Long term finasteride use and staying on top of prostate

[notoriousone]

No that's not correct. Steady state levels are the level of drug concentration in serum that a particular dosage schedule of said drug approaches but never reaches. It's a limit (calculus). Your body is constantly eliminating the drug. The elimination rate and the accumulation rate reach an equilibrium that gives an ever decreasing rate of accumulation that approaches a limit, the steady state drug level(Think about trying to walk from one side of a room to the other but each step you take is half the distance of the previous. You would approach the other side of the room, but never reach it.) This means that a .5 mg a day dosing schedule will never approach the steady state level of 2.5 mg a day.


No, there is no research that shows this to my knowledge. The study I quoted shows that the 5AR1 reduction in the brain at .5 mg a day most likely minimal. This may even be beneficial, hence the patents for dutasteride as a preventative therapy for Parkinson's.

I was searching all last night for studies that show alloP reduction in people who use finasteride, but didn't find a study showing the plasma level. You have me really interested in attempting the .5mg dutasteride. However, my cognitive sides on finasteride were extremely debilitating (I even get cognitive sides from Saw palmetto). It's just such a big risk taking due to the half life and how bad my sides were. Do you think taking .5mg once a week, then titrating up is a logical route based on my situation?

I don't want to end up in a situation where I have extreme brain fog for months on end. The study you posted above clearly shows their is no reduction of alloP in females at .5mg but I'm still hesitant.


Found this which was interesting "The time taken to reach the steady state is about five times the half life of a drug." Half life of dutasteride is 5 weeks

 

[notoriousone]

No that's not correct. Steady state levels are the level of drug concentration in serum that a particular dosage schedule of said drug approaches but never reaches. It's a limit (calculus). Your body is constantly eliminating the drug. The elimination rate and the accumulation rate reach an equilibrium that gives an ever decreasing rate of accumulation that approaches a limit, the steady state drug level(Think about trying to walk from one side of a room to the other but each step you take is half the distance of the previous. You would approach the other side of the room, but never reach it.) This means that a .5 mg a day dosing schedule will never approach the steady state level of 2.5 mg a day.


No, there is no research that shows this to my knowledge. The study I quoted shows that the 5AR1 reduction in the brain at .5 mg a day most likely minimal. This may even be beneficial, hence the patents for dutasteride as a preventative therapy for Parkinson's.

I've read several times that Finasteride only acts on type 2 (which ppl supposedly claim isn't in the brain or impacts neurosteroids). I have gotten terrible brain fog from finasteride. I'm trying to decipher why that study showed there was no drop off in alloP (or potentially a more minor one).

This study shows the drop off in alloP (and other neurosteroids) from finasteride: https://sci-hub.se/10.1515/hmbci.2010.010

The study is actually shocking because its shows at 4,8, and 12 months there is a continue drop off each quarter of all types of mood enhancing neurosteroids (not just alloP). And we can assume that finasteride had reached steady state long long before the 4th month. This studies actually quite shocking.

 

[Feelsbadman.jpg]

I've read several times that Finasteride only acts on type 2 (which ppl supposedly claim isn't in the brain or impacts neurosteroids). I have gotten terrible brain fog from finasteride. I'm trying to decipher why that study showed there was no drop off in alloP (or potentially a more minor one).

This study shows the drop off in alloP (and other neurosteroids) from finasteride: https://sci-hub.se/10.1515/hmbci.2010.010

The study is actually shocking because its shows at 4,8, and 12 months there is a continue drop off each quarter of all types of mood enhancing neurosteroids (not just alloP). And we can assume that finasteride had reached steady state long long before the 4th month. This studies actually quite shocking.

This is an interesting study but it's measuring levels of these hormones in plasma which is serum and not in the brain. Also, it is only a sample size of 12 but the fact that it was on humans at a dose of 1 mg ED is very good.

The levels of free steroids listed in Table 1 were measured in plasma
using GC-MS.

Table 5 shows
the pre- and post-treatment concentrations of potentially neuroactive steroids contained in the plasma of patients treated
for premature androgenetic alopecia using finasteride at a
dose of 1 mg/day for a period of 12 months

They then go on to conclude that these serum levels definitively reflect brain neurosteroid levels after stating they were only potentially so. A pretty big leap.

