Finasteride and Neurosteroides (DHT metabolites) - Potential Problem?

[to the lost]

Hi everybody,

I was looking on the mechanism of action of finasteride, and I found something discouraging/problematic. First of I am NOT a doctor or a neuro-scientist, so this is for me kind of a “hard-to-understand” subject, but I did reasearch. And please don’t accuse me of anything (I am neither for or against finasteride: in my previous thred – those who read it, know – that I am starting to have hair loss problems, but I am not on finasteride yet, but I would like to be if it is safe).

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Ok, let’s start:

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1.) finasteride inhibits T to DHT conversion, which means less of DHT in your body (by 5α reductase I and II, but as i understand type II more)

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2.) please look at the picture http://onlinelibrary.wiley.com/doi/10.1111/j.1527-3458.2006.00053.x/pdf (page 55, picture 1)

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It says: “[FONT=&amp]use of a 5[/FONT] α[FONT=&amp] -reductase inhibitor can be considered a[/FONT]
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[FONT=&amp]blockade of the rate-limiting step to the two-step production of neuroactive steroid metabolites”

[/FONT]
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[FONT=&amp]So the 5[/FONT] α reductase inhibitor (like finesteride) can block production of certain neurosteroids (if I understand picture correctly) like DHT (you also get less androstanediol, because it is metabolite from DHT and there is less DHT in body); DHP (get also less allopregnanolone or short THP, same reason just from progesterone) and DHDOC (get also less THDOC).

did i understand that right? (it block all reductase metabolites, not just androstanediol)

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3.) p 58 says: “[FONT=&amp]Given this finding, there has been speculation that finasteride[/FONT]​

[FONT=&amp]might be useful to inhibit progesterone metabolism, and the concomitant synthesis of[/FONT]​

[FONT=&amp]neuroactive steroids in the brain”

[/FONT]
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p. 60 has this conclusion:”[FONT=&amp] In summary, preclinical studies with[/FONT]​

[FONT=&amp]finasteride and other drugs that alter 3[/FONT] α[FONT=&amp],5[/FONT] α[FONT=&amp] -THP biosynthesis support a role for endogenous[/FONT]​

[FONT=&amp]3[/FONT][FONT=&amp]á[/FONT][FONT=&amp],5[/FONT][FONT=&amp]á[/FONT][FONT=&amp]-THP in maintaining normal GABAergic brain function, and suggest that alterations[/FONT]​

[FONT=&amp]in endogenous 3[/FONT][FONT=&amp]á[/FONT][FONT=&amp],5[/FONT][FONT=&amp]á[/FONT][FONT=&amp]-THP levels could contribute to symptoms of anxiety and[/FONT]​

[FONT=&amp]depression”

[/FONT]
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[FONT=&amp]p.61: “In male mice, finasteride reduced the anticonvulsant effects of progesterone and[/FONT]​

[FONT=&amp]fluoxetine, both of which increase 3[/FONT] α[FONT=&amp],5[/FONT] α[FONT=&amp] -THP levels (discussed above),”[/FONT]​

[FONT=&amp]if I understand this correctly finasteride (in male mice) reduces progesterone (and subsequently also lover THP)[/FONT]​

[FONT=&amp]p. 62: “…one can surmise[/FONT]
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[FONT=&amp]that finasteride would decrease levels of androsterone and etiocholanolone” (remember the picture on page 55)

[/FONT]
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[FONT=&amp]4.) so my worry is, that finasteride “mess-up” the brain neurosteroids. And those are rather important: “[/FONT]Neurosteroids are brain chemicals. Unlike most of the body's potent steroids, which are made in the sex glands, neurosteroids are only synthesized in the brain. Neurosteroids are known to be involved in behavior, stress, memory, depression, anxiety, aging of the brain, and neurodegenerative diseases” (http://scienceblog.com/community/older/1999/A/199900072.html)
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Like THP (allopregnanolog) it deficit is found in some neurological disorders (not sure if there is causation): Allopregnanolone aids neurogenesis and has been found to reverse neuron proliferative deficit and cognitive deficits in mouse model of Alzheimer's disease (http://en.wikipedia.org/wiki/Tetrahydroprogesterone).​

biosynthesis of allopregnanolone starts with the converting of progesterone into 5α-dihydroprogesterone by 5α-reductase type I. After that, 3α-hydroxysteroid oxidoreductase isoenzymes (also referred to as 3α-hydroxysteroid dehydrogenase) converts this intermediate into allopregnanolone. Anxiety and depression are common side effects of 5α-reductase inhibitors such as finasteride and dutasteride, and they are believed to be caused, in part, by the prevention of the endogenous production of allopregnanolone.​

So my fear is NOT erectile dysfunction, depression or anxiety, but the neurological damage. Is this a real concern? Can somebody explain this more in detail? I think they should do some test for that too (OR AT LEAST ONE, there is literrally none existent)..

