Post Finasteride Sydnrome, And The 5ar1 And 2 Isoenzymes

[bloom]

Anyone whom has thoroughly looked into Post Finasteride Syndrome has come to the conclusion that 5ar is not functional in this condition. This is supported by empirical observations, and studies (while limited) on PFS.

The Latest study done on hormones in the CSF and plasma of PFS victims strongly suggest that 5ar is not functional. It found increased levels of Testosterone, with decreased levels of DHT, and DHP in the CSF. Along with an increase in Testosterone, a decrease in DHP, and Allopregnanolone, in the Plasma compared with controls.

Neuroactive steroid levels and psychiatric and andrological features in post-finasteride patients. - PubMed - NCBI

levels of some neuroactive steroids analysed in CSF of PFS patients were significantly different versus those in healthy controls. In particular, the levels of PREG, as well as of its further metabolites, PROG and DHP, were significantly decreased in CSF of PFS patients. On the contrary, the levels of DHEA and T were significantly increased. The levels of metabolites of T, such as DHT, 3a-diol, and 17b-estradiol (17b-E) were also affected in CSF of PFS patients. In particular, we reported a decrease in the levels of DHT and 17b-E, associated with an increase in the 3a-diol levels.

In addition, the levels of PROG and T metabolites, such as DHT, 3a-diol, and 17b-E, were unaffected in plasma of PFS patients. Furthermore, the levels of THP that were unaffected in CSF, showed a significant decreased in plasma. In agreement to what observed in CSF, the plasma levels of DHEA and T showed a significant increase and those of DHP a significant decrease.

Many with PFS have reported (included myself) that they get better when they get sick. This study found that Cyclosporin A and immunosuppressant drug, increases peripheral 5ar activity. An interesting observation made by the authors was that there was not a significant change in plasma Androgen levels, I think this is a significant point and will come back to this.

Greater conversion of testosterone to 5 alpha-dihydrotestosterone, reflecting increased peripheral 5 alpha-reductase activity in nude mice treated ... - PubMed - NCBI

Following cyclosporine A (CsA) immunosuppressive therapy in kidney grafts, increased body hair growth (hypertrichosis and/or hirsutism) without significant variation in normal circulating plasma androgen levels (as observed in idiopathic hirsutism) has been reported by several authors. Other authors have described increased hair growth in nude mice treated with CsA.

After 1 h of incubation, 5 alpha-DHT and other 5 alpha-reduced products formed were separated and quantified using a reverse-phase chromatography column fitted to a flow-through radioactivity detector. Mean +/- SD 5 alpha-DHT formation (expressed as pmol per 100 mg of protein per h) was found to be increased in the treated groups (group 1: 3.17 +/- 0.37, group 2: 3.10 +/- 0.13, group 3: 4.26 +/- 0.20), respectively 7.5% (NS), 5.10% (NS) and 44.4% (P = 0.01) higher than in the control group (2.95 +/- 0.13). In addition to 5 alpha-DHT, enhanced formation of delta 4-androstenedione (delta 4), 5 alpha-androstan-3 beta,17 beta-diol (3 beta-diol) and 5 alpha-androstan-3 alpha,17 beta-diol (3 alpha-diol) were also observed in the treated groups. These results show a significantly increased formation of 5 alpha-DHT (and Adiol) in nude mice treated with high dose-levels of CsA.

Guysswith PFS (including myself) report improvement of symptoms when taking a GABA A receptor agonist.
This study found that Valium (a GABA A receptor agonist), greatly increased the activity of 5ar in the Diencephalon of rats. Most metabolites of 5ar are potent GABA A receptor agonists:

Sex hormones metabolism in the brain: influence of central acting drugs on 5 alpha-reduction in rat diencephalon. - PubMed - NCBI

"...Diencephalon 5 alpha-reductase activity showed a highly significant increase (p less than 0.01) after a single administration of carbamazepine, reserpine, diazepam, phenytoin, phenobarbital or disulfiram. A significant increase (p less than 0.05) was also found after a single administration of methylphenidate, caffeine or methamphetamine."

There are many known substances which can increase the activity of 5ar greatly. If it's the case that 5ar has been impaired or downregulated (as I believe it is in PFS), then why do a huge majority of guys report to get worse (including myself) when we increase Testosterone, DHT, and 5ar? The reason for this I believe is that while the 5ar2 isoenzyme appears to be under the positive gene expression of T/DHT. The gene expression of the 5ar1 isoenzyme appears to be under the NEGATIVE control of T/DHT, as this paper demonstrates.

file:///C:/Users/public.AUD54606QN-L76/Downloads/Differential_regulation_of_steroid_5alpha-reductas%20(1).pdf

The results of our experiment clearly demonstrate that both isozymes of 5-R are expressed in prefrontal cortex of adult male rats. It was previously reported that 5-R type 2 is selectively expressed in the hypothalamus

The pattern of expression of 5-R type 2 presented in this study appears to be correlated with T levels, indicating that this isozyme may be positively modulated by androgen, as described previously during late fetal/ early post-natal life (1). Our results demonstrate for the first time that 5-R type 2 expression in the brain is regulated by DHT, a product of the encoded enzyme, via a form of feed-forward regulation. This regulatory mechanism is common among developmentally important genes (19, 23). Thus, T and DHT bind to a transcription factor, the androgen receptor, which in turn activates genes that carry out morphogenetic programs implicated in sexual differentiation processes in specific brain regions (1).