The findings reported here confirm that finasteride treatment contributes to brain steroid metabolism, which is favorable for the development of depression symptoms. Therefore,
this medication should be prescribed with caution for patients
with high risk of depression

A couple of other things that seem off to me is that they state T levels remain unchanged, and their data reflects that. Every other study shows T increasing and remaining so, about 15% on finasteride treatment, E2 as well. All in all though, this shows what you would expect from a type 2 5AR inhibitor, all the downstream metabolites of 5AR2 will go down in serum. However, 5AR2 has not been shown to be active in the brain so I do not know how the authors definitely conclude that this shows Finasteride affects brain neurosteroid profile to any significant degree. I suppose some people rely on serum levels of these hormones more than endogenous local production in the brain more than others. Hard to say with n = 12. Would be interesting to examine the pseudohermaphrodites who live their whole lives with 5AR2, seemingly fine, for cognitive function and health(prevalence of depression and neurodegenerative diseases) with respect to their peers.

Furthermore, having high levels of the neurosteroids may not be beneficial in the long term, i.e. they may confer short term benefits at a long term cost through over stimulation of their respective receptors. From my anecdotal view point, I see 5AR primarily as an amplifier of prohormones. When prohormone levels are high, this is not needed. When they are low and 5AR is inhibited, then problems can arise.

Edit: To add to this, I didn't notice when first looking at this study but they do not record the progesterone levels at all. If progesterone levels are decreasing that would be a more plausible reason as to why allopregnanolone is decreasing given that in women with PMDD, it takes large doses of dutasteride to lower allopregnanolone via inhibiting 5AR.

Here is a study showing Finasteride reduces progesterone levels in women.

Prolonged use of finasteride-induced gonadal sex steroids alterations, DNA damage and menstrual bleeding in women

Abstract. The aim of the present study was to examine the effect of prolonged use of finasteride on serum levels of dihydrotestosterone (DHT), estradiol (E2), progesterone, testosterone and androstenedione in women during the menstrual period. Further, to screen and compare the 5α-reductase...

portlandpress.com

The chemical structure of Finasteride is similar to progesterone and it could be that it behaves like a synthetic progestin, lowering endogenous progesterone as inhibiting 5AR alone should not decrease Progesterone levels. Without including Progesterone levels, it's impossible to conclude from this study that the recorded decrease in allopregnanolone is due solely to 5AR inhibition and not also due to declining levels of the substrate needed to produce allopregnanolone, Progesterone.

 

[Feelsbadman.jpg]

Dosage of Finasteride used on mice in this study:

Pretreatment with finasteride (50-300 mg/kg, i.p.) produced a dose-dependent (ED50, 146 mg/kg) reversal of the protective effects of progesterone (2 x ED50 dose = 188 mg/kg). That's also way more than was used in the Parkinson's mouse study.

For a 65 kg human, this is 3250 mg - 19500 mg. It was also administered intraperitoneally (injection into abdomen) not orally.

Whenever possible, we should look at human studies as rat/mice results often don't translate to human very well.

This study follows allopregnanolone levels in women taking dutasteride.

5α-Reductase Inhibition Prevents the Luteal Phase Increase in Plasma Allopregnanolone Levels and Mitigates Symptoms in Women with Premenstrual Dysphoric Disorder

Changes in neurosteroid levels during the luteal phase of the menstrual cycle may precipitate affective symptoms. To test this hypothesis, we stabilized neurosteroid levels by administering the 5α-reductase inhibitor dutasteride to block conversion ...

www.ncbi.nlm.nih.gov

After two months of .5 mg of dutasteride a day, allopregnanolone leves were still inreasing which means 5AR1 was not being inhibited in brain to any significant extent. I believe dutasteride at .5 mg ED reaches 60% of steady state levels after 1 month and 90% of steady state after 3 months. It seems unlikely that 5AR1 levels in the brain are impacted that much by the standard dose of .5 mg. Now at 2.5mg, it clearly does.

I should note that this study also uses plasma levels to measure allopregnanolone however, they go off presence of PMDD symptoms as well.

Dutasteride levels are increased within the CNS after oral administration in rodents, (GlaxoSmithKline Research Triangle Park NC, 2005) but no studies have measured the penetrance of the drug into the human CNS. As a result, this sequential two-dose strategy was used.