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5.) and if somebody read my previous post, you know I had my hormones tested (drug free ofc). I have pretty low testosterone, and free test (lower part of reference rage but still in the reference range) but more importantly low DHT (like extremely low 3x less than minimal reference range).
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And I had few “interesting” symptoms for past year – dizziness (feeling drunk for past 6 months, it stopped in November – had MRI and CT scans, came negative), depression and anxiety, now it started low libido and no morning wood. And I think I could correlate those with low DHT. Will see what my doctor says​

so i am eager to see what everybody else thinks and hope to lear somethnig new

p.s. english is not my mother-language, so expect typos

sorry for long thread, could not get shorter

NOTE: some of the actual studies on the finasteride and neurosteroids are on page 2

 

[TheEscapist]

I've been trying to figure this out as well. I would like to know if it could cause neurological damage. That's one of the man things I want to know before trying it again.

 

[Cob984]

There are so many potential propecia problems it absolutely amazes me how casually its dished out to everyone,

not saying propecia is evil , its not, it just needs more care when prescribed

 

[to the lost]

well I talked today with my GP.. and she said that hormones are not the first thig to look at when considering neurological deseases - ofc the are not, they search for demyelinization or smth simillar - just wanted to think outside the box here. (but i also found some articles that - although the cause is unknown - it says that it has been found low Allopregnanolone levels in brain in some cases). so who can i belive?

for me, it is undoubtedly logical, that if you use something that inhibits 5-alpha reductase (also from progesterone to dyhidroprogesterone you end up with less alloprenanologe). don't wan't to cause panic or anything, just want to be sure.

and i cannot find sigle study for this. and it should be a priority. or am i having just so verry "off" my scientific logic..

p.s. i will go to endocronologist too, but in our coutry there are long waiting periods. so if somebody is going to endo (for whatever reason) plese just mention this (just low DHT and low neurosteroid and it's consequences). it would be great help

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TheEscapist @ can i ask why did you go off in the first place?

Cob984 @ yeah, my dermatologist laught at me when i sugested to take hormone check before taking a fu*ing hormone pill

and i am not having any luck with my threds here neither lol they are beeing greatly ignored. not sure why though. like some threds get 2-3 pages of replys, my threds (both) got like 2 comments (but gretly appriciated you two ). . i am new here and alredy unpopular LOL high school all over again

 

[Cob984]

this website is just very inactive in general, see hairlosshelp or the ********* for a more active discussion

 

[boobyinspector]

I think this has been discussed to death. Finasteride shouldn't cause problems because it's 5-ar-1 that is used to convert to neurosteroids and it blocks 5-ar-2 leaving 5-ar-1 alone and mostly leaving 5-ar-3 alone. Now there's some new research showing that DHT itself may act as a neurotransmitter in the brain, but this is still fresh research. This is the only way it could really cause problems.As far as DHDOC and DHP go either 5-ar can be used. Now some people may produce less 5-ar-1 enzyme in either specific regions or plasma, so they may be more at risk, no doubt about it. This could account for high variability in symptoms. But a lot of finasteride is metabolized to an active metabolite which is only 30% as active as the main drug. There really hasn't been much research on its metabolites. There are A LOT. Your liver basically massacres this drug.

 

[to the lost]

thanks for the reply. the 5-ar-2 is bloced more, yes (but i think it bloks 5-AR-1 also). anyway, iif i remember correctly, 5-AR-1 is the "main" AR for conversion from progesterone --> DHP, not sure for DHT though.

and if this is correct: ”[FONT=&amp] In summary, preclinical studies with[/FONT]

[FONT=&amp]finasteride and other drugs that alter 3[/FONT] α[FONT=&amp],5[/FONT] α[FONT=&amp] -THP biosynthesis support a role for endogenous[/FONT]​

[FONT=&amp]3[/FONT][FONT=&amp]á[/FONT][FONT=&amp],5[/FONT][FONT=&amp]á[/FONT][FONT=&amp]-THP in maintaining normal GABAergic brain function, and suggest that alterations[/FONT]​

