#146

The case for terazosin is strong. But yes, it doesn’t mean that 5-ARIs are neurotoxic. And yes, they can be combined.

1 Like
#147

Yes, and it does so more potently, so the expectation is greater selectivity than finasteride for non-5AR targets.

which causes the anxiety-ridden redditors to nocebo themselves into experiecing all sorts of side effects.

This sounds very biased. Nocebo may be true in some cases, but it’s a stretch to assume that everyone getting sides from finasteride has an anxiety disorder. Also, someone who nocebo’d themselves with finasteride wouldn’t be expected to improve with a stronger 5ARi if they believed that androgen antagonism was causing the sides, which is what most people believe.

This is based on ex-vivo and animal studies using high doses of finasteride and dutasteride would certainly also cause that effect due to also inhibiting 5ar2 and 5ar3.

Finasteride was shown to inhibit hPNMT, and this is a 5AR-independent mechanism. Although the in vitro potency was very low (which doesn’t discount this mechanism contributing to sides, although it does make it less likely), there’s no evidence that dutasteride also inhibits PNMT.

1 Like
#148

This sounds very biased.

If you have been around on reddit for long enough, you know the type of people that hang out there. Just check out the profiles of various people.

Nocebo may be true in some cases, but it’s a stretch to assume that everyone getting sides from finasteride has an anxiety disorder.

The true incidence of side effects is 2-3%. above placebo. That equals roughly 1 in 50 people. And if you count both placebo incuded and finasteride induced side effects, the incidence is as high as 1 in 25 or even higher.

Also, someone who nocebo’d themselves with finasteride wouldn’t be expected to improve with a stronger 5ARi if they believed that androgen antagonism was causing the sides, which is what most people believe.

The amount of anecdotes from people who don’t experience side effects from dutasteride but do from finasteride is pretty low on reddit. There are more anecdotes of dutasteride absolutely destroying their hair which studies also do not support at all.

Finasteride was shown to inhibit hPNMT, and this is a 5AR-independent mechanism.

I am reading through the study in question right now. First they used a novel computer simulation model to figure out possible binding interactions of finasteride. This is fairly abstract and not necessarily real.

Although the in vitro potency was very low

According to my GPT, the serum concentrations of 1mg finasteride in adult humans is 0.025µM compared to 50µM used in the in vitro study. So that is still a rather high finasteride concentration and the PNMT inhibition was still only half of that of a selective PNMT inhibitior (30%).
The same applies to the Sprague-Dawley rat model, which were fed 1mg/rat/day. And it is questionable whether the effect would translate to an actual human being. For example, finasteride in humans is not selective to 5ar1 while it is in mice.

Overall too much mechanistic speculation without much data in humans. We know that dutasteride has about the same if not slightly lower side effect profile as finasteride, but if this PNMT inhibitory effect was significant enough in humans, it would translate to a much different side effect profile, unless dutasteride’s off-target effect or selective 5ar1 compensated for that.
Also, the lack of studies on dutasteride and PNMT inhibition does not necessarily imply that it does not do so.

To add to that, there is no evidence that finasteride nor dutasteride have an effect on the progression of AD or other neurodegenerative diseases in high risk groups who could be impacted by PNMT inhibition.

This study feels like it is grasping at straws to prove any kind of mechanistic connection between finasteride and side effects.

#149

I experience side effects from finasteride. If I take 5 mg daily, it causes depression for me. I can take it twice a week without any (noticeable) side effects though. I am switching to dutasteride this summer to avoid any problems with finasteride.

2 Likes
#150

I am reading through the study in question right now. First they used a novel computer simulation model to figure out possible binding interactions of finasteride. This is fairly abstract and not necessarily real.

Although the in vitro potency was very low

According to my GPT, the serum concentrations of 1mg finasteride in adult humans is 0.025µM compared to 50µM used in the in vitro study. So that is still a rather high finasteride concentration and the PNMT inhibition was still only half of that of a selective PNMT inhibitior (30%).
The same applies to the Sprague-Dawley rat model, which were fed 1mg/rat/day.

The computational approach provides evidence that the inhibition is competitive (i.e not allosteric). This is actually important information because they used a supraphysiological concentration of norepinephrine/substrate for their assay (probably to increase the sensitivity), which will make the inhibition from a competitive inhibitor look weaker than it actually is.

The physiological concentration of norepi is 0.5uM-5uM, whereas they used a concentration of 125uM, meaning that their substrate concentration was potentially ~250x the physiological one. If you play with the Michaelis-Menten equation, you’ll see that increasing the substrate concentration by 250x will also increase the IC50 by ~250x.

I fitted their approximate data points to a logistic curve which gave an IC50 of 100uM, which corresponds to an ‘in vivo IC50’ of 0.4uM (100/250), which isn’t far off from the serum concentrations. This approximation assumes that finasteride only competes with the binding of norepi, whereas from the figures it competes with both substrates. That situation still leads to a significantly larger IC50 than the ‘in vivo IC50’, but the exact fold difference is more complicated to determine. Just playing around with the numbers is fun sometimes, don’t take it too seriously.

Screenshot 2025-01-09 at 8.23.18 PM
Screenshot 2025-01-09 at 8.23.18 PM896×388 48.1 KB

Also, the lack of studies on dutasteride and PNMT inhibition does not necessarily imply that it does not do so.

Sure, but due to the bulkier substituent on dutasteride’s amide nitrogen steric hindrance might be an issue with fitting into the binding site.

2 Likes
#151

And I had all sorts of side effects on dutasteride while having none on finasteride. The studies show a similar side effect profile though.