Our study demonstrated that 5-R type 1 expression is not controlled by androgen in the intact animal. However, it is negatively controlled by some testicular factors (in part by T and DHT) because there is a marked increase in 5-R type 1 expression in castrated animals, in which circulating T and DHT are low. Furthermore, T and DHT decrease the mRNA levels of 5-R type 1 in castrated animals. These findings are novel and surprising

Our data demonstrated an increase in 5-R type 1 expression in the castrated male rat that is hormonally similar to a female model. This observation is consistent with a previous report that 5-R activity in liver, which expresses only 5-R type 1, is more active in female than in male rats (34).

To our best knowledge, our study provides the first evidence that the expression of both 5-R isozymes in the brain, at least in the cerebral cortex, is regulated in opposite ways by androgens. This finding suggests that both isozymes may play a role in the sexual dimorphism of the CNS, besides other functions.

It may very well be the case that in PFS 5ar1 has been downregulated, so any attempt to increase T/DHT may decrease the expression of an isoenzyme already downregulated. This can also explain why a significant number of guys get better when they have a suppressed immune system. The authors of the study which found that Cyclosporine A increased peripheral activity of 5ar in rats noted that Plasma levels of Androgens were not significantly changed. So it may be the case that there is no significant increase of these Androgens in the plasma to negatively regulate the 5ar1 isoenzyme in the CNS.

The theory that 5ar1 has been down regulated in PFS can also account for the strange reports of guys (including myself) claiming improvement when they go back on a 5ar inhibitor, and why guys (including myself) get worse when we increase T/DHT.

Interestingly while Androgens seems to positively regulate the expression of 5ar2, Pituitary hormones seem to positively regulate the gene expression of 5ar1.

Differential regulation of rat testicular 5alpha-reductase type 1 and 2 isoforms by testosterone and FSH. - PubMed - NCBI

5alphaR-1 mRNA and enzyme activity increased when testosterone was suppressed, yet restoration of testosterone decreased 5alphaR-1 mRNA and enzyme activity, suggesting that testosterone negatively regulates 5alphaR-1. suppression of FSH decreased 5alphaR-1 mRNA yet FSH administration increased 5alphaR-1 mRNA, but no changes in 5alphaR-1 activity were observed within the 6 day period.

It is concluded that the 5alphaR isoforms in rat testis are differentially regulated by testosterone and FSH: testosterone negatively regulated 5alphaR-1 mRNA and enzyme activity but had no affect on 5alphaR-2, whereas FSH positively regulated 5alphaR-1 mRNA and appeared to regulate 5alphaR-2.

Heterogeneity of rat type I 5 alpha-reductase cDNA: cloning, expression and regulation by pituitary implants and dihydrotestosterone. - PubMed - NCBI

To determine the effect of pituitary hormones and dihydrotestosterone (DHT), the mRNA levels in the livers of rats treated with pituitary implants, hypophysectomized, castrated, and castrated coupled with DHT treatment were quantified by dot-blot hybridization assay using rat type I 5 alpha-reductase cDNA as probes. The results demonstrated that rat type I 5 alpha-reductase mRNA is stimulated by pituitary hormones and castration but is decreased by DHT and hypophysectomy.

This study found that Oxytocin a Pituitary Hormone Positively regulated the gene expression of 5ar1 but not 5ar2:

Oxytocin increases 5alpha-reductase activity of human prostate epithelial cells, but not stromal cells. - PubMed - NCBI

Oxytocin significantly increased the total 5-alpha-reductase activity of PrEC but not of PrSC. 5-alpha-Reductase I gene expression and enzyme activity were also increased (P<0.05) in PrEC by oxytocin. Oxytocin significantly increased type II activity, but not expression, in PrEC. Oxytocin did not significantly affect 5-alpha-reductase activity or expression in PrSC.

The question that arises now is, how has 5ar1 been down regulated in PFS? Especially considering that Finasteride does not significantly inhibit the 5ar1 isoenzyme.

Inhibition of 5ar has been shown to dramatically reduce neurosteroids (especially Allopregnanolone).
This study found that Neurosteroids increased the release of Oxytocin in certain neurons, and that Allopregnanolone specifically increased the release of Vasopressin (another pituitary hormone).

Neurosteroid regulation of oxytocin and vasopressin release from the rat supraoptic nucleus. - PubMed - NCBI

In the adult, oxytocin effects are modulated by allopregnanolone via an interaction with inhibitory GABAA receptors. This study examined the effects of allopregnanolone, progesterone and 17beta-oestradiol on oxytocin and vasopressin release from intact isolated supraoptic nuclei and from the neurophypophyses in rats of differing ages. In supraoptic nuclei from rats of 3-4 weeks old or less, all three neurosteroids induced oxytocin release from the isolated supraoptic nucleus, but only allopregnanolone induced significant release of vasopressin. Surprisingly, in these very young rats, allopregnanolone-induced oxytocin release was inhibited by GABAA receptor antagonists as well as by an oxytocin receptor antagonist

It could be the case in PFS that reduction of neurosteroids (specifically Allopregnanolone) leads to a reduction of Oxytocin and Vasopressin, which leads to a reduction in 5ar1 expression. This reduction in 5ar1 expression consequently leads to a reduction of neurosteroid production, creating a vicious cycle. This could account for why we get better when we take things which are known to increase neurosteroids (i.e. Progesterone), and why we get better when we a lot of us take high doses of vitamin C, something known to significantly increase Oxytocin.

