, 2014

Think this is it for now, no more time left

.

In the present study, we have investigated the putative effects of steroids (testosterone, 5alpha-dihydrotestosterone (DHT) and estradiol) on Cyp19 gene expression in purified adult rat pachytene spermatocytes (PSs) and round spermatids (RSs). In fact estradiol inhibits the Cyp19 gene expression in PSs and RSs.

http://www.ncbi.nlm.nih.gov/pubmed/12914527

All these findings support the view I proposed. Not saying that estrogen is less important, just adds a (huge?) layer of complexity beyond food and supplemets adjustments we can implement to address our issues.

4peatssake · Jul 4, 2014

Ray Peat said:
I believe that estrogen's "principle," in all of its actions, is to interfere with the respiratory mode of energy production. This is an integrating principle that explains estrogen's immediate, direct effects on cells and organisms, which aren't explained by the idea that it acts on the genes through a specific "estrogen receptor." (It's hard to imagine, for example, how the "estrogen receptor" doctrine could explain the fact that a single injection of estrogen can kill a large portion of brain cells.) It explains why estrogen causes cells to take up water, allowing calcium to enter, activating various enzymes and cell division. On the organismic level, it explains why estrogen mimics "shock," releasing histamine and activating the nervous and glandular stress response system. The inefficiency of metabolism which doesn't use oxygen in the normal way causes glucose to be used rapidly, and this in itself is enough to trigger the release of pituitary ACTH and adrenal cortisol. The ACTH, and related hormones, liberate free fatty acids, which cells take up instead of glucose, and this (in the so-called Randall cycle) further limits the body's ability to oxidize glucose.

People have spoken of "cascades" in relation to the adrenal glucocorticoids (e.g., cortisol) and estrogen, leading to cell damage, but really both of these hormonal cascades have to be seen as part of a more general collapse of adaptive systems, as a result of both chronic and immediate inadequacies of energy production.

Estrogen activates the adrenal stress reaction by way of the hypothalamus and pituitary, by direct actions on the adrenal glands, and by a variety of indirect effects, such as the increase of free fatty acids. It activates the excitotoxic glutamic acid pathway, and interferes with protective adenosine inhibition of nerves. It has both direct and indirect ways of promoting the formation of nitric oxide and carbon monoxide. These, and other estrogen-promoted factors, quickly and seriously interfere with mitochondrial respiration. Many of these effects contribute to increased intracellular calcium and free radical production, contributing to both the excitatory excess and the energy deficit.

The biochemical details of these cascades are mainly interesting because they show how many different kinds of stress converge on a few physiological processess--mitochondrial energy production, cellular excitation, and intercellular communication--which, when damaged thousands of times, lead to the familiar states of old age. These few functions, damaged by an infinite variety of stresses, have their own complexly adaptive ways of deteriorating, producing the various degenerative diseases.

This perspective brings dementia, heart failure, autoimmunity, immunodeficiency and other diseases of aging together, in ways that allow generalized therapeutic and preventive approaches.

The antistress, antiestrogen approaches become fundamental to prevention of aging.

The pro-estrogenic nature of the unsaturated fatty acids is probably the biggest barrier to the radical elimination of degenerative diseases. Various saturated fatty acids, including butyric, octanoic, and palmitic, have protective effects on mitochondrial respiration.

Progesterone is the basic brain-protective antiestrogen. It works to protect the brain at many levels (preventing lipid peroxidation, exitotoxicity, nitric oxide damage, energy deficit, edema, etc.) and it promotes repair and recovery.

Progesterone in most cases has effects opposite to estrogen's, improving mitochondrial energy production while preventing excessive excitation. Along with pregnenolone, progesterone is recognized as a neurosteroid with anti-excitotoxic actions, with the ability to promote repair and regeneration of the nervous system. (Roof, Stein, Faden; Schumacher, et al.; Baulieu.)

The use of aspirin, which reduces inflammation and inhibits the formation of neurotoxic prostaglandins, is known to be associated with a lower incidence of Alzheimer's disease, and in other contexts, it offers protection against estrogen. Naloxone, the antiendorphin, has been found to reverse some of the cumulative effects of stress, restoring some pituitary and ovarian function, and it promotes recovery after brain injury; in a variety of ways, it corrects some of estrogen's toxic effects.

Adenosine helps to maintain brain glycogen stores, which are lost in stress and aging. Vitamin B12 protects against nitric oxide, and improves alertness.

