Not sure if this was posted prior but if not hoped get a discussion going
I have actually learned that “In addition, finasteride can directly bind to AR just as T, thus, finasteride may act directly as a competitor to androgens and exert an inhibiting role. Finasteride effects as an inhibitor are reported as light but stable .”
I wonder if somehow fin could have been more bioavailable due to higher metabolism and block some receptors for too long. Or we had smaller ammounts of 5ar enzyme and fin started blocking AR in much higher numbers.
Also here it seems like local DHT levels (PFS vs Control) are not known. I wonder if that was measured in the past or whether this is to be done.
“Since finasteride inhibits T conversion into DHT, which is responsible for most androgen activity, it is plausible that prolonged finasteride use in predisposed individuals could simulate the effects of aging in young men” well shit, but also I took it 5 days - not prolonged usage. Though the crash itself might be bad enough to make those effects in short amount of time.
Also “The long-term effects of finasteride on both central and peripheral neural pathways of erection will require further investigations. In fact, it is known that androgens and AR have roles in regrowth of peripheral nerves and AR is also expressed in the central nervous system , –.” I think unfortunately studies revolving around CNS and brain are going to be needed.
Additionally author discusses why the AR positive cells were higher. Die to augmented regulatory loop or low local androgen levels adding a comment the 2 of the subjects were found to have low dht in CNS by Melcangi. That really makes me wonder about DHT levels at affected tissue sites(not plasma).
Also the study is pretty old and widely known here. It checked whether the genital anesthesia is caused by nerve differences and it’s not, also it confirmed the concept of AR overexpression in some tissues. The expression was 2 times higher in stromal cells, 15% higher in epithelial cells and the same in smooth muscle cells. Those AR levels were acquired through comparing microscope images. After this study if I understand correctly there was the infamous B study, but now it seems like the studies are picking up speed.
I just don’t understand how this could be prescribed after this study.
I know this was posted a while back, but it can be very important. It seems like lack of AR in nervous system obliterates małe sexual behavior. What makes me wonder is that some people have only mental symptoms without any sexual ones (like BoySuffers). Does it mean that those (mental) are independent of AR, but from disruption of neurosteroids?
Effects of the NesCre transgene and DHT treatment
To make sure that the observed alterations were specifically linked to AR gene disruption in the nervous system, we first examined whether the used transgene, by itself, could have any influence on male neuroendocrine and behavioral responses. As shown in supplemental Table 2 (available at www.jneurosci.org as supplemental material), the Nes-Cre transgene alone, in the absence of any AR invalidation, had no effects on the studied phenotypes. Second, we assessed the effects of the nonaromatizable DHT on sexual behavior of gonadectomized control and ARNesCre mice. DHT reinstated sexual behavior in 86% of mice in the control group (Fig. 7B). In contrast, none of tested ARNesCre mice showed sexual behavior during the 10 h test (Fig. 7B).
(Interesting that in no AR mice DHT had no effect and even more interesting that DHT activated sexual behavior in only 86% of castrated mice. PCS perhaps?)
Could this means that PFS can be split into post dht inhibition, post AR blocking and post neurosteroid inhibition?
It’s not been tested but it’s something I would like to see as well.
Also I was wondering whether people with 5ar deficiency have some emotional processing problems and brain fogesque stuff similar to mental symptoms category in this website. Or if people with AIS have this. I don’t think that was described in literature.
Could be that those people have different, but developed brains and we have brains that developed in one environment, but are now made to work in different?
“Several reports have been published in which patients diagnosed as suffering from a partial insensitivity androgen syndrome (PAIS) are indeed carriers of mutations in the SRD5A2 gene.”
“Serum T and DHT concentration post hCG (human chorionic gonadotropin) stimulation was measured in many cases and T:DHT ratio was calculated  and almost always a normal to high T concentration was found along with a low concentration of DHT and an increased T:DHT ratio.(In 5ar deficient folk)”
Those mimic Melcangi results, but only for csf, not plasma. Also I couldn’t find a study that looks at 5ar deficient neurosteroid levels. If they would mimic Melcangi results then we would be somewhere.
“Previous investigations showed that 5αR2 is expressed in key brain areas for emotional and socio-affective reactivity, yet the role of this enzyme in behavioral regulation remains mostly unknown.[…]
While male 5αR2 KO mice displayed no overt alterations in motoric, sensory, information-processing and anxiety-related behaviors, they exhibited deficits in neurobehavioral correlates of dominance (including aggression against intruders, mating, and tube dominance) as well as novelty-seeking and risk-taking responses. Furthermore, male 5αR2 KO mice exhibited reduced D2-like dopamine receptor binding in the shell of the nucleus accumbens - a well-recognized molecular signature of social dominance.”
Role of the androgen receptor in the central nervous system
This paper indicates that AR deficient mice have elevated levels of anxiety.
Neural Androgen Receptors Modulate Gene Expression and Social Recognition But Not Social Investigation
“The gene expression analyses of hypothalamus and amygdala indicated that Oxtr, Cd38, Esr1, Cyp19a1, Ucn3, Crh, and Gtf2i were differentially expressed between the three groups. […] In addition, the AR seems to regulate genes related to oxytocin, estrogen and William’s syndrome.”
