AnhedonicApe wrote:I didn’t read all of this because I don’t have much time but I am confused by the suggestion “Finasteride can partially block this effect” when the study they cite for this point plainly says this:
In males given T plus FIN, a condition in which 5areductase activity was blocked, increases in AR at the 7-h time point were comparable to those seen with T and DHT alone. This indicates that T up-regulates AR as effectively as DHT, at least within this time frame.
That is notedly not blocking the effect.
The study also noted:
Treatment with T or DHT significantly augmented AR 3 and 7 h after hormone administration, but only DHT sustained this increase for 21 h. This difference also was observed when males were given T plus finasteride (FIN, a 5alpha reductase inhibitor). The findings demonstrate that the two endogenous ligands have differential time course effects on neural AR
AnhedonicApe wrote:While I appreciate he appended “except cortical neurons”, nothing else in those studies is at all relevant to his sentence, so why are those studies linked at all? I find acontextual study linking is a big source of confusion to others and invariably a waste of time. I’ve just wasted five minutes looking through completely irrelevant studies. This does not give a good impression.
Sorry for the confusion. Since I mentioned the cortical region in the opening statement, I wrote it again to remind the reader that these two studies that I linked regarding neuronal AR exclude this region.
I’m also short on time, so I don’t provide reference links to everything I post on the forum since it’s too time-consuming. However, if a member wants to confirm something I said, they can for example literally search for “androgen receptor cortex finasteride pubmed” and it’s the first result of the search. It takes less than 1 minute.
AnhedonicApe wrote:’‘When you take Finasteride, you are significantly reducing DHT, so I would expect that AR expression would also be reduced.’’
Regardless of what anyone expects, finasteride induces a persistent upregulation of the AR in the cerebral cortex of sub-chronically treated rats. This was an important finding of Giatti et al and involved Roberto Melcangi. The expression of AR was highest at the final period of washout.
This is simply the normal physiological response. It’s important to note that PFS is an aberrant response.
What I’m pointing out that although AR upregulation is found in some tissue types, AR downregulation is also found in others. My point is: since the burden of evidence falls upon the research reviewer, it’s important to look into all angles relative to the topic at hand.
In this particular case, the cerebral cortex isn’t the only tissue type or region in the body. As I mentioned before, in the penis smooth muscles, T and DHT actually upregulate AR expression. In the normal prostate, Finasteride also downregulates AR expression. These are also important symptomatic tissue in PFS, aren’t they?
To clear the misunderstanding regarding AR expression, they should also research nuclear receptors auto-regulation and cross-regulation. For example, estrogen receptor activation can regulate the expression of both androgen receptors and progesterone receptors. This is also tissue-specific, causing downregulation in some tissues and upregulation in others. It’s important to find symptomatic relief options for PSF - or even a cure.
PSF deserves more in-depth look into the different angles. It’s a complex condition.
AnhedonicApe wrote:Di Loreto et al. reported 2x AR expression vs controls across measured cell lines in PFS patients with penile atrophy and pain averagely 5 years after cessation. La Marra, co-author of the study, expanded on this in his thesis noting the following:
''The percentages of AR positive cells are always higher in the cases than in the controls. Statistical analysis showed positive correlations between:
The increase of AR levels in the epithelial and stromal cells and the decrease in ability/frequency to perform sexually per the AMS
The increase of AR in the vessels cells and the intensification of ASEX sexual dysfunction and physical exhaustion
The increase of AR in the epithelial cells and the worsening of muscular weakness and feeling “burnt out” (per AMS)
Of course, CRPC is the most well studied cellular adaptation to androgen deprivation, and histone modifications occur following an initial downregulation that significantly and persistently increase AR expression as a result. It is highly unlikely this adaptive mechanism is cancer specific and upregulation in response to low androgens can be demonstrated elsewhere in nature.’’
If that’s indeed the root cause of PFS, then wouldn’t chronic supraphysiological TRT downregulate the receptors and be essentially a cure after chronic use, if androgens generally downregulate AR expression?
AnhedonicApe wrote:The regulation of the AR is complex, tissue-specific, and responses strictly depend on epigenetic status.
I would suggest as always that anyone with ideas they think are credible take them to a scientist in an appropriate field for feedback.
Although PFS research review is not my main focus, what I wanted to highlight is the misunderstanding of AR over-expression being generalized. Even in tissue types that are also relevant to PFS symptoms, the opposite effect on AR expression can be seen. One should also take into consideration the cross-regulation of nuclear receptors.