Androsterone Is A Potent Agonist / Activator Of The Farnesoid X Receptor (FXR)

haidut

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The so-called Farnesoid X Receptor (FXR) is a very interesting nuclear receptor inside the cell. It has a multitude of functions, but one of the main functions includes sensing and controlling the levels and synthesis of bile acids. As I mentioned in a few other posts, nuclear receptors activated by the bile acids are responsible for their pro-metabolic effects and are the primary benefit resulting from weight-loss surgery. FXR has been extensively studied and has been found to be one of the master regulators of metabolism and mitochondrial function. In addition, FXR experimental agonists have been shown to reverse liver fibrosis or even help liver regenerate after ischemia/necrosis, improve insulin sensitivity, lower cholesterol and triglycerides, and even reverse diabetes. So, it is not very surprising that Big Pharma is hot in pursuit of synthetic chemicals that act as agonists on the FXR receptor.

Farnesoid X receptor - Wikipedia, the free encyclopedia
Farnesoid-X Receptor (FXR) - Selfhacked
Farnesoid X receptor, the bile acid sensing nuclear receptor, in liver regeneration. - PubMed - NCBI
Farnesoid X receptor as a regulator of fuel consumption and mitochondrial function. - PubMed - NCBI


While I was researching the various pro-metabolic effects of androsterone, I came upon this study which showed that androsterone is a potent activator / agonist of FXR and it can do that in low micromolar concentrations (10 microMol). These concentrations are achievable with in vivo doses with 10mg - 15mg androsterone in humans.

"...FXR has been established to play a critical role in the regulation of bile acid synthesis in the liver, predominantly by induction of expression of SHP (6, 7). Additionally, FXR regulates the enterohepatic recirculation of bile acids both through hepatic effects such as modulation of bile acid transporter expression (38, 39) and through effects within the intestine such as regulation of ileal bile acid-binding protein expression (40). FXR expression is high in the liver and intestine, consistent with this role. However, FXR is also expressed abundantly in the kidney and adrenal gland as well as numerous other organs and in vascular smooth muscle cells (2, 41). These other sites of FXR expression are not usually considered as targets for bile acid regulation, suggesting that other potential natural ligands may exist for FXR. Here we demonstrate by NMR spectroscopy that the steroid androsterone directly binds to the FXR-LBD and induces recruitment of coactivators such as SRC-1. Furthermore, androsterone can function as an activator of FXR both in a transfection system using gal4-FXR fusion protein induction of reporter genes and in cultured cells using endogenous FXR/retinoid X receptor heterodimer activation of gene expression. Finally, androsterone treatment of castrated male mice induced expression of SHP, suggesting that androsterone may also regulate gene expression in vivo via the FXR. It will be of interest to determine whether androsterone can regulate gene expression through FXR in other organs such as the adrenal gland."
 

Regina

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The so-called Farnesoid X Receptor (FXR) is a very interesting nuclear receptor inside the cell. It has a multitude of functions, but one of the main functions includes sensing and controlling the levels and synthesis of bile acids. As I mentioned in a few other posts, nuclear receptors activated by the bile acids are responsible for their pro-metabolic effects and are the primary benefit resulting from weight-loss surgery. FXR has been extensively studied and has been found to be one of the master regulators of metabolism and mitochondrial function. In addition, FXR experimental agonists have been shown to reverse liver fibrosis or even help liver regenerate after ischemia/necrosis, improve insulin sensitivity, lower cholesterol and triglycerides, and even reverse diabetes. So, it is not very surprising that Big Pharma is hot in pursuit of synthetic chemicals that act as agonists on the FXR receptor.

Farnesoid X receptor - Wikipedia, the free encyclopedia
Farnesoid-X Receptor (FXR) - Selfhacked
Farnesoid X receptor, the bile acid sensing nuclear receptor, in liver regeneration. - PubMed - NCBI
Farnesoid X receptor as a regulator of fuel consumption and mitochondrial function. - PubMed - NCBI


While I was researching the various pro-metabolic effects of androsterone, I came upon this study which showed that androsterone is a potent activator / agonist of FXR and it can do that in low micromolar concentrations (10 microMol). These concentrations are achievable with in vivo doses with 10mg - 15mg androsterone in humans.