2 Likes
#152

And then there is a question of how much of the free, unbound serum finasteride (~10% of serum finasteride) crosses the BBB and concentrates in the cerebrospinal fluid. Imo to actually potentially have a significant impact one would have to take much higher doses than the standard 1mg one.

2 Likes
#153

I posted my stack there. Feedback welcome (here or there):

6 Likes
#154

I wish you a lot of strength!

2 Likes
#155

A warning about side effects of finasteride on BBC.com :
Finasteride: Hair loss drug was 'biggest mistake of my life'

3 Likes
#156

From the article: “It’s just a little pill. You take it and don’t really think about what it can do to you,” he says. "Every day I beat myself up saying like ‘You had a perfect life, you didn’t have to risk something over hair’.
"It was vain of me…but when you get insecure you do stupid things.
“If I were made aware of what it can do I never would have took it.”

And, maybe this is true - just like some people on rapamycin have horrible physiological responses.

On the other hand - I too started the little blue pill for hair loss at at 33 years or so - I will be 67 years in a few months, so about 34 years of constant use. Still have my hair - but also a very - very small prostate and possible cholesterol clearing from research-- coronary calcium score of zero - heart of someone under 35 years. No libido or ED issues - at 67 years. I read - that whatever age you are - that percent of the male population has ED issues at 40 years 40% – at 50 years 50% - I guess 67% - lol.

The point is many have benefited from this medication in many ways - and some have seen no effect - and some have bad effects. That’s how your physiology reacts to material introduced into the body. In most cases - stop the medication and the side effects vanish - like with rapamycin. Could be other issues. Or, maybe not.

2 Likes
#157

Personal anecdotes on trash media are not even listed on the pyramide of evidence.
Google “reddit X ruined my life” for any substance X known to man and you will find a horror story.
Depression, ED, low libido and various other conditions do naturally occur in men over the age of 20 at ever-increasing rates. As the FDA stated, there is no evidence that finasteride causes any permanent or prolonged side effects after cessation despite a decade of the PFS Foundations attempts to sue Merck.
Or perhaps I am just invincible because I am triple-vaccinated, take finasteride, statins, tirzeptatide etc. and haven’t even died once.

4 Likes
#158

Antoine - not sure if this is helpful. But while checking benefits of estradiol from my last blood test, I came across this information - about Parkinson’s Disease.

Estrogens appear to have a protective effect on neurodegenerative disorders characterized by major cognitive dysfunctions, including Parkinson’s disease and Alzheimer’s disease.

Link: The Role of Estrogen in Men’s Health

4 Likes
#159

Yes - keep in mind the pyramid of evidence:

PXL_20241206_230902184-3
PXL_20241206_230902184-33435×1935 266 KB

6 Likes
#160

Dear @RapAdmin,

I would be very pleased if all n=1 “trials” and reactions would be excluded from this forum and we as forum participants would be limited to contributions that have either a sound theoretical basis and/or a sound experimental basis. And of course test results or info about diseases or adverse effects that participants are willing to share.

1 Like
#161

That would take far more moderation time than I’m willing to devote here. Ultimately all of our experiences here are n=1, and while they hold minimal value from a scientific standpoint perhaps over time they can provide some sort of signal that can be investigated by our researcher friends, which is when the real value is derived.

7 Likes
#162

You’re right I think some papers showed neuroprotective effects of 17b-estradiol in animal models of PD. But I don’t know if that’s also the case for 17a-estradiol. I’ll have to do more research on that :nerd_face:

2 Likes
#163

What a surprise, the guy mentioned in the BBC article had a reddit account where he mentioned taking finasteride again (despite allegedly suffering from PFS from taking finasteride over a year ago), was very active on the minoxidil side-effects subreddit and is also an anti-vaxxer.

1 Like
#164

BBC are the culprit. They would have paid no attention to the guy if they weren’t looking for a way to do a hit piece on it. Probably could have picked a better guy too.

2 Likes
#165

Was your lp(a) high pre statin? My lp(a) doubled slowly over time when I started a statin. I had always been told I had great lipid numbers, but my cholesterol began to increase from a pretty steady 165 up to my age of mid 60s. Once cholesterol got to 200 with estimated LDL about 130 my doctor recommended a statin. I tried diet to no avail. And requested a coronary artery calcium scan. After a lengthy Covid delay, I tested and I thought I would have a great score. I also requested a more accurate test of APOB and of lp(a) to establish a baseline. Then I started a statin and identified the rise in lp(a). I also had my genome decoded by Nebula Genomics and they calculated propensity risk scores for many diseases and conditions using parameters estimated by recent publications. I discovered I have a very high propensity risk score for cardiovascular disease and stroke—having a predicted risk greater than 95% of their sample and in a few cases 99%. Whatever is going on in my body is not due just to lipids — otherwise I would not have had so much arterial calcification after only a few years of inadequate lipids. (If Nebula were still in existence I’d recommend testing with them if only to get the propensity risk scores which can provide some hints about mechanisms.) I recently dropped the statin and added a PSK9 inhibitor (Praluent 75). My lp(a) which had hit the 95th percentile, has been more than cut in half. And my APOB and LDL (APOB more highly predictive of risk than LDL) is in the mid 50’s. Unfortunately the numeric values of lp(a) vary by lab — they aren’t standardized. And all you get from a lab is the identification of the value at the 95th percentile. So hard to say if I have achieved a healthy value of lp(a) or even what percentile it is. (My current age is 77.) I’d be interested in hearing more about your lipid protocol—your rationale and your experience.

2 Likes