The researches didn't even know if dutasteride would enter the CNS in humans which is why they used the two doses. PMDD symptoms only decreased in the 2.5 mg group which indicates the brain levels of allopregnanolone went down only in that group. I think it's likely that serum/plasma levels of this hormone don't always reflect brain levels.

 

[notoriousone]

This is an interesting study but it's measuring levels of these hormones in plasma which is serum and not in the brain. Also, it is only a sample size of 12 but the fact that it was on humans at a dose of 1 mg ED is very good.



They then go on to conclude that these serum levels definitively reflect brain neurosteroid levels after stating they were only potentially so. A pretty big leap.


A couple of other things that seem off to me is that they state T levels remain unchanged, and their data reflects that. Every other study shows T increasing and remaining so, about 15% on finasteride treatment, E2 as well. All in all though, this shows what you would expect from a type 2 5AR inhibitor, all the downstream metabolites of 5AR2 will go down in serum. However, 5AR2 has not been shown to be active in the brain so I do not know how the authors definitely conclude that this shows Finasteride affects brain neurosteroid profile to any significant degree. I suppose some people rely on serum levels of these hormones more than endogenous local production in the brain more than others. Hard to say with n = 12. Would be interesting to examine the pseudohermaphrodites who live their whole lives with 5AR2, seemingly fine, for cognitive function and health(prevalence of depression and neurodegenerative diseases) with respect to their peers.

Furthermore, having high levels of the neurosteroids may not be beneficial in the long term, i.e. they may confer short term benefits at a long term cost through over stimulation of their respective receptors. From my anecdotal view point, I see 5AR primarily as an amplifier of prohormones. When prohormone levels are high, this is not needed. When they are low and 5AR is inhibited, then problems can arise.

Serum is going to be a proxy for what's in the brain. I read a study last night in rats showing maximal inhibition of alloP in mice (99%). I don't agree its 100% reflective of what is happening in the brain, but to think alloP drops to that degree in plasma at 3 different increments (4 months apart each and continually goes down each time) is wishful thinking IMO.

Go through tressless and this forum and you will find hundreds of reports of ppl having 'brain fog'. I personally experienced it and it was so debilitating and hard to explain. A lot of ppl come and say "I forgot my car keys, do I have brain fog?!". These ppl don't, when you get it you will know and it will freak you out. I've went through the forums and found countless mentioning of exactly what I experienced.

We probably understand less than 10% of how these neurosteroids impact. I was reading another study last night stating the geno/phenotype plays an important role in all of this. I don't really see how we can show a reduction in alloP in plasma of humans, maximal inhibition in mice, and countless case reports of debilitating mental sides and really not think it has an impact on the brain. I will round this out by saying everyone probably has some degradation in mood/stability but it for some it is so minuscule they won't even notice. I'm not saying don't try finasteride or dutasteride, it will work for most and (probably) have no long term consequence. And if you do get sides there's a 99% chance it will go back to normal. I am stating its clear that it has some effect on the brain relating to mood/anxiety.

 

[notoriousone]

I should note that this study also uses plasma levels to measure allopregnanolone however, they go off presence of PMDD symptoms as well.



The researches didn't even know if dutasteride would enter the CNS in humans which is why they used the two doses. PMDD symptoms only decreased in the 2.5 mg group which indicates the brain levels of allopregnanolone went down only in that group. I think it's likely that serum/plasma levels of this hormone don't always reflect brain levels.

It does not indicate that it only went down in that group because the levels rise going into the luteal phase anyway. Also, if you compare this with the finasteride study mentioned above we see a marked reduction in DHT in each increment of 4, 8, and 12 months (keeps going down). While this study only measured at 2 months. Although they concluded that it did not have an impact on alloP, I'm not sure how they completely came to that conclusion. It could simply be the case that there was a reduction in alloP but the luteal phase increase was that much more than the reduction in alloP. Again, I'm sure you don't have the incentive to look over these reports of mood issues in the forums but there are 100s of ppl stating what they experienced. If we have tons of case reports, maximal inhibition of alloP in rats, the finasteride study in humans showing several neurosteroid deficits, and this PMDD study has a n- count of 16 while also adding in the variable that alloP increasing over each women phases I don't really see how we can conclude it doesn't impact the brain. At the very least its inconclusive (especially without the raw data which I couldn't find).

Again, not saying ppl should get of finasteride or dutasteride. It just seems quite apparent to me that it clearly has an effect on neurosteroids. Appreciate the back and forth and would love to hear if you have a counter to any of this.

