Caffeine Is A Potent Anti-estrogen; Can Block Estrogen "receptor" Completely

[haidut]

After reading the study on caffeine and breast cancer I posted in a different thread, I found some facts that U thought warranted a separate thread. Here is the original thread.
viewtopic.php?f=75&t=6481

It looks like caffeine has such a potent anti-estrogenic activity that it is capable of completely blocking/destroying the estrogen "receptor" (ER). The potency of caffeine in blocking estrogen is being compared to fulvestrant, which is the most potent estrogen "receptor" antagonist currently on the market. Here are some notable excerpts:

"...The role of coffee constituents in modulating molecular mechanisms with impact on breast cancer cell growth in relation to ER status was further investigated. Exposure to caffeine significantly reduced the ER abundance in ER+ MCF-7 cells. In fact, 5 mmol/L caffeine almost completely abolished the ER levels."

"...At 1 mmol/L caffeine, the proliferation was reduced by 80% in MCF-7 cells (P < 0.01) and by 40% in MDA-MB-231 cells (P = 0.054). Similarly, caffeic acid reduced both MCF-7 and MDA-MB-231 cell growth, although to a lesser extent than caffeine (Fig. 1A)."

"...In a similar manner to these dietary constituents, caffeine mimicked the actions of the antiestrogen fulvestrant (ICI 182,780), which inhibits ER-dependent functions and decreases ER expression, resulting in suppression of tumor cell growth (36). Similarly, endoxifen, the bioactive metabolite of tamoxifen, inhibits estrogen-induced breast cancer growth by competitively binding ER, leading to inhibition of ER transcriptional activity and targeting ER to proteasomal degradation (37). In addition, a recent study described that a derivative of caffeic acid (CAPE) specifically bound and downregulated ER expression (38)."

Fulvestrant - Wikipedia

Now, a bit of good and bad news. The concentration that achieved full abolition of ER was 5mmol/L. Here is some info on required caffeine intake to achieve that concentration.
http://onlinelibrary.wiley.com/doi/10.1 ... 231.x/full

"...We used caffeine at concentrations mostly similar to those utilized in previous in vitro studies; however, to achieve a 2-mM blood level of caffeine, over 100 cups of coffee intake would be required [20]. Therefore, our data in which high doses of caffeine were applied to cells may not be clinically relevant. However, we believe that our work could be a precedent for elucidation of the molecular mechanisms involved in the antiproliferative action of caffeine on HCC cells."

So, the bad news is that achieving 5mmol/L concentration in vivo in human beings would be very tough. However, the good news is that one of the excerpts above says that in concentration of 1mmol/L caffeine inhibited breast cancer proliferation by 80%. To achieve a concentration of 1mmol/L in plasma, the dosage of caffeine required would be about 900mg - 1,000mg. That is a lot to consume in one sitting but I know people who do it on regular basis and feel fine. Of course, I would not advise anyone to start popping 1,000mg of caffeine in one sitting. The correct way to do it would be to slowly work your way up from smaller doses of say 200mg. Take 200mg daily for a week, then on the second week add another 200mg, and so on until in about a month you can handle 800mg - 1,000mg in one sitting. You would be surprised how quickly "tolerance" to caffeine develops. I think that we what we call tolerance is actually a sign of metabolic (and especially liver) health.
If someone knows of a way to increase plasma concentrations of caffeine by ingesting it together with something else please let me know. It would make for a very interesting experiment.
Thoughts?

 

[jyb]

If someone knows of a way to increase plasma concentrations of caffeine by ingesting it together with something else please let me know. It would make for a very interesting experiment.
Thoughts?

I wonder how good/bad large caffeine is in larger doses. For example, is the adrenalin response (or whatever is causing jitteriness or other caffeine excess symptoms) physiological (normal response due to energy depletion) or pathological (has no basis to exist)? Because if caffeine acts like thyroid and increases metabolism, I would expect taking an excess would deplete you of energy eventually (if you're well fed, it would take more than a coffee, but a coffee only has a few dozens or hundreds mg's of caffeine) and in that case the stress response is physiological and normal. So, are you saying you can take the larger doses and that the stress response is irrational and can be avoided?

 

[haidut]

If someone knows of a way to increase plasma concentrations of caffeine by ingesting it together with something else please let me know. It would make for a very interesting experiment.
Thoughts?