High-dose ascorbic acid increases intercourse frequency and improves mood: a randomized controlled clinical trial. - PubMed - NCBI

Ascorbic acid (AA) modulates catecholaminergic activity, decreases stress reactivity, approach anxiety and prolactin release, improves vascular function, and increases oxytocin release. These processes are relevant to sexual behavior and mood

The AA group reported greater FSI (but, as hypothesized, not other sexual behavior) frequency, an effect most prominent in subjects not cohabiting with their sexual partner, and in women. The AA but not placebo group also experienced a decrease in Beck Depression scores.

Oxytocin - Wikipedia

The activity of the PAM enzyme system is dependent upon vitamin C (ascorbate), which is a necessary vitamin cofactor. By chance, sodium ascorbate by itself was found to stimulate the production of oxytocin from ovarian tissue over a range of concentrations in a dose-dependent manner.[21] Many of the same tissues (e.g. ovaries, testes, eyes, adrenals, placenta, thymus, pancreas) where PAM (and oxytocin by default) is found are also known to store higher concentrations of vitamin C.[22]

Considering that the latest study found that T/DHT levels were relatively normal in the PFS group. That guys generally get worse when increasing these Androgens. And that 5ar2 is under the positive gene expression of T/DHT. A more appropriate approach to PFS may be to increase 5ar1 activity, which may include focusing on Neurosteroids, and Pituitary Hormones since these seem to increase the gene expression of 5ar1. 5ar1 is an important part of the PFS puzzle I believe.

 

[axolotl]

Great write up, as usual, of the current progress on this.

Just mocked up this in the inimitable MS paint to make sure I'm understanding...

I wonder if a potential treatment would be immunomodulators in combination with oxytocin and vasopressin supplementation. Something I'm curious about is why, when an illness strikes and 5ar1 is upregulated, the presumably restarted "loop" of neurosteroid creation and pituitary secretion does not self maintain and continue regulating 5ar1?

 

[bloom]

Great write up, as usual, of the current progress on this.

Just mocked up this in the inimitable MS paint to make sure I'm understanding...

I wonder if a potential treatment would be immunomodulators in combination with oxytocin and vasopressin supplementation. Something I'm curious about is why, when an illness strikes and 5ar1 is upregulated, the presumably restarted "loop" of neurosteroid creation and pituitary secretion does not self maintain and continue regulating 5ar1?

Wow beautifully done diagram. With the suppressed immune system, I think the way it helps those of us with PFS is that it increases intracellular 5ar activity, while not significantly increasing blood levels of Androgens. So there is no increase of Androgens in the blood to negatively regulate 5ar1 in the CNS.

In addition to 5 alpha-DHT, enhanced formation of delta 4-androstenedione (delta 4), 5 alpha-androstan-3 beta,17 beta-diol (3 beta-diol) and 5 alpha-androstan-3 alpha,17 beta-diol (3 alpha-diol) were also observed in the treated groups. These results show a significantly increased formation of 5 alpha-DHT (and Adiol) in nude mice treated with high dose-levels of CsA.

without significant variation in normal circulating plasma androgen levels (as observed in idiopathic hirsutism) has been reported by several authors.

"loop" of neurosteroid creation and pituitary secretion does not self maintain and continue regulating 5ar1?

I don't know, but I think PFS is an 'Epigenetic' condition. In the case of PFS I think the gene expression of 5ar1 has been downregulated. 5ar1 seems to be extremely important in the CNS, of both males and females. Epigenetics is the study of changes in gene expression (i.e. silencing, and promotion of gene expression). Epigenetic changes in gene expression can happen rapidly and persist throughout a lifetime. Which can account for why guys can develop PFS so rapidly, and why it can last so long or even indefinitely. Here's a pretty good article explaining the basics of Epigenetics. Again good diagram I like it


Epigenetics (Walsh Research Institute)

 

[bloom]

Wow beautifully done diagram. With the suppressed immune system, I think the way it helps those of us with PFS is that it increases intracellular 5ar activity, while not significantly increasing blood levels of Androgens. So there no increase of Blood Androgens to negatively regulate 5ar1 in the CNS.







I don't know, but I think PFS is an 'Epigenetic' condition. In the case of PFS I think the gene expression of 5ar1 has been downregulated. 5ar1 seems to be extremely important in the CNS, of both males and females. Epigenetics is the study of changes in gene expression (i.e. silencing, and promotion of gene expression). Epigenetic changes in gene expression can happen rapidly and persist throughout a lifetime. Which can account for why guys can develop PFS so rapidly, and why it can last so long or even indefinitely. Here's a pretty good article explaining the basics of Epigenetics. Again good diagram I like it


Epigenetics (Walsh Research Institute)

Oh and I will add that increasing 5ar1 in the CNS, may increase certain pituitary hormones, like Oxytocin and Vasopressin as a result of increasing Neurosteroids (specifically Allopregnanolone) as mentioned in the above study. It may decrease others like say LH, and FSH, since it still converts T into DHT.

 

[bloom]

Great write up, as usual, of the current progress on this.

Just mocked up this in the inimitable MS paint to make sure I'm understanding...

I wonder if a potential treatment would be immunomodulators in combination with oxytocin and vasopressin supplementation. Something I'm curious about is why, when an illness strikes and 5ar1 is upregulated, the presumably restarted "loop" of neurosteroid creation and pituitary secretion does not self maintain and continue regulating 5ar1?

Something I'm curious about is why, when an illness strikes and 5ar1 is upregulated, the presumably restarted "loop" of neurosteroid creation and pituitary secretion does not self maintain and continue regulating 5ar1?