"...FXR has been established to play a critical role in the regulation of bile acid synthesis in the liver, predominantly by induction of expression of SHP (6, 7). Additionally, FXR regulates the enterohepatic recirculation of bile acids both through hepatic effects such as modulation of bile acid transporter expression (38, 39) and through effects within the intestine such as regulation of ileal bile acid-binding protein expression (40). FXR expression is high in the liver and intestine, consistent with this role. However, FXR is also expressed abundantly in the kidney and adrenal gland as well as numerous other organs and in vascular smooth muscle cells (2, 41). These other sites of FXR expression are not usually considered as targets for bile acid regulation, suggesting that other potential natural ligands may exist for FXR. Here we demonstrate by NMR spectroscopy that the steroid androsterone directly binds to the FXR-LBD and induces recruitment of coactivators such as SRC-1. Furthermore, androsterone can function as an activator of FXR both in a transfection system using gal4-FXR fusion protein induction of reporter genes and in cultured cells using endogenous FXR/retinoid X receptor heterodimer activation of gene expression. Finally, androsterone treatment of castrated male mice induced expression of SHP, suggesting that androsterone may also regulate gene expression in vivo via the FXR. It will be of interest to determine whether androsterone can regulate gene expression through FXR in other organs such as the adrenal gland."
Haidut, do you have thoughts regarding females taking your androsterone?
 

haidut

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Haidut, do you have thoughts regarding females taking your androsterone?

There is an old study from the 1950s showing it was effective treatment for hirsutism in women and even at high doses did not have negative side effects except the sedation. I think combined a combination of androsterone and progesterone is the most potent aromatase inhibitor on the market. Better than any of the synthetic AI on the market and with so many other benefits. As little as 2mg - 3mg of each steroid, in combination with the other, should lower estrogen dramatically. I also think androsterone may also protect from the mood swings progesterone seems to give some women and has much more potent anti-depressant activity. What's not to like? :):
 

Pointless

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This FXR stuff is really fascinating. Here's a good review of the studies.

Recent advances in the development of farnesoid X receptor agonists

"These results highlight the effect of FXR activation on liver growth and regeneration and their potential important implication in clinical practice."

"FXR activation has been shown to prevent and resolve liver fibrosis in rodents"

"Administration of 6-ethyl CDCA [Pointless: a FXR agonist] reduced plaque formation by 95%, reduced aortic expression of the inflammatory cytokines interleukin (IL)-1β, IL-6, and CD11b (31). FXR activation also reduced hepatic expression of sterol regulatory element binding protein 1c, resulting in reduced triglyceride and cholesterol content in the liver and amelioration of hyperlipidemia (31). These findings suggest that FXR ligands might be used in the prevention and treatment of atherosclerosis."

"FXR has been shown to be important in preventing gallstone formation in susceptible mice."

"Mice lacking FXR were found to spontaneously develop hepatocellular adenomas and carcinomas after 12 months"

Could be a missing link for Peatarians seeking to resolve liver issues.
 

haidut

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This FXR stuff is really fascinating. Here's a good review of the studies.

Recent advances in the development of farnesoid X receptor agonists

"These results highlight the effect of FXR activation on liver growth and regeneration and their potential important implication in clinical practice."

"FXR activation has been shown to prevent and resolve liver fibrosis in rodents"

"Administration of 6-ethyl CDCA [Pointless: a FXR agonist] reduced plaque formation by 95%, reduced aortic expression of the inflammatory cytokines interleukin (IL)-1β, IL-6, and CD11b (31). FXR activation also reduced hepatic expression of sterol regulatory element binding protein 1c, resulting in reduced triglyceride and cholesterol content in the liver and amelioration of hyperlipidemia (31). These findings suggest that FXR ligands might be used in the prevention and treatment of atherosclerosis."

"FXR has been shown to be important in preventing gallstone formation in susceptible mice."

"Mice lacking FXR were found to spontaneously develop hepatocellular adenomas and carcinomas after 12 months"

Could be a missing link for Peatarians seeking to resolve liver issues.

Thank you, this is very nice summary. FXR also seems to be a master activator of mitochondrial biogenesis and some other thermogenic steroids like progesterone and allopregnanolone also potently activate it.
 
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allblues

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According to wikipedia, cafestol, present in coffee is a FRX agonist.

Edit; Oh, and it is also a pregnane X receptor agonist.
 

nullredvector

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What does this mean for CFS? Especially related to the recently posted paper that showed decreased bile acids in CFS patients.
Does TUDCA have relevancy here?
What about the gallbladder? Can FXR agonism be therapeutic to it?
 

Pointless

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What does this mean for CFS? Especially related to the recently posted paper that showed decreased bile acids in CFS patients.
Does TUDCA have relevancy here?
What about the gallbladder? Can FXR agonism be therapeutic to it?