Pyruvic acid has brain-protective effects, apparently through its decarboxylation (producing carbon dioxide) rather than through its use as an energy source, since other ketoacids are similarly protective. (The ketoacids occur in some natural foods.) The directly brain-protective effect of carbon dioxide offers many clues that should be interpreted in relation to estrogen's toxicity, since many of their effects on nerves are opposite. Estrogen blocks the production of energy while it stimulates nerve cells to use energy more rapidly, and carbon dioxide promotes the production of energy, while restraining the excitation which expends energy. The presence of carbon dioxide is an indicator of proper mitochondrial respiratory functioning.

Bold is Peat's.

Estrogen and brain aging in men and women: Depression, energy, stress

Suikerbuik · Jul 4, 2014

Thank you 4Peatssake this is a good starting point from where to search for and I am aware of this. It states some effects caused by estrogen, i.e. liberation of free fatty acids, induction of calcium influx, etc. but that is just part of the story. And although it says, it causes ACTH production and likely histamine release from mast cells, because of estrogen receptors on the surface. I'd like to know what else it may do? what else proteins it may interact with? that for example play a role in our energy metabolism.

The cell death for example is that only calcium mediated? Or is there more, like estrogen interacting with proteins that induce cytochrome c release thus caspase activation?

That's why I said genomic effects and non-genomic effects. It's not matter of one or both in my opinion. And it isn't (anymore?) that current science only looks at the genomic effects. It also looks like Peat has written this article in 1999/ 2000 or so. We are not in that era of time anymore, sciences goes terribly fast these days. Not all is good but that has always been the case. At this time it is certainly known that estrogen has many many genomic effects too. This is how (partly?) the aspirin inhibits estrogen, via de cyp19 promoter. And also when I read the references in Peat's article I stumbled upon effects mediated by estrogen by altering gene transcription.

Nor you can say that when you see short terms effects, this must be caused by some effects not relying on gene transcription, because gene transcription doesn't act quick. Read the first link I posted in this topic. See how super fast estrogen influences gene transcription - matter of minutes only (even seconds??). That is really mind blowing in my opinion.

Also a point criticism. Most of these studies Peat mentions are done on rodents. Not really unreliable for the effects being observed but it is now known that estrogen plays a role in regulating immunity too, which works different in us compared to rodents. Also some aspects of the metabolism are not the same. We can't solely rely on effects seen in rodents and we actually have to look deeper now.

Nor it tells me everything about the estrogen metabolism in detail, which I am interested in. But the more I think and read about it, the more I think this isn't something yet we have many definitve answers on. And certainly go beyond knowlegde of many on a forum.

Such_Saturation · Jul 4, 2014

It destructures your cell water.

Suikerbuik · Jul 4, 2014

Well.. Okay cool, but what gives estrogen these properties? Is it the intracellular interaction with proteins? is it gene expression? in essence lowering ATP aggravated by calcium? That is what I want to know. What and if necessary how??

And if you mean it is just plain estrogen causing direct structural changes to waterclusters. Then what gives estrogen these properties over progesterone and testosterone and other steroids? The structure isn't showing much differences to me (see link below). Is it some particular group?

http://flipper.diff.org/app/pathways/85

Such_Saturation · Jul 4, 2014

It should have to do with Lewis acids and bases, for example Ray Peat says progesterone is a powerful electron acceptor and with Ling's model the effect that a substance has on protein when it is adsorbed on them is crucial.

<<...(for example, ATP and progesterone has powerful adsorptive effects) on proteins changes the charge concentration on ionizable groups. When the charge concentration is in one configuration (more acidic), the preferred counterion is potassium, and in another (less acidic) configuration, it is sodium. >>

The preferrence of potassium over sodium only occurs when the water is structured. It is basic to life. Respiration naturally structures water.

<<Koch’s understanding of the oxidative apparatus of life, as a matter of electron balances, involved the idea that molecules with a low ionization potential, making them good electron donors, amines specifically, interfered with respiration, while quinones, with a high affinity for electrons, making them electron acceptors, activated respiration. The toxic effects of tryptophan derivatives, indoles, and other amines related to the behavior of their electrons. (Serotonin wasn’t known at the time Koch was doing his basic research.) Koch believed that similar electronic functions were responsible for the effects of viruses.>>

4peatssake · Jul 4, 2014

If you look deeply at Ray Peat's work you will notice that a lot of his sources are "older" studies - not all of them but a lot. There is good reason for this but beyond the scope of the thread.