[FONT=&amp]in endogenous 3[/FONT][FONT=&amp]á[/FONT][FONT=&amp],5[/FONT][FONT=&amp]á[/FONT][FONT=&amp]-THP levels could contribute to symptoms of anxiety and[/FONT]
​

[FONT=&amp]depression”

then finasteride should NOT have had any effect (why would it mess with THP, metabolite of DHP and progesterone, if 5-AR-1 is not affected by finasteride). or did i misunderstood something?

if you can give me a study from your last claim (DHT as neurotransmitter) it would be greatly appreciated or some forum or somethnig..
[/FONT]

 

[boobyinspector]

My guess is that it's doing it through some other means such as its metabolites. There's at least 4 metabolites that they have detected. These may act completely different. The same happens in the world of psychopharmacology where something like bupropion the active drug is a powerful dopamine reuptake inhibitor yet most of it converts to hydroxybupropion which does some DAT inhibition but mostly does norepinephrine transporter inhibition. So there you have a completely different mechanism from the metabolite of the main drug.

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As far as the study, I think I read it in some paper discussing the study I didn't actually see it, but I did find a study at least showing dihydrotestosterone proponate implicated in neurotransmitter turnover in the medial prefrontal cortex:

Androgen inhibits neurotransmitter turnover in the medial prefrontal cortex of the rat following exposure to a novel environment snip....... these data suggest that, in the MPFC of male rats, androgen and estrogen receptors act in an opposing fashion to modify neurotransmitter turnover. This suggests that local changes in the relative levels of androgen and estrogen can have profound effects on the neurobiological response of the medial prefrontal cortex to stimuli

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The problem is no one is studying the metabolites of finasteride, it's like they don't really care. At least with psyche drugs there's a bit more info on some of this stuff.

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I suggest if you are worried pair your fina with Zoloft:

SSRIs (antidepressants like Zoloft) have been shown to upregulate levels
of progesterone and allopregnanolone (THP) [PMID 12957330] as well as
neurogenesis [PMID 14872203, 15001810, 14512209]

 

[to the lost]

yeah that was my main complain - it would be a LOT easier is there was at least one study for metabolites of finasteride.. it is not like there was no time for that (the drug is like 2 decades out)..but, as i said, i do NOT want to cause panic, just thought to see if somebody knew more on this subject

for the last part of the reply - and i will now sound like so ungrateful - but i think you are wrong. I do not think you can just "pair fina with zoloft". the mechanism of action is different (did not research zoloft, but i assume) and like zoloft is an anti-depressant and anti-anxieity, propecia side effect are just those two (among others). But it would be also wrong to say that propecia does just oposite from zoloft, if they have different mechanism of action. It would have to be an AR inhibitor to compare (like some other medicine where there were test for matabolites)

 

[boobyinspector]

Well, I take Zoloft and I have no issues Granted I was taking it before I started propecia. I consider myself lucky as I never get side effects from meds.

 

[to the lost]

yeah me neither.. but wen i saw i had low DHT i took one step back and did not jump on finasteride right away..

well, for the topic, i foud some studies for finasteride and neurosteroids (will go through it tomorrow) here it is, if somebody is intrested (not it has been done on mice, mot humans). http://www.ncbi.nlm.nih.gov/pubmed/18758053

"The animal study using these methods demonstrated that finasteride dose-dependently inhibits the stress-induced elevation of the brain AP, a potent positive modulator of the gamma-aminobutyric acid (GABA) type A receptors, and a 10 mg/kg dose of finasteride can almost completely deplete AP in the brains. The study also found that the 20alpha-reduction of PROG is enhanced when its 5alpha-reduction pathway is inhibited in the brains. No change was found in the brain levels of 3alpha-DHP, another GABAergic neurosteroid, and Doctor by the administration of finasteride."

2.) http://www.semel.ucla.edu/publicati...ole-neurosteroid-allopregnanolone-ethanol-ind

"However, despite an approximately 99% decrease in whole brain allopregnanolone content, finasteride pretreatment had remarkably little effect on either ethanol-induced conditioned place preference or ethanol-induced c-fos expression"

the 99% reduction in allopregnanolone is like a lot but didn't had time for the whole study, so it could be something missing here

3.) http://joe.endocrinology-journals.org/content/208/3/301.full.pdf

this is not so relevant, i thnik, because it is an experiment on foetuses

4.) http://researchonline.lshtm.ac.uk/19806/

"This effect was prevented by blocking 3alpha,5alpha-reduced neurosteroid synthesis with a 5alpha-reductase inhibitor: finasteride. Immunohistochemistry confirmed that the DNLL blockade induced an increase in 3alpha,5alpha-reduced neurosteroids in the contralateral ICC. This study shows that when GABAergic inhibition is reduced, the brain compensates within minutes by locally increasing synthesis of neurosteroids, thereby balancing excitatory and inhibitory inputs in complex neural circuits."

