Are microdoses of mifeprestone the ultimate receptor level anti-glucorticoid?
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The lack of binding of steroids other than glucocorticoids to the glucorcorticoid receptor (GR) is well known.
Testosterone has an affinity of 0.3% compared to dexamethosone. Roughly, that means it has an affinity 3% to 4.5% as cortisol.
Progesterone is a mild agonist of the GR.It turns out, the anti GR effects of these steroids are likely due to downregulation of the receptor.
Trenbolone at a HED of 25mg week (acetate ester), reduced GR expression by 50%. Testosteorne did so too, but to a lesser extent.
https://onlinelibrary.wiley.com/doi/10.1111/and.12622
Even the faustian options are dissapointing.
Trenbolone has roughly 30 to 45% the affinity as GR. Methylated trenbolone (Metribolone) though has an affinity of 100-150% to 260-390% relative to cortisol.
Furthermore, metribolone has a long half life due to being methylated. Therefore, it will occupy it's receptor for extended periods.
However, in the case of Metribolone, no human studies have been done. Therefore, since there is no known pharmacodynamics of metribolone, we cannot estimate a necessary dose.There is an exception to these steroids. Mifeprestone. The progesterone and glucocorticoird antagonist.
It's affinity to the GR is 0.1 to 1.25 nM. That is several times lower than cortisols which is 15–25 nM.
To occupy 50% of it's receptors, it needs a 2.5nM concentration, whereas cortisol needs a 10-15nM.A single 200mg oral dose of mifeprestone produces 1.77 mg/L a few hours after ingestion.
That is a concetraiton of 4120nM
This is 1648x the concentration needed to block 50% of cortisol receptors.
The half life of mifeprestone is between 25-30 hours too, so peak levels will probably build up to 1.7–2.1× of 4120nM
Considering this.... we can assume that after 7 days of Mifeprestone, we can estimate it's levels are 7004nM.
Therefore to build up to a concentration of 2.5nM we would in theory need only
2800th of 200mg pill/75 micrograms
Grok says I am right
This is somewhat similar to the doses taken in other contraceptive pills! So 75ug may sound small but it is what Norgestrel is dosed at.
However... 98% of mifeprestone is protein bound
Therefore, on top of the 75 micrograms, we need another 3750 micrograms.
Roughly, we need to take 4mg of mifeprestone a day to reach blood concentrations to occupy cortisol receptors by 50%HOWEVER
Mifeprestone only has a bioavailability of 40 - 69%. Therefore, we can easily improve the amount absorbed by dissolving it in DMSO.
If you use DMSO as a solvent - you only need 1.6 - 2.68mg of mifeprestone to block 50% of the GR receptors.
Wha reduces cortisol receptors by 50%? For an 80kg man, we need a HED of 3.5mg trenbolone acetate a day to reduce cortisol receptors.
You can just use more mifeprestone, but it is sold in single 200mg pills - due to the non linear dose curve of receptor occupation, you would need around 36mg of mifeprestone to reach a 90% inhbition - if you buy it from an online pharmacy, this would mean a single pill only lasts 5-6 days.
I think it is much more economical to dissolve it in DMSO and use other anti-GR agents such as microdoses of trenbolone.
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I think the blood concentrations were done in women too, so bigger men, probably need much less.. like 2mg in DMSO is more than enough.
As a side note, Haidut once considered to release this as a product but said whats the point...
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@alfredoolivas I like this but I'm concerned about the mixing of this plus trenbolone. Tren's evil effects on endogenous production and hair and more seem to be due to PR agonism, but obviously, you can balance that out with mifeprestone. The problem is, it's LIKELY very difficult to match the half lives and dosages, so for some time between doses you are either going to get more PR agonism or antagonism due to simple "area under the curve" math. So how could you feasible do this? Also, I'm super curious to see if maybe trestolone could be used instead, but I don't know much about it.
Edit: just realized mifeprestone is just RU486 which is often compared to 6 keto progesterone. Do we know the affinities for 6 keto, because it could be comparable to RU486 and thus eliminate the need for anything else?
Edit 2: Why not use progesterone instead of tren? It is also anti-estrogen/protective, and it LIKELY wouldn't cause endogenous shutdown due to balancing out the PR antagonism from RU486.
Edit 3: Although prog is a mild GR agonist it shouldn't matter much, right? As long as it takes up a spot cortisol would otherwise have it should work along with mifeprestone.
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@engineer No endogenous steroids that aren't gluco or mineralocorticoids have any meaningful affinity for the GR. So I doubt 6 keto will. Mifeprestone is a version of dienolone with an additional aromatic ring, it is the most unsaturated steroid with 5 double bonds and 1 triple bond, so i doubt any endogenous steroid will come close to it's binding affinity
@engineer said in Are microdoses of mifeprestone the ultimate receptor level anti-glucorticoid?:
Why not use progesterone instead of tren? It is also anti-estrogen/protective, and it LIKELY wouldn't cause endogenous shutdown due to balancing out the PR antagonism from RU486.