I wonder how good/bad large caffeine is in larger doses. For example, is the adrenalin response (or whatever is causing jitteriness or other caffeine excess symptoms) physiological (normal response due to energy depletion) or pathological (has no basis to exist)? Because if caffeine acts like thyroid and increases metabolism, I would expect taking an excess would deplete you of energy eventually (if you're well fed, it would take more than a coffee, but a coffee only has a few dozens or hundreds mg's of caffeine) and in that case the stress response is physiological and normal. So, are you saying you can take the larger doses and that the stress response is irrational and can be avoided?

As far as I know caffeine only causes the stress response in people with poor glycogen stores. So, taking caffeine with something like pure fructose or a larger dose of sucrose either greatly diminishes the stress response or stops it completely. It all comes down to liver function really, since liver function determines how well/efficiently carbs get turned into glycogen. Since fructose forces even a poor functioning liver to produce and store glycogen I'd expect taking even a large dose of caffeine 400mg+ combined with 20g-30g pure fructose to have minimal stress effects. For those who do not have access to pure fructose I guess two glasses of apple juice should suffice since apple juice is about 70% fructose.
Since caffeine improves liver function, with time a person should be able to ingest more caffeine and less carbs until eventually glycogen stores are so well rpelenishable by th eliver that you could take caffeine on "empty stomach" and still experience no ill effect since you'd have plenty of glycogen to run on.
But to answer your question - I don't know of anything in caffeine that in and of itself would cause a stress response. It's the insufficient "fuel" that causes it. Also, caffeine is dopaminergic and some other dopaminergic drugs have similar effects due to increased metabolism.

 

[jyb]

Since caffeine improves liver function, with time a person should be able to ingest more caffeine and less carbs until eventually glycogen stores are so well rpelenishable by th eliver that you could take caffeine on "empty stomach" and still experience no ill effect since you'd have plenty of glycogen to run on.
But to answer your question - I don't know of anything in caffeine that in and of itself would cause a stress response. It's the insufficient "fuel" that causes it. Also, caffeine is dopaminergic and some other dopaminergic drugs have similar effects due to increased metabolism.

Yeah but I meant, coffee using up energy is normal if it acts like thyroid, so if you take a very huge amount then you'd expect all your energy to be used up eventually. But you're saying that's not necessarily the case.

As for eating fructose... In my experience just eating more sat fat food improves coffee tolerance. On low fat I need to be very careful with eating sugar with it, whereas on a high sat fat diet I can drink coffee all afternoon and be relaxed with only breakfast or lunch as my last meal - it doesn't deplete glycogen stores as easily.

 

[haidut]

Since caffeine improves liver function, with time a person should be able to ingest more caffeine and less carbs until eventually glycogen stores are so well rpelenishable by th eliver that you could take caffeine on "empty stomach" and still experience no ill effect since you'd have plenty of glycogen to run on.
But to answer your question - I don't know of anything in caffeine that in and of itself would cause a stress response. It's the insufficient "fuel" that causes it. Also, caffeine is dopaminergic and some other dopaminergic drugs have similar effects due to increased metabolism.

Yeah but I meant, coffee using up energy is normal if it acts like thyroid, so if you take a very huge amount then you'd expect all your energy to be used up eventually. But you're saying that's not necessarily the case.

As for eating fructose... In my experience just eating more sat fat food improves coffee tolerance. On low fat I need to be very careful with eating sugar with it, whereas on a high sat fat diet I can drink coffee all afternoon and be relaxed with only breakfast or lunch as my last meal - it doesn't deplete glycogen stores as easily.

Actually I am saying that coffee will "deplete" you, it's just that it depletes your energy stores not your energy per se. Thyroid will do the same - try taking even 1/8 grain of thyroid first thing in the morning and you will see the same effects. Unless you are young and/or in top health condition and your glycogen stores are fine even after a full night of sleep. But anyways, you get the point - metabollism boosters need fuel to work well and not stress you out.
As far as the fat helping with caffeine side effect - it is likely due to the fact that fat slows down caffeine absorption rate, so it would take you much longer to absorb it and the plasma concentrations you achieve will be lower. Since caffeine's effects are dependent mostly on plasma concentrations, lowering those concentrations with fat may or may not be desirable. Depends on the case I guess. People who want to have small amounts of caffeine in their blood for longer periods of time would benefit from fat co-ingestion. Maybe a good case would be taking caffeine before bed to protect your body from the stress of night. Given the lower plasma concentrations when taken with fat it should not interfere with sleep.
Others who need caffeine's performance boosting effects in sports events or mental exertion like exams would probably want the higher plasma concentrations and thus take caffeine with sugary drink but no fat.