5.) http://www.unboundmedicine.com/medl...escence_and_prepulse_inhibition_in_adulthood_

6.) and the last i could find - mother of all evidence lol and i assume the reason that finasteride got the "depression" side effect label - http://www.ncbi.nlm.nih.gov/pubmed/20486040

"The 5-alpha-reductase inhibitor finasteride is used for the treatment of androgenic alopecia, benign prostate hyperplasia and prostate cancer. Besides inhibiting the conversion of testosterone to the biologically more active 5alpha-dihydrotestosterone, it also inhibits the production of neurosteroids. Decreased neurosteroid levels are postulated to be involved in the pathophysiology of psychiatric disorders such as depression."

feel free to coment and if somebody finds other studies, please share...

 

[boobyinspector]

Interesting rat study. It's confusing because the brain primarily uses 5-ar-1, so it would mean either finasteride or one of its metabolites inhibits 5-ar-1. One thing that should be noted is there is some correlation with finasteride lowering levels of DHEAs. So this could be the mechanism by which AP falls. If you look at the full study they have some nice graphs with the AP. Even at 0.5mg they show it much lower than saline during stress tests, which is when AP increases and is usually pretty much at 0 during times of no stress. Coincidentally the same thing happens with DHEAs, so there may be a correlation. I happen to take DHEA 25mg/day just in case. It's not high enough to cause any estrogen issues but high enough to provide a little extra if needed to manage cortisol or other stress factors.

 

[to the lost]

a few more studies

1.) a.) another behevioral effect of alloprenanolone http://www.ncbi.nlm.nih.gov/pubmed/23294582

Moreover, intrahippocampal ALLO increased head-dipping behaviour independently of the neonatal treatment, while intrahippocampal ALLO decreased PPI only in finasteride and ALLO groups. The results obtained in the present study indicate the importance of neonatal neurosteroid levels in the development of hippocampal function and their relevance in a behavioural phenotype that some have likened to that present in schizophrenia

b.) another evidence that finasteride could be blocking the 5AR-type 1. (it is an assumption, because it says that low allopregnanolone could cause anxiety - also a potential finasteride symptom)

These results demonstrate that in response to emotional stimuli, allopregnanolone reduces activity in regions associated with generation of negative emotion. Furthermore, allopregnanolone may enhance activity in regions linked to regulatory processes. Aberrant activity in these regions has been linked to anxiety psychopathology. These results thus provide initial neuroimaging evidence that allopregnanolone may be a target for pharmacologic intervention in the treatment of anxiety disorders and suggest potential future directions for research into neurosteroid effects on emotion regulation neurocircuitry.

2.) on Alzheimer's disease - don't think it is so relevant, but I have mentioned AD in previous post so.. (did not quite understand if "defect" of neuroblastoma SH-SY5Y cell is the ONLY cause - as far i understand, AD attack this cell and the production of neurosteriods is decreased.) http://content.karger.com/ProdukteD...bstractBuch&ArtikelNr=339189&ProduktNr=257028

"AD pathogenic factors may therefore induce neurodegeneration by decreasing in nerve cells endogenous production of neuroprotective neurosteroids"

b.) on MS http://www.sciencedirect.com/science/article/pii/S0306987710000939

Progesterone derivatives seem to act as promyelinating factors in the slow but continuous process of myelin maintenance in the adult human brain. Diminished production of these myelin-promoting factors may lead to the formation of structurally altered and less stable myelin

3.) "Therefore, the attention of biomedical research has been recently addressed in evaluating whether neuroactive steroids, such as progestagens, androgens and estrogens may also affect neuroinflammatory pathways. Observations so far obtained suggest a general anti-inflammatory effect with a beneficial relapse on several neurodegenerative experimental models, thus confirming the potentiality of a neuroprotective strategy based on neuroactive steroids"

http://jme.endocrinology-journals.org/content/early/2012/09/10/JME-12-0127.short

and

http://www.ncbi.nlm.nih.gov/pubmed/8840083

so clearly the neurosteroids are correlated with protection WHEN the inflammation occurs, but could they be the cause of some of the deseases? (probablly it is not so simple or the would be already a cure, but just to be sure)