Well in PFS a lot of guys when they first go on Finasteride claim to feel great, and report improvements in libido and mood. I think this is due to lowering DHT and consequently increasing 5ar1 expression particularly in the CNS. But as time goes on the 5ar inhibition ultimately causes a severe depletion of neurosteroids, ultimately causing a worsening in mood and libido and possibly PFS. In PFS it could be the case of hypopituitarism causing low levels of Pituitary hormones, causing low 5ar1 expression. Or 5ar1 downregulation (particularly in the CNS), leading to low neurosteroid levels--->low Pituitary hormones--->low 5ar1 expression. Which is the main culprit hypopituitarism, or 5ar1 downregulation in the CNS? I don't know, either way I think it's safe to say low 5ar1 activity in the CNS is a huge problem in PFS. It could very well be the case that ones needs to keep certain Pituitary hormones highly elevated for a while to get 5ar1 back online.

 

[bloom]

Well in PFS a lot of guys when they first go on Finasteride claim to feel great, and report improvements in libido and mood. I think this is due to lowering DHT and consequently increasing 5ar1 expression particularly in the CNS. But as time goes on the 5ar inhibition ultimately causes a severe depletion of neurosteroids, ultimately causing a worsening in mood and libido and possibly PFS. In PFS it could be the case of hypopituitarism causing low levels of Pituitary hormones, causing low 5ar1 expression. Or 5ar1 downregulation (particularly in the CNS), leading to low neurosteroid levels--->low Pituitary hormones--->low 5ar1 expression. Which is the main culprit hypopituitarism, or 5ar1 downregulation in the CNS? I don't know, either way I think it's safe to say low 5ar1 activity in the CNS is a huge problem in PFS. It could very well be the case that ones needs to keep certain Pituitary hormones highly elevated for a while to get 5ar1 back online.

I'll also add that increasing androgens may decrease 5ar1 ubiquitously throughout the body however, 5ar1 seems to play such an important role in the CNS that low levels of it there can be felt quite hard

 

[bloom]

GABA receptor stimulation increases the release of vasopressin and oxytocin in vitro. - PubMed - NCBI

The release of oxytocin and vasopressin from rat neurointermediate lobes was determined in vitro. The electrically evoked release of posterior pituitary hormones was markedly potentiated by the GABA receptor agonist, isogauvacin, an effect which was abolished by the GABAA receptor antagonist bicuculline. Spontaneous hormone outflow was not affected by the substances tested. The results suggest the existence of a GABA receptor on the terminal fibres in the pituitary, facilitating the release of oxytocin and vasopressin.

So this is a very interesting study showing that a GABA A receptor agonist increased the release of Oxytocin and Vasopressin. These are two Pituitary hormones, I've posted quite a few studies showing that Pituitary hormones positively regulate the gene expression of 5ar1. There could positive feedback loop between certain neurosteroids, certain Pituitary hormones, and 5ar1 expression of which a 5ar inhibitor may disrupt.

 

[Terma]

Bloom, not trying to hijack another thread of yours, but the other's impossible to follow. Has anyone looked into endogenous opioid control of 5-AR?

Opioid drugs like morphine which are strongest at mu-opioid receptor are so effective at increasing 5-AR (Aromatase and 5-alpha reductase gene expression: modulation by pain and morphine treatment in male rats) that I've been wondering, if they might not be one of the major endogenous modulators of 5-AR, through endogenous endorphins vs dynorphin. It's hard to find exact experiments on 5-AR, but looking at the correlations (Ageing of the neuroendocrine system in the brain of male rats: receptor mechanisms and steroid... - Abstract - Europe PMC), mu-opioids strongly increase 5-AR, while kappa-opioid receptors are dysphoric and increase prolactin and usually counterbalance mu-opioid roughly. So, I'd expect k-opoid to lower 5-AR (I do not know this part for sure, but I'd expect at least an indirect negative regulation). k-opioids are released very closely with CRH (hypothalamus) and in normal settings some their actions require CRH and are normally downstream of it or rather they amplify the effects of CRH (The Dynorphin-Kappa Opioid System as a Modulator of Stress-induced and Pro-addictive Behaviors, κ-opioid receptor - Wikipedia). It can trigger vasopressin but it should inhibit oxytocin (https://deepblue.lib.umich.edu/bitstream/handle/2027.42/97182/0091270010361256.pdf?sequence=1). Note that mu-opioids also lower oxytocin even though they increase 5-AR, but I didn't think that will matter much.

That said glucocorticoids are more likely responsible for some problems in depressive/social symptoms like CRH feedback receptor and other receptor downregulation: http://www.nature.com/articles/nature11436 (in this one, Mifepristone was the ONLY agent capable of fixing aversive behavior in the rats - fluoxetine and k-antagonist didn't work). This is my major interest in Mifepristone, but then again Mifepristone may and I would say should indirectly affect k-opioid receptors (found no studies on this). But the dynorphins/k-opioids add another dimension, and since they're so closely tied into the stress response with CRH(/CRF) in the hypothalamus and pituitary I'm finding them fascinating. They get even more involved because chronic stress downregulates part of the k-opioid receptor effects (Kappa opioid receptor and social stress in males and females — UC Davis), while studies tested the acute effects more than chronic. For the record there have been threads on it on longecity on k-opioid for a few years, but some of the info people postulated appears to be wrong, based on info in studies. Those people ended up microdosing Salvia (k agonist) to fight depression. I'm skeptical, but ibogaine (another) has a good track record.