I tried TUDCA and didn't notice anything. The only thing that has helped me with bile acid and gallbladder problems is taurine and fat solubles. Without tons of those, I get greasy stools. I'm hoping the androsterone can help here.

It seems that all we know right now is what's in the studies. FXR agonists prevent gallstone formation and improve bile acid reabsorption.
 

nullredvector

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The only thing that has helped me with bile acid and gallbladder problems is taurine and fat solubles.
Yeah those definitely help. My gallbladder issue is chronic distention and pain (I wonder if its actually appendicitis).
Does low fat help you?
 

Pointless

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Yeah those definitely help. My gallbladder issue is chronic distention and pain (I wonder if its actually appendicitis).
Does low fat help you?

No, I've done very low fat and it's not much of a difference. I still eat pretty low fat, but it's for metabolic reasons. I have no pain or distension. I only feel it if I dig my hands under my right rib cage. I have no appendix, and I suffer from ileal inflammation from Crohns disease (ciproheptadine is great for this).. My biggest issue is greasy stools that are greenish/gray. I'll report how androsterone affects me.
 

Pointless

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I did some experiments with androsterone for greasy stools and fat malabsorption. 4 mg twice a day, but no less, was enough to eliminate the problem. The problem returned after cycling off the androsterone. I think it might be speeding up subject's hair loss, though the problem is largely hypothyroid. So I switched over to a heaping spoonful of instant decaf coffee every morning, and that works just as well, if not better than androsterone, because of the cafestol. I'm hoping it will raise my cholesterol, too.
 

raypeatclips

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I did some experiments with androsterone for greasy stools and fat malabsorption. 4 mg twice a day, but no less, was enough to eliminate the problem. The problem returned after cycling off the androsterone. I think it might be speeding up subject's hair loss, though the problem is largely hypothyroid. So I switched over to a heaping spoonful of instant decaf coffee every morning, and that works just as well, if not better than androsterone, because of the cafestol. I'm hoping it will raise my cholesterol, too.

Could you elaborate on that decaf part please? The decaf has helped with greasy stools and fat malabsorption? Is that a heaping tablespoon, or teaspoon?
 

Pointless

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Could you elaborate on that decaf part please? The decaf has helped with greasy stools and fat malabsorption? Is that a heaping tablespoon, or teaspoon?

Cafestol is an FXR agonist, and it can raise cholesterol levels. However, regular drip coffee almost completely remove cafestol from coffee. French press, boiled beans, and turkish coffee preparation have the highest concentrations of cafestol, but instant coffee has a bit, too. The decaf is because I am sensitive to caffeine. I may work up to caffeinated coffee in the future as I get my liver sorted out.

I use a regular, American spoon. I know it's bigger than a teaspoon, but I don't know exactly how large it is.
 

LeeLemonoil

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LeeLemonoil

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Cafestol is an FXR agonist, and it can raise cholesterol levels. However, regular drip coffee almost completely remove cafestol from coffee. French press, boiled beans, and turkish coffee preparation have the highest concentrations of cafestol, but instant coffee has a bit, too. The decaf is because I am sensitive to caffeine. I may work up to caffeinated coffee in the future as I get my liver sorted out.

I use a regular, American spoon. I know it's bigger than a teaspoon, but I don't know exactly how large it is.

Co2-Extracts of Coffe might be a good source of Cafestol (and for perfumery/pheromone use?)
 

LeeLemonoil

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@Pointless
Do you figure Cafestols' actions are a net good thing? Raising LDL and Cholesterol and so forth .. it goes agianst mayn of the "conventional" views on serum-lipids, but I understand that from a Peat POV this action could mean better Androgen-synthesis?

Does coffee consumption alter plasma lipoprotein(A) concentrations? A systematic review. - PubMed - NCBI
Comparison of effect of cafetière and filtered coffee on serum concentrations of liver aminotransferases and lipids: six month randomised controlled trial.
 

Antonello

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I did some experiments with androsterone for greasy stools and fat malabsorption. 4 mg twice a day, but no less, was enough to eliminate the problem. The problem returned after cycling off the androsterone. I think it might be speeding up subject's hair loss, though the problem is largely hypothyroid. So I switched over to a heaping spoonful of instant decaf coffee every morning, and that works just as well, if not better than androsterone, because of the cafestol. I'm hoping it will raise my cholesterol, too.
oral or topical?
 
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