 

[Feelsbadman.jpg]

It does not indicate that it only went down in that group because the levels rise going into the luteal phase anyway.

What are you talking about.

The percent changes (mean (SD)) in allopregnanolone levels from follicular to luteal phases were as follows: during placebo 170.9% (158.5) and during dutasteride (2.5 mg per day) −12.8% (58.1).

To expand on the above, the increase in allopregnanolone levels during the luteal phase of the menstrual cycle is almost certainly due to the surge in the precursor to allopregnanolone, progesterone, that happens immediately prior to the luteal phase and not due to an increase in 5AR.

Menstrual Cycle - Women's Health Issues - Merck Manuals Consumer Version

Menstrual Cycle and Women's Health Issues - Learn about from the Merck Manuals - Medical Consumer Version.

www.merckmanuals.com

The ovulatory phase begins with a surge in luteinizing hormone and follicle-stimulating hormone levels. Luteinizing hormone stimulates egg release (ovulation), which usually occurs 16 to 32 hours after the surge begins. The estrogen level decreases during the surge, and the progesterone level starts to increase.

During the luteal phase, luteinizing hormone and follicle-stimulating hormone levels decrease. The ruptured follicle closes after releasing the egg and forms a corpus luteum, which produces progesterone.

If there was a change in 5AR levels during the change from follicular to luteal phases then we could expect to also see a change in DHT levels yet that does not occur.

Reexamination of testosterone, dihydrotestosterone, estradiol and estrone levels across the menstrual cycle and in postmenopausal women measured by liquid chromatography-tandem mass spectrometry - PubMed

Measuring serum androgen levels in women has been challenging due to limitations in method accuracy, precision sensitivity and specificity at low hormone levels. The clinical significance of changes in sex steroids across the menstrual cycle and lifespan has remained controversial, in part due...

pubmed.ncbi.nlm.nih.gov

Samples were obtained in ovulatory women in the early follicular phase (EFP), midcycle and mid luteal phase (MLP). Overall, the levels of T, DHT, E2 and E1 in premenopausal women measured by LC-MS/MS were lower overall than previously reported with immunoassays. In premenopausal women, serum T, free T, E2, E1 and SHBG levels peaked at midcycle and remained higher in the MLP, whereas DHT did not change.

So with 5AR levels remaining seemingly constant, it takes 2.5 mg of dutasteride ED to stabilize allopregnanolone in women with PMDD. Also something to consider, due to the feed forward nature of DHT and 5AR, men will have more 5AR enzyme than women yet women will most likely have higher allopregnanolone due to having higher levels of progesterone, the precursor hormone to allopregnanolone.




Anecdotes in and of themselves are worthless, no offense. What I will say is there are far more users of finasteride and dutasteride who say nothing because they have no side effects.

Also, from what you've told me (you mentioned saw palmetto gave you brain fog), I don't think you should discount psychosomatic causes to your issues. You are heavily fixated on allopregnanolone, probably because you read about it on forums like these as being the cause for brain fog. My point is, you have no idea if that is even your issue and to be fair, it likely is not(Remember some people live their whole lives without 5AR2 enzyme and brain fog is not a reported complaint that I'm aware of from them). Saw Palmetto is an extremely weak 5AR inhibitor, so much so that the believed method of action is through blocking/reducing androgen receptors, not even 5AR inhibition, so the chances of it reducing allopregnanolone are almost 0. Don't underestimate the power of placebo, that's why they are included in every single study that is worth anything.

Something that would be interesting with the anecdotes you refer to would be to look at the trends in the number of reports by date and if they are consistent since the release of Finasteride and Dutasteride or if they only became more prevalent in the past decade or so when online communities turned their attention from sexual side effects to neurological ones.

 

[notoriousone]

What are you talking about.


Anecdotes in and of themselves are worthless, no offense. What I will say is there are far more users of finasteride and dutasteride who say nothing because they have no side effects.

Also, from what you've told me (you mentioned saw palmetto gave you brain fog), I don't think you should discount psychosomatic causes to your issues. You are heavily fixated on allopregnanolone, probably because you read about it on forums like these as being the cause for brain fog. My point is, you have no idea if that is even your issue and to be fair, it likely is not(Remember some people live their whole lives without 5AR2 enzyme and brain fog is not a reported complaint that I'm aware of from them). Saw Palmetto is an extremely weak 5AR inhibitor, so much so that the believed method of action is through blocking/reducing androgen receptors, not even 5AR inhibition, so the chances of it reducing allopregnanolone are almost 0. Don't underestimate the power of placebo, that's why they are included in every single study that is worth anything.

