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

[bdawg]

Activators of the farnesoid X receptor negatively regulate androgen glucuronidation in human prostate cancer LNCAP cells. - PubMed - NCBI

This study suggests that Androsterone, when it activates the FxR, reduces glucoronidation of androgens n prostate-cancer cells.
Glucoronated androgen-conjugates seem to inactivate the androgens, and reducing the conjugation is therefore protective against cancer - not surprisingly so.

I wouldnt say its a great thing - keeping DHT active in the prostate is playing with fire. Normally DHT gets broken down into androsterone and 3alphadiol in the prostate which have weak AR affinity, which might be why elevated blood DHT levels dont necessarily lead to prostate cancer risk

"It is suggested that the conjugating activity of UGT enzymes in androgen target tissues is a mechanism for modulating the action of steroids and/or protecting the tissues from deleterious high concentrations of androgens."

Inactivation of androgens by UDP-glucuronosyltransferases in the human prostate. - PubMed - NCBI

 

[LeeLemonoil]

@bdawg

good point, I'll need to reread both publications.
To my knowledge though, the "most protective" derivate of DHT is 3beta-diol, not alpha. And those compounds can be glucoronidated as well, which might not be so beneficial. It likely comes down to a very intricate homeostatsis/feedback mehanism of unconjugatd and conjugated androgens, where FxR-activation plays a major part in.

Here is another recent publication about FxR involvement in another sex-hormone related cancer, maybe this gives some new ideas/insights.




High Farnesoid X Receptor (FXR) expression is a strong and independent prognosticator in invasive breast carcinoma. - PubMed - NCBI
↓ Full text
High Farnesoid X Receptor (FXR) expression is a strong and independent prognosticator in invasive breast carcinoma.
Farnesoid X Receptor (FXR), a nuclear receptor superfamily member, is related with bile acids, glucose and lipids metabolism and recently with cancer. In the present study the clinical significance of FXR expression in invasive breast carcinoma was evaluated. FXR protein expression was assessed immunohistochemically on paraffin-embedded breast cancer tissues obtained from 115 breast cancer patients and was statistically analyzed with clinicopathological parameters, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) expression, as well as with tumor cells' proliferative capacity and overall and disease-free patients' survival. FXR positivity was noted in 91 (79.1%) and high FXR expression in 51 (44.3%) out of 115 invasive breast carcinoma cases. High FXR expression was significantly associated with smaller tumor size (p=0.0318) and increased tumor cells' proliferative rate (p=0.0375). Invasive breast carcinoma patients presenting high FXR expression showed significantly longer overall and disease-free survival times compared to those with low FXR expression (log-rank test, p=0.0052 and p=0.0058). In multivariate analysis, FXR expression was identified as independent prognostic factor of overall and disease-free patients' survival (Cox-regression analysis, p=0.0023 and p=0.0049, respectively). The present data support evidence that FXR may be implicated at the earlier stage of breast malignant disease progression, being a strong and independent prognosticator of favorable overall and disease-free survival in invasive breast carcinoma.

 

[bdawg]

@bdawg

good point, I'll need to reread both publications.
To my knowledge though, the "most protective" derivate of DHT is 3beta-diol, not alpha. And those compounds can be glucoronidated as well, which might not be so beneficial. It likely comes down to a very intricate homeostatsis/feedback mehanism of unconjugatd and conjugated androgens, where FxR-activation plays a major part in.

Here is another recent publication about FxR involvement in another sex-hormone related cancer, maybe this gives some new ideas/insights.