 

[Such_Saturation]

Perhaps one gram is too much to allow us to also bask into the benefits of adenosine which Ray Peat also likes. But surely caffeine also shares some of her structure, who knows?

Adenosine seems to have a variety of antioxidant functions, and one mechanism seems to be its function as an antiexcitatory transmitter. One of estrogen's excitant actions on the brain probably involves its antagonism to adenosine (Phillis and O'Regan, 1988).

Adenosine: Sleep inducing protective effect. Adenosine is structurally very similar to inosine, another natural substance (found in meat, for example) which is a component of "inosiplex," an antiviral drug (Brown and Gordon, Fed. Proc. 29, 684, 1970, and Can. J. Microbiol. 18, 1463, 1972) or immunostimulant which has also been found to have an anti-senility effect (Doty and Gordon, Fed. Proc. 29). Adenosine is a free radical scavenger, and protects against calcium and glutamate excitotoxicity. (I. Yokoi, et al., "Adenosines scavenged hydroxyl radicals and prevented posttraumatic epilepsy," Free Radical Biol. Med. 19(4), 473-479, 1995; M. P. Abbracchio, et al., "Adenosine A(1) receptors in rat brain synaptosomes: Transductional mechanisms, efects on glutamate release, and preservation after metabolic inhibition," Drug Develop. Res. 35(3), 119-129, 1995.) It also appears to protect against the relative hyperventilation that wastes carbon dioxide, and endotoxin can interfere with its protective action. Guanosine, in this same group of substances, might have some similar properties. Thymidine and cytidine, which are pyrimidine-based, are endogenous analogs of the barbiturates, and like them, they might be regulators of the cytochrome P450 enzymes. Uridine, in this group, promotes glycogen synthesis, and is released from bacteria in the presence of penicillin.

 

[Dean]

Thoughts?

So, have you changed your mind on theanine as a good combo with caffeine? Is it that fructose accomplishes the same thing, more cheaply? Also, how many "sittings" per day of caffeine intake?

 

[haidut]

Thoughts?

So, have you changed your mind on theanine as a good combo with caffeine? Is it that fructose accomplishes the same thing, more cheaply? Also, how many "sittings" per day of caffeine intake?

Where did I hint that I have changed my mind on theanine? Theanine would be useful to lessen/block the effect of caffeine on ACTH and cortisol. However, if you don't have glycogen then caffeine will trigger the stress response no matter how much theanine you ingest. So, fructose/sucrose is needed and theanine is only needed if caffeine still gives you the stress response even with decent carb consumption.

 

[YuraCZ]

A week ago I started from no coffee to 5 cups a day. How can I recognize if stress hormones are elevated? Maybe some specific puls/temp. ratios in specific time of the day or something? I'm still sensitive to loud noises and maybe a little headache.. But metabolism is sped up, that's for sure.

 

[haidut]

A week ago I started from no coffee to 5 cups a day. How can I recognize if stress hormones are elevated? Maybe some specific puls/temp. ratios in specific time of the day or something? I'm still sensitive to loud noises and maybe a little headache.. But metabolism is sped up, that's for sure.

Sensitivity to loud noises are supposed to be caused by potassium deficiency. At least that's one of the reasons Ray suggested.
Jumping from 0 to 5 cups a day in just 1 week is a bit too much IMHO. If you get cold hands/feet and start feeling agitated then it's probably too much caffeine so it's best to back down.

 

[YuraCZ]

A week ago I started from no coffee to 5 cups a day. How can I recognize if stress hormones are elevated? Maybe some specific puls/temp. ratios in specific time of the day or something? I'm still sensitive to loud noises and maybe a little headache.. But metabolism is sped up, that's for sure.

Sensitivity to loud noises are supposed to be caused by potassium deficiency. At least that's one of the reasons Ray suggested.
Jumping from 0 to 5 cups a day in just 1 week is a bit too much IMHO. If you get cold hands/feet and start feeling agitated then it's probably too much caffeine so it's best to back down.