4.) more on finasteride and neuroactive steroids

a.) http://pmr.cuni.cz/Data/Files/PragueMedicalReport/pmr_110_2009_03/pmr2009a0025.pdf (verry useful, p. 227 show actual decrease in neurosteroids)
b.) http://fens2010.neurosciences.asso.fr/abstracts/r1/a011_55.html

that it for now. any replies are welcome

 

[Fanjeera]

There are two studies out already that show how allopregnanolone drops with finasteride in humans. Why bother with the rat ones?
Here's one I already brought up in the muscle twitching thread: http://www.lf1.cuni.cz/Data/Files/PragueMedicalReport/pmr_110_2009_03/pmr2009a0025.pdf
The other one was done with 1 mg and the results were the same: allopregnanolone dropped.
Therefore, finasteride can cause depression and, of course, difficulties in studying and mind flexibility. Isn't this already mentioned on the leaflet?

 

[boobyinspector]

Here's a study showing DHEA increases allopregnanolone. http://www.sciencedirect.com/science/article/pii/S0015028204032194

DHEA administration induced an increase in allopregnanolone and β-EP content in hippocampus, hypothalamus, and anterior pituitary and in serum or plasma.

Granted it's not in humans but i'll post them if I come across any. I already take 25mg dhea every morning along with my finasteride.

 

[to the lost]

Fanjeera @ yeah, I posted that study on allopregnanolone (czech study). But this tread is a progression, I started with limited knowlegde and I found more and more studies. so it is great that some of other users join in. As you can see i posted some studies that show some importance of that neurosterid.

boobyinspector @ great contribution. can i ask you something. you said that you take DHEA. can you explain that (pills, topical, what brand, where to buy)? i'm pretty new on all of that hair loss things..

and what about (unresearched) long term effects? like wikipedia listed them few http://en.wikipedia.org/wiki/Dehydroepiandrosterone

and one more thing. DHEA comes from cholesterol ---> converted to Pregnenolone. and DHEA is "the precursor of androstenedione" (says wikipedia http://en.wikipedia.org/wiki/Pregnenolone). But allopregnanolone (THP) comes from dehydroprogesterone (by 5-AR reductase type 1). How can one elevate the other?


p.s. why is this thread in section "DEALING WITH SIDE EFFECTS"? we are not dealing with sides, or are we? and why is it moving so much, i have hard time finding it.

 

[Admin]

As I understand it from the first post, this thread is discussing adverse effects of Finasteride on the human body.

Admin

 

[boobyinspector]

I get natrol brand from vitaminlife at 25mg 300 pills for like 25 bucks. It's dirt cheap and lasts almost a year. A lot of people believe there is a danger of dhea being converted to DHT but that rarely happens as it is used directly in tissues once the sulfate is removed. It increases IGF-1 which could help finasteride work better. There was a study showing that people who responded better to finasteride had higher IGF-1 levels. DHEA itself can bind to gaba receptors taking the place of allopregananolone. It's possible as a result the allopregnanolone that is available is used elsewhere rather than more spread out. It's also quite possible that we are not aware of a lot of functionality within the brain since well we know very little about it and constantly discover new things. Here's the info about igf-1 and finasteride:

The expression of insulin-like growth factor 1 in follicular dermal papillae correlates with therapeutic efficacy of finasteride in androgenetic alopecia. snip.... [h=4]CONCLUSION:[/h]In a small uncontrolled study of 9 patients with Androgenetic Alopecia, an increased expression of IGF-1 messenger RNA levels in the DP was associated with patient response to finasteride.

Not a huge study but still interesting nevertheless. http://www.ncbi.nlm.nih.gov/pubmed/12894070

 

[WhereDaHair]

I do wish this thread stayed in the main room. I think it's really important and deserves more traffic.

I've seen a lot of threads in the main room that could have been moved but weren't. I say this with respect though as I think the forums are very well run here. Just wondering if it could be reconsidered to be back in the main room...

 

[to the lost]

As I understand it from the first post, this thread is discussing adverse effects of Finasteride on the human body.

Admin

hm, well it is a "speculative" side effect (did not hear for not a single case of finesteride induced neurodegenerative disorder), nor it is a official side effect. just "brain storming" here (and making my doctors life hard lol)

PLUS like WhereDaHair said, i think that here it would be overseen. I am hoping for more traffic, so maybe there would be more replys (for now only boobyinspector and I have posted some studies, and I know i can not do it alone - my knowlede is far too incomplete)