I understand your argument against rodent studies but that's pretty standard as human trials in many cases are dangerous at best. Incidentally, he notes in his statement below that it was human estrogens that led to the basic discoveries about estrogen's toxicity.

Peat has written extensively about estrogen and his viewpoint is not changed as far as I am aware. In his article on "natural estrogens" he makes mention of thousands of publications describing what estrogen does.

Ray Peat said:
Over the last 100 years, thousands of publications about estrogen's toxicity have created a slight resistance to the consumption of the major estrogen products. One ploy to overcoming this resistance is to call certain products “natural estrogen,” as distinguished from “synthetic estrogens.” The three main estrogens in our bodies are estradiol, estrone, and estriol, though there are many other minor variants on the basic molecule. These three estrogens, singly or in combinations, are being sold as natural estrogens, with their virtues explained in various ways. Implicit in many of these explanations, is the idea that these are safer than synthetics. They are sometimes contrasted to the “horse estrogen” in Premarin, as if they are better because they are like the estrogens that people produce. But it was exactly the normal human estrogens, produced by the ovaries, that led to the basic discoveries about the toxicity of estrogen, its ability to produce cancer in any organ, to cause seizures, blood clots, birth defects, accelerated aging, etc.

Suikerbuik said:
It also looks like Peat has written this article in 1999/ 2000 or so. We are not in that era of time anymore, sciences goes terribly fast these days.

The problem with "science" these days - like medicine - is that it has been built upon a faulty foundation, which has been exposed by Ray Peat and a number of others before him. When you say "we have to look deeper now" are you thinking Ray Peat has not looked deeply into the role of estrogen and that he's missed something?

I think it's important to be clear that Ray is pretty clear in his position on what estrogen does. It may not satisfy you or everyone and I applaud everyone for doing their own diligence and talking about that. Nonetheless, it's equally important to make his views clearly known here - especially about estrogen - as it is a major component of his work.

That he says

Ray Peat said:
I believe that estrogen's "principle," in all of its actions, is to interfere with the respiratory mode of energy production.

is probably where I would begin if I were to deeply revisit this topic.

I'd also factor in this statement by Peat - especially when looking at other studies, in particular those that focus on receptor theories. Again, the foundation upon which one begins to study is key.

Ray Peat said:
Estrogen marketing has entered a new phase, based on the idea of “specific estrogen-receptor modulators,” the idea that a molecule can be designed which has estrogen's “good qualities without its bad qualities.” This specific molecule will be “good for the bones, the heart, and the brain,” without causing cancer of the breast and uterus, according to the estrogen industry. Meanwhile, soybeans are said to contain estrogens that meet that goal, and it is often said that “natural estrogens” are better than “synthetic estrogens” because they are “balanced.”

Estrogen's effects on cells are immediate and profound, independent of the “estrogen receptors.”

Underlining is mine.

Such_Saturation · Jul 4, 2014

It is immediate because it is a field effect mediated by water dipoles. And most molecules with that phenol part will interfere with respiration.

Suikerbuik · Jul 5, 2014

@Such_saturation, great this is something useful and certainly not magic :). For example the reaction by which pregnenolone is converted into progesterone, explains it all too:

Thus, the two substrates of this enzyme are 3β-hydroxy-Δ5-steroid and NAD+, whereas its 3 products are 3-oxo-Δ5-steroid, NADH, and H+.

That the receptor theory is flawed doesn’t mean receptors do not exist. I see a receptor as a protein receptive to a molecule, depeding on the environment. Thus developing a drug to some ‘receptor’ is ridiculous and also assuming that the drug will induce the same effects as the original ligand.

Which was nicely described by Such_saturation some time ago ( at least in my interpretation):

He has said that the whole cell is the receptor, and the state of the cell defines a large part of the effect that the messenger has.

Nor I think or said that all the changes in the transcriptome are induced by the estrogen receptor. It is the whole interactome leading to changes in transcription. I don't mind if these are mediated by the estrogen receptors yes or no.. If these effects are observed upon exposure to estrogen then it's clear that estrogen is involved. And changes in the cellular environment is what I am looking after, and preferable knowing why too.

When you say "we have to look deeper now" are you thinking Ray Peat has not looked deeply into the role of estrogen and that he's missed something?