This is a little crammed but I'm strapped for time and energy.

 

[RedStaR]

Well in PFS a lot of guys when they first go on Finasteride claim to feel great, and report improvements in libido and mood. I think this is due to lowering DHT and consequently increasing 5ar1 expression particularly in the CNS. But as time goes on the 5ar inhibition ultimately causes a severe depletion of neurosteroids, ultimately causing a worsening in mood and libido and possibly PFS. In PFS it could be the case of hypopituitarism causing low levels of Pituitary hormones, causing low 5ar1 expression. Or 5ar1 downregulation (particularly in the CNS), leading to low neurosteroid levels--->low Pituitary hormones--->low 5ar1 expression. Which is the main culprit hypopituitarism, or 5ar1 downregulation in the CNS? I don't know, either way I think it's safe to say low 5ar1 activity in the CNS is a huge problem in PFS. It could very well be the case that ones needs to keep certain Pituitary hormones highly elevated for a while to get 5ar1 back online.

Finateride lowers neurosteroids without inhibiting 5-AR I, I don't think they are related.

 

[bloom]

Finateride lowers neurosteroids without inhibiting 5-AR I, I don't think they are related.

That's right it does this through inhibition of 5ar2 and 3. I'm trying to make the argument that 5ar1 has been downregulated in PFS. This can explain why a lot of our symptoms get worse when we try and increase Testosterone and DHT. The 5ar1 enzyme is NEGATIVELY regulated by T and DHT. It's often reported these androgens cause anxiety and a worsening of mental symptoms this is the case for me. Also a lot of guys including myself report to get better when we go back on a low dose of a 5ar inhibitor (again the case with me). Low 5ar1 activity can account for this. Lowering DHT---->increased 5ar1 gene expression.

file:///C:/Users/public.AUD54606QN-L76/Downloads/Differential_regulation_of_steroid_5alpha-reductas%20(1).pdf

Our results demonstrate for the first time that 5-R type 2 expression in the brain is regulated by DHT, a product of the encoded enzyme, via a form of feed-forward regulation

Our study demonstrated that 5-R type 1 expression is not controlled by androgen in the intact animal. However, it is negatively controlled by some testicular factors (in part by T and DHT) because there is a marked increase in 5-R type 1 expression in castrated animals, in which circulating T and DHT are low. Furthermore, T and DHT decrease the mRNA levels of 5-R type 1 in castrated animals. These findings are novel and surprising

Interestingly a lot of the studies I mentioned above demonstrate that certain Pituitary hormones positively regulate the gene expression of 5ar1. And a lot of guys (again myself included) report to get better when we increase certain Pituitary hormones (i.e. LH, FSH, Oxytocin). A few studies I mentioned above demonstrate that neurosteroids seem to increase certain Pituitary hormones. A recent study I posted showed that a GABA A receptor agonist (5ar produces neurosteroids most of which are potent GABA A receptor agonists) increased the release of Oxytocin, and Vasopressin, both Pituitary hormones. There's also a paper i'm reading through which shows a feedback loop between neurosteroids and Pituitary hormones. I'll post it once i've thoroughly gone through it. I think that a 5ar inhibitor could disrupt a regulatory loop between neurosteroids, Pituitary hormones, and 5ar1 activity.

 

[bloom]

Bloom, not trying to hijack another thread of yours, but the other's impossible to follow. Has anyone looked into endogenous opioid control of 5-AR?

Opioid drugs like morphine which are strongest at mu-opioid receptor are so effective at increasing 5-AR (Aromatase and 5-alpha reductase gene expression: modulation by pain and morphine treatment in male rats) that I've been wondering, if they might not be one of the major endogenous modulators of 5-AR, through endogenous endorphins vs dynorphin. It's hard to find exact experiments on 5-AR, but looking at the correlations (Ageing of the neuroendocrine system in the brain of male rats: receptor mechanisms and steroid... - Abstract - Europe PMC), mu-opioids strongly increase 5-AR, while kappa-opioid receptors are dysphoric and increase prolactin and usually counterbalance mu-opioid roughly. So, I'd expect k-opoid to lower 5-AR (I do not know this part for sure, but I'd expect at least an indirect negative regulation). k-opioids are released very closely with CRH (hypothalamus) and in normal settings some their actions require CRH and are normally downstream of it or rather they amplify the effects of CRH (The Dynorphin-Kappa Opioid System as a Modulator of Stress-induced and Pro-addictive Behaviors, κ-opioid receptor - Wikipedia). It can trigger vasopressin but it should inhibit oxytocin (https://deepblue.lib.umich.edu/bitstream/handle/2027.42/97182/0091270010361256.pdf?sequence=1). Note that mu-opioids also lower oxytocin even though they increase 5-AR, but I didn't think that will matter much.

That said glucocorticoids are more likely responsible for some problems in depressive/social symptoms like CRH feedback receptor and other receptor downregulation: http://www.nature.com/articles/nature11436 (in this one, Mifepristone was the ONLY agent capable of fixing aversive behavior in the rats - fluoxetine and k-antagonist didn't work). This is my major interest in Mifepristone, but then again Mifepristone may and I would say should indirectly affect k-opioid receptors (found no studies on this). But the dynorphins/k-opioids add another dimension, and since they're so closely tied into the stress response with CRH(/CRF) in the hypothalamus and pituitary I'm finding them fascinating. They get even more involved because chronic stress downregulates part of the k-opioid receptor effects (Kappa opioid receptor and social stress in males and females — UC Davis), while studies tested the acute effects more than chronic. For the record there have been threads on it on longecity on k-opioid for a few years, but some of the info people postulated appears to be wrong, based on info in studies. Those people ended up microdosing Salvia (k agonist) to fight depression. I'm skeptical, but ibogaine (another) has a good track record.