Seems that this paper states that AR expression controls oxytocin receptor expression, but no AR means around 10% more oxtr. Not good.
I am still trying to connect oxytocin to something(no AR or 5ar preferably) as I am definitely lacking the release of it. So no pleasure in music (and life too? And obviously no love feelings and all other oxytocin things). Or oxytocin stems from ex. Gaba deregulation and no allopregnanolone?
I am so vigorously trying to connect ar or 5ar failure to PFS here, but the thing is that it seems like post aromatase inhibition can induce PFS like symptoms including male genital changes. Or Pas has some quirks that distinguish it from PFS? Anybody knows?
And another curious thing is that people got worsening of PFS ingesting aromatase inhibitors which mimics people with PFS ingesting finasteride and making themselves worse. Buuut, some people with PFS allegedly take AI without bigger? problems, but probably would not be able to take fin again(or would they🤨?)
“Dysfunction of the dopaminergic system also played a role in the subacute and chronic effects of FIN. Chronic administration of FIN decreased DA concentration and its metabolites in dopaminergic brain regions . These findings were observed only in the FIN injected group during adolescence or the testosterone surge period.”
This study is the nail in the coffin of my armchair research. I don’t know how this study exists and the poison is prescribed at the same time.
Unfortunately this study includes the menacing phrases like: some unknown downstream effects. I guess we need a lot of quality research. And shit needs to be off the markets ASAP. Also more menacing than that is this picture
Also serious investigation of PFS brain will be needed in the future as the next step(probably will be very costly). (or rat PFS brain? If rats get the same pfs. I was almost sure they do, but I guess it isn’t entirely straightforward)
The reality is we don’t know the mechanism of any of the post-drug syndromes (PFS, PAS, PSSD, etc). The population known to be affected is just too small to attract much academic research interest, which is why PFS Network is directly funding targeted inquiries.
I would caution against spending too much time reading papers about phenomena that seem to be related, as it is not uncommon for medical conditions with similar symptoms to have divergent etiologies. People here have been doing this sort of informal research for years with very little to show for it.
I guess you are right. There are many quirks and interesting facts that one could learn, but not much comes out of them while doing armchair science. Plus we don’t know whether the mechanisms for different group of symptoms are somehow different and I was (am still) very interested in coming up with some probable prediction. But I guess the answer isn’t as simple as AR something or 5ar methylation.
Oh and a lot of those studies I brought up are on ARKO or 5ARKO mice so static conditions really, taking and stopping drugs - not so static.
I can’t comment on any of the science as that’s why above my head
But to answer your possibly rhetorical question “why would they prescribe this”
Not to get political but I wouldn’t be surprise that this drug was put out there to weaken men just like every other movement to beat us down.
They don’t want strong virile men in the world
That’s why you have all these woke liberal nonsense movements that just turn men into pussies
They rest they clean up with Finasteride
They wanted to hurt us and make money in the process doing it.
Say what you want about me but I wouldn’t be surprised
I would say this is not really true. Easier way would be to pump chicken full of estrogens or sth. It is prescribed, because the sideeffects are so far out and not very well described in medical literature in their entirety that people refuse to believe that this is even possible from drug used for prostate or hair - so human nature.
There are strong financial incentives for pharmaceutical companies and doctors to continue supplying finasteride while remaining ignorant of its potential effects. No social conspiracy is required.
And who do you think provides those financial incentives?
Think about it
Consumer demand to remedy alopecia and BPH is obvious and exists despite the potential side effects. Awareness of side effects limits demand. If there were no side effects, the parties involved would profit even more than they currently do.
There is no obvious incentive for multinational corporations or individual doctors to castrate men at random. Countless wealthy, powerful, and influential people take this drug.
Fair enough…I also don’t wanna deter from the point of the thread
Fair point tho
I guess this thread is all over the place now.
I just want to leave some hope here now. As for his post from '11(damn, 12 years ago) Dubya_B recovered his emotions for few hours by triple testosterone patches. Maybe the emotions are caused by AR/5AR related dysfunctions too. So if they are caused by this novel androgen insensitivity then at least this reduces the complexity of this disease.
(But the truth is even with this post it is impossible to say whether at/5ar dysfunctions are responsible or high doses of T temporary resurrected GABA? system through other means.)
Edit. joetz was able to restore emotions for brief moments messing with neurotransmitter related amino acid combinations. Well I think this all is very inconclusive as always and it’s time to slow down with digging through this forum looking for patterns.
I just think it’s deficiencies across the board
I know when I took test my erections were bigger and redder
Had more weight
Like the vital nutrients actually got to it
But that was years ago
Honestly I’d try it again if I could
A guy called nofun did not take any drugs, but has a lifetime ejaculatory anhedonia and discovered that he has some 5ar2 mutations (from his post form 2017). I guess I am going to make a single thread compiling some interesting facts or studies not posted here updated monthly.
If it’s a brain issue
How the hell do you even fix that?
Or does the brain malfunction because of the AR and one the AR is fixed the brain is back online?