Ofourse he looked as deep as possible with deservedly conclusions, but ofcourse he is missing things too.. Don’t take this as an offense. If Peat is right, and all my personal experiences only convince this (based on what is said to be caused by estrogen), this will only be clear from further studies.

But it was exactly the normal human estrogens, produced by the ovaries, that led to the basic discoveries about the toxicity of estrogen, its ability to produce cancer in any organ, to cause seizures, blood clots, birth defects, accelerated aging, etc.

Was just an observation that the studies from the article were mostly ranging from '92-'99 and were done on rodents. Though above malfunctions in humans must have a reason to occur (estrogen), but how and why, since these do not occur in everyone. What distinguishes between people? Just random and bad food? (something I'm not so sure of)

Other studies that promote the initial goal I had with this topic.
http://carcin.oxfordjournals.org/content/32/3/279.full.pdf

The next is also worth reading regarding the existence and functioning of ER-a. Certainly not definitive, but worth to take into consideration.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2877833/

Such_Saturation · Jul 5, 2014

Well once you aknowledge that pumps and channels don't exist, and that the "membrane" is at least fifty percent protein, there's a whole lot of receptors in there!

pboy · Jul 5, 2014

a basic way I look at it from what I understand is that it inclines cells to hold more water, and dilates it, opens more channels...usually in response to an injury or maybe growth hormone. Its purpose is too dilute the cell to allow more nutrition in and more waste out, either to help heal rapidly or to help grow rapidly. I don't think estrogen is 'bad', it would be well regulated, only produced as much as needed and quickly detoxified when not needed if healthy. The idea that 'something triggers estrogen' or 'something binds to estrogen receptors" is really just a way of saying, " the substance triggers an estrogen like response" , meaning basically, it triggers an injured response...so its just an indication that the substance is likely injurious, and it promotes cells or vessels to dilate and hold more water temporarily...and I suppose it has other suporessive action at the same time, like slowing down adaptation and high energy requiring, higher thought patterns...to have more energy for the injured cells or vessels. To be honest, ive researched health and stuff for many years and with estrogen, its so out there theres really no definitive conclusion to draw. Its pretty much regarded as everything from good to bad, phytoestrogens regarded anywhere from good to bad, some people say its good at certain ages and not in others, good in men or not good in men, reacts with various other hormones and body functions in certain ways, theres supposedly many different types of estrogen, and no one or no one reference says the same thing.

This is my approach...I don't know or care if estrogen is even a real thing or exists at all, it plays no factor at all into simple reality and no knowledge of it is necessary to be healthy and happy day to day. It actually makes things worse and annoying thinking such a thing exists and matters

4peatssake · Jul 5, 2014

pboy said:
This is my approach...I don't know or care if estrogen is even a real thing or exists at all, it plays no factor at all into simple reality and no knowledge of it is necessary to be healthy and happy day to day. It actually makes things worse and annoying thinking such a thing exists and matters

Tell that to a perimenopausal estrogen dominant woman who's just been prescribed estrogen by her doctor.

But how I wish it were true pboy.

Such_Saturation · Jul 5, 2014

I think the cell will bloat before it can restructure its water and bloating triggers division. So you have a very simple mechanism that tries to get out of stress by directly accelerating natural selection with a strong epigenetic adaptation with each successive bloating. A poison becomes a messenger of itself. This escalates its potency. So any evolutionary role we might have for it is nullified when xenoestrogens keep entering your body constantly. It becomes infinite adaptation to nothingness, because there is no definite problem to address. Cancer follows.

Suikerbuik · Jul 5, 2014

Disagree with you pboy. Knowlegde is power and for some like me, motivation to keep doing what I am doing. Also helpful to help others out. No one, at least not me, is going to take such a view. It’s like “the blind lead the blind”.

Instead of reading all kinds of conclusions and opinions from people, like you seemingly did. I want to see what those conclusions are based on myself and form my own conclusions and at the same time know what’s all about.

As said it’s a huge aspect of Peat. And practically, if there are results and you know why, you can move forward. Estrogen like you say is about balance, when that balance sides away and you know that. First you don’t have to worry, and second you know what you can do to adjust that. Maybe estrogen isn’t an issue and you have wasted years of being afraid of having estrogen issues and applying all kinds of things.

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Estrogen, What Does It Really Do?

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