This is a little crammed but I'm strapped for time and energy.

Yeah i've been on morphine based drugs since developing PFS, they certainly do improve symptoms especially mental symptoms. A lot of guys report this. That study you mentioned specifically stated they found that Morphine increased the gene expression of 5ar1.

p450-aromatase and 5-alpha reductase type 1 mRNA expression in the brain, liver and testis.

In the morphine-treated rats, there were increases of 5-alpha reductase mRNA expression in the liver and aromatase mRNA expression in the brain and gonads.

However I don't using morphine or anything which interacts with the opioid receptor is a good long term strategy for PFS.

 

[RedStaR]

That's right it does this through inhibition of 5ar2 and 3. I'm trying to make the argument that 5ar1 has been downregulated in PFS. This can explain why a lot of our symptoms get worse when we try and increase Testosterone and DHT. The 5ar1 enzyme is NEGATIVELY regulated by T and DHT. It's often reported these androgens cause anxiety and a worsening of mental symptoms this is the case for me. Also a lot of guys including myself report to get better when we go back on a low dose of a 5ar inhibitor (again the case with me). Low 5ar1 activity can account for this. Lowering DHT---->increased 5ar1 gene expression.

file:///C:/Users/public.AUD54606QN-L76/Downloads/Differential_regulation_of_steroid_5alpha-reductas%20(1).pdf





Interestingly a lot of the studies I mentioned above demonstrate that certain Pituitary hormones positively regulate the gene expression of 5ar1. And a lot of guys (again myself included) report to get better when we increase certain Pituitary hormones (i.e. LH, FSH, Oxytocin). A few studies I mentioned above demonstrate that neurosteroids seem to increase certain Pituitary hormones. A recent study I posted showed that a GABA A receptor agonist (5ar produces neurosteroids most of which are potent GABA A receptor agonists) increased the release of Oxytocin, and Vasopressin, both Pituitary hormones. There's also a paper i'm reading through which shows a feedback loop between neurosteroids and Pituitary hormones. I'll post it once i've thoroughly gone through it. I think that a 5ar inhibitor could disrupt a regulatory loop between neurosteroids, Pituitary hormones, and 5ar1 activity.

Looks like you're on a public computer.

Anyway, it doesn't really make sense to me since Dht is hydrolyised by the very same 5-ar it downregulates (more likely an HPA negative feedback loop than an intrinsic downregulation).

What makes more sense is the case of AR desensitization along with upregulation. I would assume dutasteride would not make you feel slightly recovered if that were the case. And I would assume low doses of finassteride does not slightly recover neurosteroid synthesis either. Rather the slight feeling of recovery is likely due to a third variable entierly, which sounds as plausible to be honest. We know that all endocrine and paracrine hormones are normal is PFS subjects, with neurosteroid profile simillar to finasteride users, and an upregulated AR density. This points to either:
1) Permenant downregulation of 5-AR 1 in brain or overall
2) Permenant downregulation of 5-AR 3 (maybe 4,5,6 as well, we don't know)
3) Epigenetic changes in AR dna, leading to over- or under- stimulation, causing downstream effects on other receptors/tissue

I would guess that 5AR synthesis (at least 1 and 2) are intact based on normal DHT plasma levels, and progression of hair loss and acne. On the other hand, CSF metabolites tell a different story, so maybe the other isozymes play a bigger role than we thought in the brain.

Sorry I'm on iPad so I can't write up a more comprehensive post.

 

[bloom]

Looks like you're on a public computer.

Anyway, it doesn't really make sense to me since Dht is hydrolyised by the very same 5-ar it downregulates (more likely an HPA negative feedback loop than an intrinsic downregulation).

What makes more sense is the case of AR desensitization along with upregulation. I would assume dutasteride would not make you feel slightly recovered if that were the case. And I would assume low doses of finassteride does not slightly recover neurosteroid synthesis either. Rather the slight feeling of recovery is likely due to a third variable entierly, which sounds as plausible to be honest. We know that all endocrine and paracrine hormones are normal is PFS subjects, with neurosteroid profile simillar to finasteride users, and an upregulated AR density. This points to either:
1) Permenant downregulation of 5-AR 1 in brain or overall
2) Permenant downregulation of 5-AR 3 (maybe 4,5,6 as well, we don't know)
3) Epigenetic changes in AR dna, leading to over- or under- stimulation, causing downstream effects on other receptors/tissue

I would guess that 5AR synthesis (at least 1 and 2) are intact based on normal DHT plasma levels, and progression of hair loss and acne. On the other hand, CSF metabolites tell a different story, so maybe the other isozymes play a bigger role than we thought in the brain.

Sorry I'm on iPad so I can't write up a more comprehensive post.

