Gut Inflammation Induced by Finasteride Withdrawal: Therapeutic Effect of Allopregnanolone in Adult Male Rats. Melcangi, 2022

Gut Inflammation Induced by Finasteride Withdrawal: Therapeutic Effect of Allopregnanolone in Adult Male Rats
by Silvia Diviccaro,Silvia Giatti, Lucia Cioffi, Eva Falvo, Monika Herian, Donatella Caruso and Roberto Cosimo Melcangi *
Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano, Via Balzaretti 9, 20133 Milan, Italy
*Author to whom correspondence should be addressed.
Academic Editor: Monique Vallée
Biomolecules 2022, 12(11), 1567; https://doi.org/10.3390/biom12111567

Received: 23 September 2022 / Revised: 21 October 2022 / Accepted: 22 October 2022 / Published: 26 October 2022

Abstract

The treatment with finasteride (i.e., an inhibitor of 5α-reductase) may be associated with different side effects (i.e., depression, anxiety, cognitive impairment and sexual dysfunction) inducing the so-called post finasteride syndrome (PFS). Moreover, previous observations in PFS patients and an experimental model showed alterations in gut microbiota populations, suggesting an inflammatory environment. To confirm this hypothesis, we have explored the effect of chronic treatment with finasteride (i.e., for 20 days) and its withdrawal (i.e., for 1 month) on the levels of steroids, neurotransmitters, pro-inflammatory cytokines and gut permeability markers in the colon of adult male rat. The obtained data demonstrate that the levels of allopregnanolone (ALLO) decreased after finasteride treatment and after its withdrawal. Following the drug suspension, the decrease in ALLO levels correlates with an increase in IL-1β and TNF-α, serotonin and a decrease in dopamine. Importantly, ALLO treatment is able to counteract some of these alterations. The relation between ALLO and GABA-A receptors and/or pregnenolone (ALLO precursor) could be crucial in their mode of action. These observations provide an important background to explore further the protective effect of ALLO in the PFS experimental model and the possibility of its translation into clinical therapy.

Keywords: pro-inflammatory cytokines; serotonin; dopamine; gut steroids; pregnenolone; GABA-A receptor; post-finasteride syndrome

full text https://www.mdpi.com/2218-273X/12/11/1567/htm

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Is there any way to increase allopregnanolone? I think that all these sensations of inflammation that many of us feel that come and go, that have better and worse days come from this decrease in allo. One other thing I would like to know, is there a blood test to identify our allo levels?

There is a drug named Zulresso (Brexanolone), but it is only available in the US for post-partum depression…

you can get allo from idealabs i use 1mg every other day

How u feel? What your symptons?

its helped with everything except sexual sides at the moment . i sleep 8 hours ,no anxiety, better mood, seems to help thyroid too as temps are higher and digestion has got a lot better … which i guess is what this study is saying too.

i found if i use too much though it can be to much sedation and lowers sex drive but thats normal from a potent gaba agonist . so i just had to find my sweet spot .

also when i say sexual sides i mean libido and wanting sex but i guess this is more a dopamine thing

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do you feel pain your body, muscle loss, weakness?

i still have some muscle weakness but it is a lot better than it was i used to not be able to ride a push bike more than few hundred meters as my legs would be so sore , now i can ride to work and unless its really windy or have to go up hills my legs feel fine

i have not been to the gym in awhile so can not answer on muscle building but its on my to do list for the new year

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SAGE therapeutics recently re-did its phase 3 trials for oral allopregnanolone (zuranolone) for use in depression after failing in late 2019 due to subject non-compliance. they say the trial met primary and key secondary endpoints and they will be applying for NDA fairly soon. Will hopefully be available off-label to test out in PFS patients in next couple years but these things can be disappointing.

https://investors.biogen.com/news-releases/news-release-details/sage-therapeutics-and-biogen-announce-phase-3-skylark-study

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Have you noticed any improvement of anhedonia and flat emotions (assuming you were suffering from them initially)?

Sage Therapeutics tried to get the PFS Foudation to run a trial of allopregnenolone back in 2015 for PFS. I specifically remember Dr Santman telling me that then. He did not feel it would do enough to alleviate symptoms so they opted against it.

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They need to get on this immediately. Bad move w Dr Santman.

I don’t think this is accurate

Hindsight is 20/20. I do not post this to bash him as he has done more than 99% of us have to further research on this issue. However, the reality is that he told me in a phone conversation in 2015 that a pharmaceutical company that was branding allopregenenolone reached out to the foundation with interest in trialing it for PFS. He told me directly he did not think it would be that beneficial and they were likely going to opt against it. Maybe he was right to put focus elsewhere? We really won’t know for years to decades.

The big question is whether the low allopregnanolone level is the driving mechanism of the persistence of PFS symptoms, or whether persisting low allopregnanolone levels are merely a consequence of a mechanism we do not know.

Of course we know allo has important functions, and possibly some of PFS symptoms could be at least partially relieved by it’s supplementation.

Very important findings nonetheless.

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Well depressed people have low allo and they generally don’t get numb or shrinking genitals.

Still it might be good to alleviate symptoms. I also find the use in post partum depression interesting as they use it only for a short time, but the positives stay.

My guess is that the allo the woman get persistently changes other enzymes, kinda like we know fin does, but in another direction.

As a matter of fact, during development many processes in the body are started by one hormone “spiking”. Like it starts the fire, and then you only have to keep adding fuel to the fire.

With fin we kind of put our fire out, and for us with PFS it seems like it won’t start again even though we keep adding fuel.

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this is true

suppressed allo production is not enough to explain all of the symptoms of PFS

there will be multiple other factors that caused and mechanistically created PFS

won’t figure out PFS without thinking in higher and more dimensions

I just don’t think this right. You might have misunderstood or maybe this was based on bad and old information.

My understanding is that SAGE would not even grant allopregnanolone to PFS patients for compassionate use. It was their right to do so, and I understand why they wouldn’t want to risk the nature of their clinical trials bc PFS is such a relatively rare and misunderstood situation, but I’m pretty sure they would have wanted to get access to allo to try with PFS patients if that were possible.

Could Allopregnanolone be a cure for PFS or is it just something that helps ?

No. I’ve also taken SAGE-217 during the clinical trials, and it did nothing.
It is NOT an allop analogue, though.

Obviously PFS is a multi-face issue, you can fix one issue but another will be there. I don’t think there’s a central origin that’s causing all the symptoms. However, this study once again shows gut (colon, in this case) changes.

Every recovery you’ll find, changed their diet/lifestyle. It’s obvious we can get a lot of traction when modifying the gut. I don’t think a “cure” will be one drug, it’ll be a series of treatments/therapies.

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