Something that would be interesting with the anecdotes you refer to would be to look at the trends in the number of reports by date and if they are consistent since the release of Finasteride and Dutasteride or if they only became more prevalent in the past decade or so when online communities turned their attention from sexual side effects to neurological ones.

Serum is going to be a proxy for what's in the brain. I read a study last night in rats showing maximal inhibition of alloP in mice (99%). I don't agree its 100% reflective of what is happening in the brain, but to think alloP drops to that degree in plasma at 3 different increments (4 months apart each and continually goes down each time) is wishful thinking IMO.

This sums up my main points succinctly^. I don't really see how you can think finasteride doesn't reduce alloP/neurosteroids and have an effect on cognition. The evidence is all over the place in studies.

 

[Feelsbadman.jpg]

Serum is going to be a proxy for what's in the brain. I read a study last night in rats showing maximal inhibition of alloP in mice (99%). I don't agree its 100% reflective of what is happening in the brain, but to think alloP drops to that degree in plasma at 3 different increments (4 months apart each and continually goes down each time) is wishful thinking IMO.

This sums up my main points succinctly^. I don't really see how you can think finasteride doesn't reduce alloP/neurosteroids and have an effect on cognition. The evidence is all over the place in studies.

Weak correlations between serum and cerebrospinal fluid levels of estradiol, progesterone and testosterone in males

Neuroactive steroids seem to be implicated in a variety of neurophysiological and behavioral processes, such as sleep, learning, memory, stress, feeding and aging. Numerous studies have also addressed this implication in various cerebral disorders and ...

www.ncbi.nlm.nih.gov

This doesn't mention allopregnanolone but it talks about serum levels vs what is happening in the brain for progesterone as well as T and E:

Background
Neuroactive steroids seem to be implicated in a variety of neurophysiological and behavioral processes, such as sleep, learning, memory, stress, feeding and aging. Numerous studies have also addressed this implication in various cerebral disorders and diseases. Yet, the correlation and association between steroids in the periphery, e.g. blood, and the central compartments, e.g. cerebrospinal fluid (CSF), have not yet been comprehensively assessed. As the brain is not directly accessible, and the collection of human CSF usually requires invasive procedures, easier accessible compartments, such as blood, have always attracted attention. However, studies in humans are scarce. In the present study we determined estradiol, progesterone and testosterone levels in CSF and serum of 22 males without cerebral disorders or diseases.
Conclusions
Total steroid levels of estradiol, progesterone and testosterone in CSF and serum of males without neurological disorders were determined. Weak to very weak correlations between CSF and serum were found thus suggesting that concentrations in the periphery do not parallel concentrations in the central compartments. Further research is needed to clarify to what extent and under which conditions serum levels of estradiol, progesterone and testosterone may possibly serve as a biomarker reflecting the respective concentrations in the CSF or in the brain.

You are basically taking mouse studies and stating that this decline in serum proves finasteride/dutasteride reduce neurosteroids in the brain and this definitively is bad.

1. We don't know definitely what is happening the brain but most likely, for allopregnanolone in the brain, finasteride does not reduce it and dutasteride at .5mg ED may reduce it marginally.

2. You are assuming that more allopregnanolone is good. Allopregnanolone is a stress hormone. Like other stress hormones, it most likely confers short term benefits at long term costs. Reducing it may have longevity benefits for cognitive function.

I'm not denying that serum levels are inhibited, I just don't think this is necessarily a negative.

Bottom line for you, don't take Finasteride or Dutasteride. It is clearly not worth the risk since you value your serum allopregnanolone levels and have convinced yourself that is the source of your brain fog.

 

[notoriousone]

Weak correlations between serum and cerebrospinal fluid levels of estradiol, progesterone and testosterone in males

Neuroactive steroids seem to be implicated in a variety of neurophysiological and behavioral processes, such as sleep, learning, memory, stress, feeding and aging. Numerous studies have also addressed this implication in various cerebral disorders and ...

www.ncbi.nlm.nih.gov

This doesn't mention allopregnanolone but it talks about serum levels vs what is happening in the brain for progesterone as well as T and E:


You are basically taking mouse studies and stating that this decline in serum proves finasteride/dutasteride reduce neurosteroids in the brain and this definitively is bad.