Well the latest study did find that DHT, DHP, and allopregnanolone were low in the CSF of PFS victims, and that Testosterone was high. That strongly suggests low 5ar activity. The study also found that T and DHT levels were relatively normal in the PFS group. Since it's been pretty well established that these Androgens positively regulate 5ar2 activity. 5ar2 status should be fine in PFS if T/DHT levels are normal. The only explanation I could find (and I think it's a pretty convincing explanation), is that 5ar1 is low. This can explain the low DHT, DHP, and Allo in the CFS, and the elevated T. It can also account for the elevated levels of Progesterone in the plasma, and low levels of DHP and Allo in the plasma . It can also explain why we get worse when we increase these androgens, and why we experience some relief when we take a 5ar inhibitor. Increase DHT--->Lower 5ar1 expression--->lowering of neurosteroids worsening of PFS symptoms
Decrease DHT--->increased 5ar1 expression--->increase of neurosteroids and DHT (in the CNS), improvement of PFS symptoms

Anyway, it doesn't really make sense to me since Dht is hydrolyised by the very same 5-ar it downregulates

It only downregulate 5ar1, not any of the other 5ar enzymes. In fact it increases the gene expression of 5ar2.

3) Epigenetic changes in AR dna, leading to over- or under- stimulation, causing downstream effects on other receptors/tissue

That doesn't explain the abnormal CSF levels of hormones, or the abnormal plasma levels of hormones. However low 5ar activity can account for these abnormalities.

I would guess that 5AR synthesis (at least 1 and 2) are intact based on normal DHT plasma levels

I think that 5ar2 levels would certainly be fine if your T/DHT levels were normal. However not necessarily 5ar1 since it is negatively regulated by T/DHT. Also plasma Progesterone levels were higher in the PFS group in the latest study, DHP and Allopregnanolone levels were also lower. Low 5ar1 can account for this, especially considering Progesterone has a higher affinity for 5ar1. Suggesting it has a much bigger role in metabolising Progesterone.

Steroid 5α-reductase in adult rat brain after neonatal testosterone administration - Sánchez - 2011 - IUBMB Life - Wiley Online Library

5a-R1 is known to have a higher affinity for progesterone than for T (8),

 

[Terma]

Yeah i've been on morphine based drugs since developing PFS, they certainly do improve symptoms especially mental symptoms. A lot of guys report this. That study you mentioned specifically stated they found that Morphine increased the gene expression of 5ar1.

However I don't using morphine or anything which interacts with the opioid receptor is a good long term strategy for PFS.

Yeah I didn't word those sentences that well. I meant specifically looking into the endogenous opioid regulation of 5-AR, endorphins and especially dynorphin (k-opioid). (I stopped using all true opioid substances for the moment, and damn they are hard to replace) I think they are prominent but the topic is a little esoteric so will run into a wall with research more than likely.

 

[RedStaR]

Well the latest study did find that DHT, DHP, and allopregnanolone were low in the CSF of PFS victims, and that Testosterone was high. That strongly suggests low 5ar activity. The study also found that T and DHT levels were relatively normal in the PFS group. Since it's been pretty well established that these Androgens positively regulate 5ar2 activity. 5ar2 status should be fine in PFS if T/DHT levels are normal. The only explanation I could find (and I think it's a pretty convincing explanation), is that 5ar1 is low. This can explain the low DHT, DHP, and Allo in the CFS, and the elevated T. It can also account for the elevated levels of Progesterone in the plasma, and low levels of DHP and Allo in the plasma . It can also explain why we get worse when we increase these androgens, and why we experience some relief when we take a 5ar inhibitor. Increase DHT--->Lower 5ar1 expression--->lowering of neurosteroids worsening of PFS symptoms
Decrease DHT--->increased 5ar1 expression--->increase of neurosteroids and DHT (in the CNS), improvement of PFS symptoms



It only downregulate 5ar1, not any of the other 5ar enzymes. In fact it increases the gene expression of 5ar2.



That doesn't explain the abnormal CSF levels of hormones, or the abnormal plasma levels of hormones. However low 5ar activity can account for these abnormalities.



I think that 5ar2 levels would certainly be fine if your T/DHT levels were normal. However not necessarily 5ar1 since it is negatively regulated by T/DHT. Also plasma Progesterone levels were higher in the PFS group in the latest study, DHP and Allopregnanolone levels were also lower. Low 5ar1 can account for this, especially considering Progesterone has a higher affinity for 5ar1. Suggesting it has a much bigger role in metabolising Progesterone.

Steroid 5α-reductase in adult rat brain after neonatal testosterone administration - Sánchez - 2011 - IUBMB Life - Wiley Online Library

That still does not completely explain
1) low neurosteroids in CSF and brain
2) normal plasma DHT

If it does, then we need to assume that 5-AR II and III play no role in neurosteroid synthesis in the brain (not true based on existing studies for finasteride administration stration of non PFS subjects). And that 5-AR plays no role in DHT plasma levels, which we also know provides around 30% in healthy controls.

If you can find a specific marker of 5-ar 1/2, then that could lend credence to the 5-ar downregulation theory.

In fact, do you have a study in vitro that shows enzyme downregulation in the presence of androgens?

 

[axolotl]

^Struggling to find an in vitro example of that, but obviously the in vivo example in the first post is quite convincing. Regarding a specific marker, 3a diol g is almost universally low in PFS sufferers, yet DHT is usually OK and often high. As a marker of 5AR activity, this implies functional 5AR2 with a compromise to 5AR1.