High Farnesoid X Receptor (FXR) expression is a strong and independent prognosticator in invasive breast carcinoma. - PubMed - NCBI
↓ Full text
High Farnesoid X Receptor (FXR) expression is a strong and independent prognosticator in invasive breast carcinoma.
Farnesoid X Receptor (FXR), a nuclear receptor superfamily member, is related with bile acids, glucose and lipids metabolism and recently with cancer. In the present study the clinical significance of FXR expression in invasive breast carcinoma was evaluated. FXR protein expression was assessed immunohistochemically on paraffin-embedded breast cancer tissues obtained from 115 breast cancer patients and was statistically analyzed with clinicopathological parameters, estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) expression, as well as with tumor cells' proliferative capacity and overall and disease-free patients' survival. FXR positivity was noted in 91 (79.1%) and high FXR expression in 51 (44.3%) out of 115 invasive breast carcinoma cases. High FXR expression was significantly associated with smaller tumor size (p=0.0318) and increased tumor cells' proliferative rate (p=0.0375). Invasive breast carcinoma patients presenting high FXR expression showed significantly longer overall and disease-free survival times compared to those with low FXR expression (log-rank test, p=0.0052 and p=0.0058). In multivariate analysis, FXR expression was identified as independent prognostic factor of overall and disease-free patients' survival (Cox-regression analysis, p=0.0023 and p=0.0049, respectively). The present data support evidence that FXR may be implicated at the earlier stage of breast malignant disease progression, being a strong and independent prognosticator of favorable overall and disease-free survival in invasive breast carcinoma.

interesting, might be due to androgen activity somehow promoted by FXR keeping a lid on estrogenic expression in breast cancer

 

[Wagner83]

I wouldnt say its a great thing - keeping DHT active in the prostate is playing with fire. Normally DHT gets broken down into androsterone and 3alphadiol in the prostate which have weak AR affinity, which might be why elevated blood DHT levels dont necessarily lead to prostate cancer risk

Some time ago I found this:

Tissue dihydrotestosterone levels and clinical response to hormonal therapy in patients with advanced prostate cancer.
Geller J, de la Vega DJ, Albert JD, Nachtsheim DA.
Abstract
Dihydrotestosterone (DHT) levels were measured by RIA in tumor tissue from 32 men with advanced prostate cancer and correlated with their clinical responses to antiandrogen therapy. In 24 patients with tumor tissue DHT levels greater than 2.5 ng/g, 20 initially responded to therapy with partial objective regression or were objectively stable for 12 or more months, while 4 patients relapsed in less than 1 yr. The average disease-free interval in this group was 24 months, with 9 patients still continuing in partial objective regression or objective stability. Of 8 patients with DHT levels less than 2.0 ng/g, 5 had either objective progression or were objectively stable for 6 months or less; 2 other patients have completed remissions ranging from 16-24 months, while 1 patient remains objectively stable for 21 months to date. The average disease-free interval in patients with DHT levels less than 2.0 ng/g was 9.75 months, which is significantly less (P less than 0.001) than that of patients with DHT levels greater than 2.5 ng/g. There was no discernible relationship between the Gleason histological grade of prostate cancer and initial clinical response to therapy in these same patients. In summary, this study supports the thesis that tissue DHT levels may be a useful marker for predicting the clinical response of prostate cancer to antiandrogen therapy.

PMID:
6689681
DOI:
10.1210/jcem-58-1-36

 

[bdawg]

Some time ago I found this:

Tissue dihydrotestosterone levels and clinical response to hormonal therapy in patients with advanced prostate cancer.
Geller J, de la Vega DJ, Albert JD, Nachtsheim DA.
Abstract
Dihydrotestosterone (DHT) levels were measured by RIA in tumor tissue from 32 men with advanced prostate cancer and correlated with their clinical responses to antiandrogen therapy. In 24 patients with tumor tissue DHT levels greater than 2.5 ng/g, 20 initially responded to therapy with partial objective regression or were objectively stable for 12 or more months, while 4 patients relapsed in less than 1 yr. The average disease-free interval in this group was 24 months, with 9 patients still continuing in partial objective regression or objective stability. Of 8 patients with DHT levels less than 2.0 ng/g, 5 had either objective progression or were objectively stable for 6 months or less; 2 other patients have completed remissions ranging from 16-24 months, while 1 patient remains objectively stable for 21 months to date. The average disease-free interval in patients with DHT levels less than 2.0 ng/g was 9.75 months, which is significantly less (P less than 0.001) than that of patients with DHT levels greater than 2.5 ng/g. There was no discernible relationship between the Gleason histological grade of prostate cancer and initial clinical response to therapy in these same patients. In summary, this study supports the thesis that tissue DHT levels may be a useful marker for predicting the clinical response of prostate cancer to antiandrogen therapy.