I have this issue less often.. But I dont know if it's just caffeine or progesterone or diet. Probably everything together. But drink less maybe 3 cups a day is good idea..

 

[Dean]

Thoughts?

So, have you changed your mind on theanine as a good combo with caffeine? Is it that fructose accomplishes the same thing, more cheaply? Also, how many "sittings" per day of caffeine intake?

Where did I hint that I have changed my mind on theanine? Theanine would be useful to lessen/block the effect of caffeine on ACTH and cortisol. However, if you don't have glycogen then caffeine will trigger the stress response no matter how much theanine you ingest. So, fructose/sucrose is needed and theanine is only needed if caffeine still gives you the stress response even with decent carb consumption.

Ok, thanks for the explanation. I just didn't remember the fructose/sucrose caveat in the discussions about coupling caffeine and theanine. I apologize if my wording insinuated anything.

 

[haidut]

Thoughts?

So, have you changed your mind on theanine as a good combo with caffeine? Is it that fructose accomplishes the same thing, more cheaply? Also, how many "sittings" per day of caffeine intake?

Where did I hint that I have changed my mind on theanine? Theanine would be useful to lessen/block the effect of caffeine on ACTH and cortisol. However, if you don't have glycogen then caffeine will trigger the stress response no matter how much theanine you ingest. So, fructose/sucrose is needed and theanine is only needed if caffeine still gives you the stress response even with decent carb consumption.

Ok, thanks for the explanation. I just didn't remember the fructose/sucrose caveat in the discussions about coupling caffeine and theanine. I apologize if my wording insinuated anything.

No problem, just asking I thought that I maybe did change my mind and forgot about it. Old age you see...Time for pregnenolone.

 

[XPlus]

I tried 200mg just before bed last night.
It's a long sleepless night and I can't stop eating (and visiting the loo)
It feels like running a Concorde on coal.

 

[Philomath]

If someone knows of a way to increase plasma concentrations of caffeine by ingesting it together with something else please let me know. It would make for a very interesting experiment.
Thoughts?

I've been taking 300mg of caffeine powder in my espresso with just plain sugar and lowfat milk (1/2 cup).
So far, no stress issues that I'm aware of. I've also had the 4x strength instant coffee with no stress response.
I was very nervous the first time I ingested 400mg caffeine but the sugar helps.
I'd be happy to try different "sugar" sources, ie oj, apple juice, milk, fructose.
I'm glad you posted this Haidut. I've wanted to know just what the safe upper limit of caffeine was.

 

[XPlus]

My bad headache from yesterday is gone, surprisingly, despite the lack of sleep. 2.5g Taurine along with milk and 12gm gelatine didn't help. Still, I don't feel as tired as I was yesterday. Muscles puffed. Loose frequent stools was probably the worse side effect.

 

[oxidation_is_normal]

Can one of you help me understand:
How do you know when an estrogen receptor is blocked? Estrogen can act on many tissues (maybe all?), so do they all have receptors? Wouldn't it have to be demonstrated in what numbers the receptors exist? Maybe it has...

 

[schultz]

I'm surprised some of the people on this forum have such a low caffeine intake. A grande coffee from Starbucks has 330mg of caffeine and a venti has 415mg of caffeine. A lot of people get 2 or 3 of these a day, upwards of 1,000mg of caffeine. In Canada a lot of people drink Tim Hortons coffee and a large has 270mg of caffeine. This means that a grande coffee is the equivalent of "3 cups" of coffee. Someone may have 2 grande coffees a day and think that they only have "2 coffees" a day, but they actually have more like 6 coffees a day.

Maybe people are getting more caffeine than they realize? or maybe we drink more coffee in Canada...

 

[RPDiciple]

i get 1000-1200mg a day

 

[haidut]

Can one of you help me understand:
How do you know when an estrogen receptor is blocked? Estrogen can act on many tissues (maybe all?), so do they all have receptors? Wouldn't it have to be demonstrated in what numbers the receptors exist? Maybe it has...

Well, Ray doe snot believe in the receptor theory. He says that essentially the entire cell serves as a receptor so there is no lock and key mechanism but cellular energy that determines what is allowed inside the cell and what is not. I suppose that in the current study they used both estrogen and caffeine and determined at what concentration of caffeine estrogen was completely prevented from "binding" to the "receptor" and "activating it". In other words, at what concentrations of caffeine did estrogen stop having effects on the cell.