1. We don't know definitely what is happening the brain but most likely, for allopregnanolone in the brain, finasteride does not reduce it and dutasteride at .5mg ED may reduce it marginally.

2. You are assuming that more allopregnanolone is good. Allopregnanolone is a stress hormone. Like other stress hormones, it most likely confers short term benefits at long term costs. Reducing it may have longevity benefits for cognitive function.

I'm not denying that serum levels are inhibited, I just don't think this is necessarily a negative.

Bottom line for you, don't take Finasteride or Dutasteride. It is clearly not worth the risk since you value your serum allopregnanolone levels and have convinced yourself that is the source of your brain fog.

I find it highly unlikely that alloP drops significantly in https://sci-hub.se/10.1515/hmbci.2010.010 in the plasma but assuming it isn't a proxy for what's happening in the brain is short sighted. Especially cause it continually drops at every increment up to 1 year.

Also, the study you site to say that dutasteride doesn't reduce alloP is titled:

5α-Reductase Inhibition Prevents the Luteal Phase Increase in Plasma Allopregnanolone Levels and Mitigates Symptoms in Women with Premenstrual Dysphoric Disorder​

 

[Feelsbadman.jpg]

I find it highly unlikely that alloP drops significantly in https://sci-hub.se/10.1515/hmbci.2010.010 in the plasma but assuming it isn't a proxy for what's happening in the brain is short sighted. Especially cause it continually drops at every increment up to 1 year.

You are assuming that it IS a proxy. I just posted a study that shows this assumption is not correct for allopregnanolone's precursor, progesterone.

Also, the study you site to say that dutasteride doesn't reduce alloP is titled:

5α-Reductase Inhibition Prevents the Luteal Phase Increase in Plasma Allopregnanolone Levels and Mitigates Symptoms in Women with Premenstrual Dysphoric Disorder​

Already covered that.

I should note that this study also uses plasma levels to measure allopregnanolone however, they go off presence of PMDD symptoms as well.

Bottom line, I'm not here to convince you to take drugs. This was my research and my conclusions. If you don't agree with it, no worries. Don't take Finasteride and Dutasteride. Simple as and move on.

 

[Mr. Slap Head]

Please top me

 

[Feelsbadman.jpg]

I am not looking to feed this troll but just to clarify this misinformation being pushed to others who may read this thread:

I find it highly unlikely that alloP drops significantly in https://sci-hub.se/10.1515/hmbci.2010.010 in the plasma but assuming it isn't a proxy for what's happening in the brain is short sighted. Especially cause it continually drops at every increment up to 1 year.

Also, the study you site to say that dutasteride doesn't reduce alloP is titled:

5α-Reductase Inhibition Prevents the Luteal Phase Increase in Plasma Allopregnanolone Levels and Mitigates Symptoms in Women with Premenstrual Dysphoric Disorder​

This study uses Finasteride which does not inhibit 5 Alpha Reductase type 1 to any significant degree. 5AR type 1 is the primary type of 5AR in the brain. This is common knowledge. Yet somehow you come to the conclusion that plasma is a proxy for what's happening in the brain.

Allopregnanolone is not only produced in the brain. It's also produced in the adrenal cortex and this is the main source of circulating allopregnanolone. It can be produced anywhere Progesterone, 5AR, and 3α-HSD are present.

Allopregnanolone and dehydroepiandrosterone response to corticotropin-releasing factor in patients suffering from Alzheimer's disease and vascular dementia - PubMed

The present study firstly showed that allopregnanolone levels are reduced both in AD and in VD and that dementia has a preserved stimulated response of allopregnanolone to CRF. Overall, however, the total response of allopregnanolone to CRF remains reduced in respect to controls. Further studies...

pubmed.ncbi.nlm.nih.gov

A major neurosteroid gamma-aminobutyric acid (GABA) agonist is allopregnanolone: the main source of circulating allopregnanolone is the adrenal cortex.

https://pubmed.ncbi.nlm.nih.gov/24172649/

It is less well appreciated that progesterone and its metabolite allopregnanolone are also male hormones, as they are produced in both sexes by the adrenal glands. In addition, they are synthesized within the nervous system.