PMID:
6689681
DOI:
10.1210/jcem-58-1-36

Interesting, thanks for this

 

[Wagner83]

@Obi-wan

 

[Koveras]

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."

I have a hunch that activation of the FXR is involved in melanogenesis and why some report skin darkening on androsterone.

 

[bdawg]

I have a hunch that activation of the FXR is involved in melanogenesis and why some report skin darkening on androsterone.

Doesn't the reverse also happen, androsterone being an anti-estrogen prevents estrogen induced skin darkening?

 

[Koveras]

Doesn't the reverse also happen, androsterone being an anti-estrogen prevents estrogen induced skin darkening?

In theory, but so far I've only seen reports of skin darkening in the androsterone thread

 

[Wagner83]

In theory, but so far I've only seen reports of skin darkening in the androsterone thread

Well Ray said supplementing an active steroid metabolite could have widespread unexpected effects and create disbalances, so perhaps for some of these people the effects are just that.

 

[bdawg]

Well Ray said supplementing an active steroid metabolite could have widespread unexpected effects and create disbalances, so perhaps for some of these people the effects are just that.

Yet Rays ok with DHT use?

 

[bdawg]

I have a hunch that activation of the FXR is involved in melanogenesis and why some report skin darkening on androsterone.

Guggulsterone also inhibited α-melanocyte stimulating hormone- or forskolin-induced increases in melanogenesis, suggesting an action on the cAMP-dependent melanogenic pathway. Co-incubation with chenodeoxycholic acid, a well-known farnesoid-X receptor agonist, did not affect IBMX-induced melanogenesis. These results suggest that guggulsterone exerts a melanogenic inhibitory effect through the downregulation of tyrosinase expression.

https://www.ncbi.nlm.nih.gov/pubmed/22797252

 

[Wagner83]

Yet Rays ok with DHT use?

I feel like I linked to this mail exchange a hundred times Ray Peat Email Advice Depository
I expect that he would adapt his thoughts given the context and still recommend to treat metabolism from the top (digestion, thyroid, maybe upstream hormones like pregnenolone, coffee..), so I personally don't understand his words as "people can use dht liberally" , but that's just my opinion.

 

[bdawg]

I feel like I linked to this mail exchange a hundred times Ray Peat Email Advice Depository
I expect that he would adapt his thoughts given the context and still recommend to treat metabolism from the top (digestion, thyroid, maybe upstream hormones like pregnenolone, coffee..), so I personally don't understand his words as "people can use dht liberally" , but that's just my opinion.

yeah agree, the DHT bit seems inconsistent with the other stuff he says

and overall my experience agrees with him

 

[LeeLemonoil]

Highly interesting that FXR mediates anti-cancer action by leptin-related actions. As we have discussed in the thread, FXR is a master regulator in every/fuel regulation too. It’s all very complicated and intertwined

Activated FXR Inhibits Leptin Signaling and Counteracts Tumor-promoting Activities of Cancer-Associated Fibroblasts in Breast Malignancy. - PubMed - NCBI

 

[LeeLemonoil]

Activation of Farnesoid X Receptor impairs the tumor-promoting function of breast cancer-associated fibroblasts. - PubMed - NCBI

 

[LeeLemonoil]

Then there is Farnesol, another potent activator of FXR, recently speculated to be "the" endogenous ligand. There a numerous positive health-effects described for Farnesol and derivates, including anti-cancr effects.