Been thinking about a more direct action of Fin on the AR too. @RedStaR, you mentioned in the messy thread that you had a reaction to your first pill in terms of feeling prickling in your penis. I felt a complete disconnection from it and a very similar prickling 15 minutes after taking the dose that gave me PFS this May (I crashed mentally two days later and have all the ongoing problems, many are getting slowly worse). The more I think about it, I'm finding it hard to believe this could be anything other than direct interaction with the androgen receptors. I don't think 15-20 minutes would be long enough for DHT to be completely tanked after 5AR was inhibited, though correct me if I'm wrong. Fin is very similar structurally to DHT so this is a distinct possibility. This study, The antiandrogenic effect of finasteride against a mutant androgen receptor, notes that:

More than 100 single amino acid substitution mutations in the AR have been identified in clinical samples, a large proportion of which has mutations in the ligand binding domain. These mutations may arise as a consequence of selective pressure following androgen deprivation therapy (ADT). There is a school of thought in the literature that AR mutants could bind to non-androgen steroids.

Now, as I took one pill in 2011 and abandoned it, I am wondering if this could be part of what happened to me. I'm just hypothesising, but there was an immediate effect I'm just not sure could be explained by simply binding to 5AR, though I am of course ignorant to how fast the impact of this could take hold.

 

[RedStaR]

^Struggling to find an in vitro example of that, but obviously the in vivo example in the first post is quite convincing. Regarding a specific marker, 3a diol g is almost universally low in PFS sufferers, yet DHT is usually OK and often high. As a marker of 5AR activity, this implies functional 5AR2 with a compromise to 5AR1.

Been thinking about a more direct action of Fin on the AR too. @RedStaR, you mentioned in the messy thread that you had a reaction to your first pill in terms of feeling prickling in your penis. I felt a complete disconnection from it and a very similar prickling 15 minutes after taking the dose that gave me PFS this May (I crashed mentally two days later and have all the ongoing problems, many are getting slowly worse). The more I think about it, I'm finding it hard to believe this could be anything other than direct interaction with the androgen receptors. I don't think 15-20 minutes would be long enough for DHT to be completely tanked after 5AR was inhibited, though correct me if I'm wrong. Fin is very similar structurally to DHT so this is a distinct possibility. This study, The antiandrogenic effect of finasteride against a mutant androgen receptor, notes that:

More than 100 single amino acid substitution mutations in the AR have been identified in clinical samples, a large proportion of which has mutations in the ligand binding domain (www.mcgill.ca/androgendb). These mutations may arise as a consequence of selective pressure following androgen deprivation therapy (ADT). There is a school of thought in the literature that AR mutants could bind to non-androgen steroids.

Now, as I took one pill in 2011 and abandoned it, I am wondering if this could be part of what happened to me. I'm just hypothesizing, but there was an immediate effect I'm just not sure could be explained by simply binding to 5AR, though I am of course ignorant to how fast the impact of this could take hold.

I remember coming across 2 examples both done on prostate tissue, one of which was cancerous. The finding was that castration reduces 5-AR II by less than 50%, and 5-AR I was unaffected, while T, T+fin, and DHT+fin all raised both isozymes above control, with DHT and T+fin having a bigger impact on 5-AR II and vice versa. I'll see if I can dig up that study.

I think the resumption of hair-loss is a concrete indicator in itself of continued 5-AR II activity. I also think that it is also an indicator of a continued normal function of AR. A prostate exam would be a decent sanity check as well since these are physical manifestations of AR activity.

I've disregarded the mutated AR variants for now, except in the case that certain mutations of AR happen only locally in the brain.

Another mutation theory has to do with 5-AR enzymes, where some epigenetic variants (which has been documented outside of finasteride use) has shown a normal affinity for testosterone, but less so for other ligands.

I'm currently prescribing to the hypothesis of disrupted 5-AR function, in addition to a possible glucocorticoid resistance. The other thread is quite similar to what I have reached, but I might not continue research on the matter consistently.

 

[BeLiKeWater]

I think the most probable cause of origin of the downregulation could be the days after quitting finasteride the blood was plagued by DHT suddenly and with some feedback mechanism the 5ar1 got supressed, this thread is amazing let it live. Tycroz a memeber of Solvepfs.com claimed that he recovered libido and erections via cycling tomatoe juice that is a 5ar inhibitor. Im thinking if getting back to finasteride for a while and the stop it little by little could be the cure.

 

[Alex Jaramillo]

@bloom I think you are correct about inhibition of type 1 inhibition causing a lot of issues. As you stated above type 1 and pituitary hormones are linked. Why do I think you are correct? Well... because almost all post Accutane people have proved lower pituitary hormones such as LH, FSH, HGH>IGF-1. What is interesting is that not all of them have lowered DHT like myself but ALL OF THEM have lowered pituitary hormones. I never experienced any joint pain, insomnia, ED, depression, suicidal ideation or chronic fatigue before taking a chemo therapy drug called Accutane. I guess the real question is if one has cancer maybe taking such a substance would be justified (to them at least). As a lot of people on this forum are starting to come to grips with the fact that many degenerative conditions can be healed or prevented in the first place. It does not take a genius to make correlations of how you felt before and after taking a given substance. All isoenzymes of 5 alpha reductase play an important role in both males and females. Tampering with any of these long term will cause problems. Im glad we can all learn from each other so that we can focus on the solutions. Im not sure yet if that solution will be the same for all of us though. Very interesting post!

 

[lampofred]

If lowered 5ar type 1 is the problem in PFS, then increasing progesterone relative to estrogen and increasing thyroid function should be a way to cure it. Peat said 5ar is induced as a protective response to estrogen. When the body doesn't have the resources to produce the necessary amount of progesterone to combat estrogen, it produces these backup 5ar-derived adrenal steroids to counteract estrogen. But if you restore thyroid function to optimal then you don't need the 5ar derived steroids.