Frontiers | Allopregnanolone, the Neuromodulator Turned Therapeutic Agent: Thank You, Next?

www.frontiersin.org

Acute stress in rodents fast induces allopregnanolone biosynthesis underlying its role in stress response and demonstrating allopregnanolone present in brain is synthesized independently from peripheral glands (24).

Finasteride in humans, not rats, would only inhibit the allopregnanolone being produced via progesterone being metabolized by 5AR2 and then 3α-HSD which would not be in the brain. In rats, Finasteride has similar affinity to 5AR1 as 5AR2 so it's not comparable to humans. Saying it's shortsighted to not assume that plasma levels of allopregnanolone are a proxy for what is happening in the brain is... shortsighted.

The study I posted on PMDD was done on humans, used dutasteride, and it showed that .5 mg a day was not enough to stabilize allopregnanolone levels in brain based on plasma levels AND symptoms but 2.5 mg was. The key word here is stabilize. Ask yourself, if dutasteride inhibiting allopregnanolone in the brain was so detrimental, why would they be using this as a treatment and why did it work?

Psychiatry Online

ajp.psychiatryonline.org

why would allopregnanolone antagonism prevent symptoms of PMDD? Apart from the obvious—that women’s reproductive-related mood disorders are not all the same—sepranolone and dutasteride also stabilize allopregnanolone signaling. As such, their efficacy is consistent with observations that changes in hormone levels (as opposed to the levels themselves) are important regulatory signals, a well-described phenomenon in the form of fast-rate feedback of ACTH secretion (16) or pulsatile frequency-dependent actions of gonadotropin hormone-releasing hormone on gonadotropin release (17).

This is from a psychiatry journal. Notice they state that dutasteride stabilizes allopregnanolone signaling and not inhibits? This is what I was trying to extrapolate on before, perhaps poorly since it was ignored, in regards to more allopregnanolone is not always necessarily good. It's seem to be more important to have stable levels which dutasteride apparently provides in PMDD patients and it would presumably do so in males as well.

Here is yet more evidence that neither Finasteride nor Dutasteride increase the risk for Dementia.

The risk of dementia with the use of 5 alpha reductase inhibitors - PubMed

As the strength of the association decreased with increased exposure, the higher risk seen in the initial two years likely represents the presentation and treatment of urinary symptoms which coexist with mild cognitive impairment and eventually progresses to a diagnosis of dementia.

pubmed.ncbi.nlm.nih.gov

Results: New initiation of 5ARI medication was associated with an increased risk of dementia during the first (HR 2.18, 95% CI 2.01-2.35) and second (HR 1.52, 95% CI 1.39-1.67) year, however this risk was nonsignificant among the men with the longest exposure to 5ARIs (HR 1.06, 95% CI 0.98-1.14). There was no difference in the results between types of 5ARIs.
Conclusion: As the strength of the association decreased with increased exposure, the higher risk seen in the initial two years likely represents the presentation and treatment of urinary symptoms which coexist with mild cognitive impairment and eventually progresses to a diagnosis of dementia.

If the "inhibition" of allopregnanolone in the brain by dutasteride was linked to dementia, the strength of association would not decrease with increased exposure. It would increase.

The reduction of serum allopregnanolone with 5ARI is to be expected and this inhibition is primarily the allopregnanolone from the adrenal cortex, not the brain. The only human study that I'm aware of looking at allopregnanolone and dutasteride had to use 2.5 mg ED to stabilize allopregnanolone levels in the brain in women with PMDD.

This is why I believe the concerns around 5ARI and allopregnanolone are really just massively overblown hype with no real convincing evidence to support it.

There is a real potential risk with 5ARI's though and it is curious how it is ignored and people choose to focus on meme tier PFS foundation cash grab topics like "allopregnanolone" instead. Probably because of the internet bro science hype.

There are multiple studies showing reduced insulin sensitivity and increased diabetes risk with finasteride and dutasteride although there is at least one that contradicts these and as of 2019, some of the top endocrinologists in the world had no answers to this discrepancy. If there is anything to worry about in regards to safety with taking a 5ARI, this would be it. It is better to be aware of this potentially increased risk so that lifestyle choices can be modified to mitigate any increased risk.

This thread discusses the studies surrounding this issue. https://www.hairlosstalk.com/intera...associated-with-metabolic-alterations.106703/

 

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More evidence Dutasteride does not produce any form of cognitive/neurological impairment.