But there are two older studes (2006/7) that hint at somewhat cautioning effects of Farnesol and that FXR crosstalks/interplays with Estrogen Receptor mediated action - don't know if this is valid science that can still stand and if so - if it only applies to Farnesol or also to Androsterone


Farnesol induces thyroid hormone receptor (THR) beta1 but inhibits THR-mediated signaling in MCF-7 human breast cancer cells. - PubMed - NCBI
Farnesol induces thyroid hormone receptor (THR) beta1 but inhibits THR-mediated signaling in MCF-7 human breast cancer cells.
Abstract
Anti-cancer effects of farnesol are well established, although mechanisms mediating these effects are not fully understood. Since farnesol has been shown to regulate gene transcription through activation of the farnesoid X receptor and the peroxisome proliferator-activated receptors-alpha and -gamma, we hypothesized that farnesol may also mediate some of its effects through other nuclear hormone receptors. Here we showed that in MCF-7 human breast cancer cells, farnesol induced the expression of thyroid hormone receptor (THR) beta1 mRNA and protein at concentrations that inhibited cell growth. Changes in the expression of THR responsive genes, however, suggested that farnesol inhibits THR-mediated signaling. Protein extracts from cells treated with farnesol displayed decreased binding to oligodeoxynucleotides containing a consensus sequence for the THR response element, despite the higher THRbeta1 content, providing a mechanism to explain the decreased transcriptional activity of cellular THRs.


Farnesol, a mevalonate pathway intermediate, stimulates MCF-7 breast cancer cell growth through farnesoid-X-receptor-mediated estrogen receptor act... - PubMed - NCBI
Farnesol, a mevalonate pathway intermediate, stimulates MCF-7 breast cancer cell growth through farnesoid-X-receptor-mediated estrogen receptor activation.
Abstract
Farnesoid X receptor (FXR) is a metabolic nuclear receptor expressed in the liver and traditionally considered as a bile acid sensor. Yet, FXR has been recently demonstrated in other tissues and cells, such as the kidneys, the adrenals, and arterial smooth muscle cells. Immunohistochemical data reported in this study point to the expression of FXR in human breast cancer. In addition, FXR expression was also found by Western blotting and immunofluorescence microscopy in breast-cancer-derived cell lines MCF-7 (estrogen receptor [ER]-positive) and MDA-MB-231 (ER-negative). The FXR activator farnesol, a mevalonate pathway intermediate, exerts a mitogenic effect on MCF-7 cells. The growth stimulation is completely suppressed by antiestrogens. In contrast, MDA-MB-231 cells appear farnesol-insensitive, suggesting an involvement of ER in farnesol mitogenicity. In accordance with this interpretation, farnesol induces in MCF-7 cells a decrease of ER level, consistent with a phenomenon of receptor downregulation. Farnesol also increases progesterone receptor (PgR) expression in MCF-7 cells and stimulates ER-mediated gene transactivation in MVLN cells (MCF-7 cells stably transfected with an ER reporter gene). Of note, both effects of farnesol on ER expression and activity are completely suppressed by antiestrogens. In addition, farnesol-induced PgR is markedly reduced by FXR gene silencing (siRNA), demonstrating the involvement of FXR in the estrogenic effects of farnesol. Finally, coimmunoprecipitation experiments (FXR immunoprecipitation followed by Western blot analysis of ER in the immunoprecipitate) produced definite evidence that FXR interacts with ER. Altogether, these observations reveal the hitherto unreported presence of FXR in breast cancer and show that the latter receptor functionally interacts with ER. The occurrence of such a crosstalk calls for some caution regarding the pharmacological use of FXR agonists.

 

[Broken man]

@haidut Is it bad idea to take andro with progesterone?

 

[Coderr]

If we take Androsterone, would we be the man desired by women?

 

[Xref]

If we take Androsterone, would we be the man desired by women?

Stop thinking in terms of cause and effect you are NOT a robot.
It MIGHT have a positive effect.

Do your research and experiment..
We might both benefit, uh?