I couldn't find any studies on progesterone's anti glucocorticord effects. Maybe it inhibits signalling and acts as a 11 beta hsd inhibitor, but it's effects are very hard to quantify.
Also, to counteract the mifreprestone, you would need 100s of milligrams of progesterone. In these doses, it probably will block the uptake of mifeprestone.Tren acetate and ru486 have similar half lives. Tren enanthate has even longer half life. I struggle to believe that a few mgs of tren daily is harmful... I will look into it more.
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@alfredoolivas said in Are microdoses of mifeprestone the ultimate receptor level anti-glucorticoid?:
Tren acetate and ru486 have similar half lives. Tren enanthate has even longer half life. I struggle to believe that a few mgs of tren daily is harmful... I will look into it more.
A few mg of tren will essentially shut out cortisol from the receptors. So, are the bodybuilders taking much higher doses just for the extreme AR agonism? If so, then it seems like just a few mgs wouldn't be so bad.
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@engineer Yep. It has an affinity for the AR nearly double that of DHT. Vigorous Steve ran a mild cycle of 250mg of test and microdoses of tren and anavar and posted blood work. I'll look into it.
The thing that bugs me is why is the dose used in cushings syndrome close to a gram? It makes no sense. The only way I see that possilbe is that the PR and AR antagonism may really upregulate the GR. But in the end of the day, we have to experiment to see if microdoses are a true anti cortisol agent. I'll try in a few months. Buying the pill and extracting the active ingredient from the pill in DMSO.
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y tho
……….
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@sunsunsun cortisol le bad
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Took me some time to realize this is RU486. I don't think there was any Haidut podcast where he didn't mention RU486
So at the dosages you propose what would the effect on progesterone be ?
Do you know where it can be obtained ?
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Can you tell me please what we're trying to accomplish here? I haven't followed that thread. Does this lower inflammatory cytokine effects?
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@Ecstatic_Hamster
At first I thought Alfredo's eying the incredibly anabolic effects of tren without it turning him gay and into an overemotional, overdramatic wuss. He may secretly be thinking about that. It would be counteracting the progesteron receptor agonism of tren.
Here, however, he really focussed in on the anticortisol action: So suppression of cortisol equals suppression of catabolism, i.e. less muscle wasting.
Don't know to what scenario this will apply, though.
To old people to retain muscle and prevent sarcopenia? Or to young and healthy guys to improve gains and to retain them for longer without overconsumption of protein and AAS? To anyone of any age to simply fully independent of muscle but to chill down and override elevated stress from whatever origin?@Ecstatic_Hamster said in Are microdoses of mifeprestone the ultimate receptor level anti-glucorticoid?:
Does this lower inflammatory cytokine effects?
Since it lowers cortisol, I reckon it would enhance inflammatory cytokines' effects by lowering the endogenous break on them.
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@CrumblingCookie said in Are microdoses of mifeprestone the ultimate receptor level anti-glucorticoid?:
He may secretly be thinking about that.
I will hopefully be running parabolan next month if my blood work is okay. 75mg. 25mg is sufficient to lower cortisol receptors by 50% and the IC50 for ru486 is a few mg a day, so I thought the pair would synergise
@CrumblingCookie said in Are microdoses of mifeprestone the ultimate receptor level anti-glucorticoid?:
Don't know to what scenario this will apply, though.
To mog
@mauritio it would likely occupy all progesteorone receptors, it's birth control, you can get it through online pharmacies I think.
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@alfredoolivas antagonizing progesterone? what good is it if gainers the world but antagonizes the progesterone?
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@sunsunsun that's why you have tren, which is a progesterone receptor agonist
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@sunsunsun lets see...
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Is the goal here to increase muscle mass? Because if so, I think the effects of steroids are actually quite simple and don’t have that much to do with GR directly in this way. Actually, if you consider it in the context of muscle, saying that the effects work that way doesn't really explain much.
Anyway, it reminded me of that study where they say that a heterodimer forms between AR and GR
Oxandrolone blocks glucocorticoid signaling in an androgen receptor-dependent manner
Conversely, experiments in cell culture systems demonstrated significant antagonism of cortisol-induced transcriptional activation by oxandrolone in cells expressing both the AR and GR. Inhibition(of oxandrolone antagonism) was not overcome by increased cortisol concentration, and no inhibition by oxandrolone was observed in cells expressing GR alone, confirming that non-competitive mechanisms were involved.
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@TexugoDoMel The goal is to MOG and transform into a low cortisol FREAK
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@alfredoolivas said in Are microdoses of mifeprestone the ultimate receptor level anti-glucorticoid?:
it would likely occupy all progesteorone receptors, it's birth control, you can get it through online pharmacies I think.
Then I don't think it's really worth the hassle.
Id still be curious to hear how something like this feels and affects a person...