Neuropsychological Assessment in Elderly Men with Benign Prostatic Hyperplasia Treated with Dutasteride - Clinical Drug Investigation

Background and Objective Benign prostatic hyperplasia (BPH) is a common disease found in elderly men and 5α-reductase (5α-R) inhibitors are a commonly used treatment option. 5α-reduced steroids are compounds that play a role in several functions across different organs and systems. In the adult...

link.springer.com

Results
In a sample of BPH patients (n = 40; mean age 71.4 ± 7.4 years), men receiving dutasteride showed no significant differences during the neuropsychological assessment in comparison with an age-matched control group, consisting of BPH men not receiving dutasteride (p < 0.05). No significant associations were recorded between treatment duration and any of the administered tests.

Evidence to support the claim that allopregnanolone can have detrimental cognitive effects. It is a stress hormone, like I have been saying throughout this thread, and, when chronically elevated through chronic acute stress, not conducive to long term cognitive health. Dutasteride has been shown to help stabilize allopregnanolone levels.

Long-term continuous allopregnanolone elevation causes memory decline and hippocampus shrinkage, in female wild-type B6 mice

Chronic stress in various forms increases the risk for cognitive dysfunction, dementia and Alzheimer's disease. While the pathogenesis behind these fi…

www.sciencedirect.com

Long-term continuous allopregnanolone elevation causes memory decline and hippocampus shrinkage, in female wild-type B6 mice
Highlights
•The long-term continuous allopregnanolone treatment led to a steroid elevation similar to that of chronic stress.
•The continuous steroid elevation caused learning and memory impairment and reduced hippocampus weight in wild-type mice.
•Correlation between learning and memory function and hippocampus weight was lost after allopregnanolone elevation.
•Continuous allopregnanolone elevation may be an important link in the mechanism behind stress-induced cognitive decline.
Abstract
Chronic stress in various forms increases the risk for cognitive dysfunction, dementia and Alzheimer's disease. While the pathogenesis behind these findings is unknown, growing evidence suggests that chronic increase in neurosteroid levels, such as allopregnanolone, is part of the mechanism. We treated wild-type C57BL/6J mice with allopregnanolone for 5 months, using osmotic pumps. This treatment led to moderately increased levels of allopregnanolone, equivalent to that of mild chronic stress. After an interval of no treatment for 1 month, female mice showed impaired learning and memory function in the Morris water maze (MWM) in combination with diminished hippocampus weight and increased cerebellum weight, both correlating to MWM performance. Male mice showed a minor reduction in memory function and no differences in brain structure. We conclude that chronic allopregnanolone elevation can lead to cognitive dysfunction and negative brain alterations. We suggest that allopregnanolone could play a key role in the pathogenesis of stress-induced cognitive disturbances and perhaps dementia.

Brief but Chronic Increase in Allopregnanolone Cause Accelerated ...: Ingenta Connect

www.ingentaconnect.com

Brief but Chronic Increase in Allopregnanolone Cause Accelerated AD Pathology Differently in Two Mouse Models
Previously, we have shown that chronic treatment with allopregnanolone (ALLO) for three months impaired learning function in the Swe/PS1 mouse model. ALLO is a neurosteroid, produced in the CNS and a GABAA receptor agonist. ALLO modulates the general inhibitory system in the CNS by enhancing the effect of GABA. Chronic treatment with other GABAA receptor active compounds, such as benzodiazepines, ethanol and medroxy-progesterone acetate has been associated to cognitive decline and/or increased risk for dementia. In this study, we sufficed with a treatment period of one month for the Swe/PS1 mouse, and included another Alzheimer's disease mouse model; the Swe/Arc model. We found that one month of chronic treatment with elevated ALLO levels within physiological range impaired learning and memory function in the Swe/Arc female and male mice. Male Swe/PS1 mice also showed marginally impaired function, while the female mice did not. Furthermore, the chronic ALLO treatment caused increased levels of soluble Aβ in the Swe/PS1 mouse model while the levels were unchanged in the Swe/Arc model. Therefore, both Swe/Arc and Swe/PS1 mice showed signs of accelerated disease progression. Still, further studies are required to determine the mechanisms behind the cognitive impairment and the increased Aβ-levels caused by mildly elevated ALLO-levels.