FOUND THE CAUSE OF PSSD!!! SEROTONIN - PPARy - nNOS *REVEALED*

This is a place to post research you have done on the topic along with your conclusions.
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JayR
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FOUND THE CAUSE OF PSSD!!! SEROTONIN - PPARy - nNOS *REVEALED*

Unread post by JayR »

ORIGINAL ARTICLE LINK --> https://area1255.blogspot.com/2019/08/n ... -cure.html
The cause of PSSD has had many theories, but I'm going to skip to the chase.
The REASON we CAN'T treat PSSD *(effectively)* is because we are Obsessing on theories that only "HINT" at one point of the problem.
Where does "the point" originate from, though?
I believe I've found the answer...
It lies in PPARy or "Peroxisome proliferator-activated receptor gamma".
--> Serotonin REDUCES PPARy which normally ACTS to INITIATE Androgen Receptor (AR) activities; that's *WHY* we get DOWNREGULATION of androgen receptors with SSRI - because the "nuclear" receptor of PPARy is being downregulated (persistently) by SSRI's - which causes a continual reduction in Androgen Receptor amounts (densities) and activities. SSRI's like Luvox & Prozac "get in the middle" and cut off the "supply and demand" connection to nNOS from the Androgen Receptor - leading to LESS neuronal nitric oxide synthase and *NO* non-contact erections (erections without touch). STUDY --> https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5641178/
--> PPAR stimulates Androgen Receptors and activities --> https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5428145/

5-HT1A & 5-HT1B receptors REDUCE androgen receptors as MESOLIMBO has So Said.
STUDY --> https://www.nature.com/articles/s41598-017-15832-5

5-HT regulates PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA PPAR/PPARy --> https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2957204/

5-HT1A & 5-HT1B receptors do this via THREE pathways...
PPARy reduction --> study --> https://www.ncbi.nlm.nih.gov/pubmed/25937083
Reduction of cAMP (cyclic adenosine monophosphate) --> https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5121227/ cAMP/PKA and Androgen Receptors --> https://www.ncbi.nlm.nih.gov/pubmed/8702703
Reduction of nNOS --> less blood flow --> less Androgen Receptor "food" or nourishment --> https://gut.bmj.com/content/44/2/143

***FORSKOLIN may also PREVENT FLUTAMIDE and other ANTI-ANDROGENS FROM BINDING/WORKING***
STUDY --> https://www.ncbi.nlm.nih.gov/pubmed/9521705

***MORE EVIDENCE***
PPAR is involved in LEVODOPA induced DYSKINESIAS - a "symbol" of how WELL Dopamine works in the FACE less PPARy (IT DOESN'T!!!)
STUDY --> https://www.ncbi.nlm.nih.gov/pubmed/25486547


***GENETICS***
nNOS contributes to STRESS-induced Depression --> https://www.ncbi.nlm.nih.gov/pubmed/17854383
SOME PEOPLE have GENEs that make them have *MORE* or *LESS* neuronal nitric oxide Synthase --> https://www.ncbi.nlm.nih.gov/pubmed/20888049
nNOS is *LOW* in the LOCUS COERULEUS --> https://www.ncbi.nlm.nih.gov/pubmed/15569249

***EXPLORING SCIENTIFICALLY PROVEN APHRODISIACS***
Exploring scientifically proven herbal aphrodisiacs [STUDY] --> https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3731873/

PSYCHOTROPIC DRUGS AND SEXUAL DYSFUNCTION [https://www.ncbi.nlm.nih.gov/pubmed/2645849/]
Format: AbstractSend to
Arch Gen Psychiatry. 1989 Mar;46(3):275-84.
Effects of psychotropic drugs on human erection and ejaculation.
Segraves RT1.
Author information
1
Department of Psychiatry, Case Western Reserve University, Cleveland, OH.
Abstract
Evidence concerning pharmacological effects on human sexuality suggests that dopaminergic receptor activation may be associated with penile erection. Erection also appears to involve inhibition of alpha-adrenergic influences and beta-adrenergic stimulation plus the release of a noncholinergic vasodilator substance, possibly vasoactive intestinal peptide. Ejaculation appears to be mediated primarily by alpha-adrenergic fibers. Serotonergic neurotransmission may inhibit the ejaculatory reflex. An understanding of the neurobiological substrate of human sexuality may assist clinicians in choosing psychotropic agents with minimal adverse effects on sexual behavior and may also contribute to the development of pharmacological interventions for sexual difficulties.

PMID: 2645849 DOI: 10.1001/archpsyc.1989.01810030081011
[Indexed for MEDLINE]
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JayR
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Re: FOUND THE CAUSE OF PSSD!!! SEROTONIN - PPARy - nNOS *REVEALED*

Unread post by JayR »

***EMOTIONS AND MOTIVATION***
Dopamine D1 Receptors INCREASE Emotions & Emotional Motivation --> https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2809781/
Jaxx
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Re: FOUND THE CAUSE OF PSSD!!! SEROTONIN - PPARy - nNOS *REVEALED*

Unread post by Jaxx »

Good to see you are looking into pssd again Jay!
pii
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Re: FOUND THE CAUSE OF PSSD!!! SEROTONIN - PPARy - nNOS *REVEALED*

Unread post by pii »

What happend to the Cure ? told pepole u have if they donate money to you https://area1255.blogspot.com/2018/10/t ... l.html?m=1
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TalkingAnt
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Re: FOUND THE CAUSE OF PSSD!!! SEROTONIN - PPARy - nNOS *REVEALED*

Unread post by TalkingAnt »

Interesting studies, thanks. But I don't think you have interpreted them correctly.

PPARy is a nuclear receptor (on surface of cell nucleus) with many ligands. It is basically a "nutrient detector" because it binds to various fats, etc, and influences cellular metabolism. What that one study found is that 5-HT receptor activation reduces a protein kinase GSK-3B. GSK-3B normally degrades a protein β-catenin involved in gene transcription. Without β-catenin degradation, it builds up. This build up reduces the number of PPARy receptors. So the effect is something like:
Too much 5HT -> Too little GSK-3B -> increased β-catenin -> reduced PPARy
With less PPARy, cell proliferation of cancer is a bigger risk. As far as the relevance to PSSD, it could mean that if serotonin levels are consistently elevated throughout the body, the risk of cancer is higher. It is not clear how high serotonin levels have to be to have this effect. This study blasts heart muscle cells with tons of serotonin so it might not be clinically relevant in the body or brain.

In another study you posted, they show "PPARy coactivator 1a" aka PGC-1a is also a coactivator of the androgen receptor. PGC-1a is not the same as PPARy. PPARy is a receptor, while PGC-1a is a coactivator (similar to a ligand). PGC-1a can bind to PPARy in a certain way that effects gene transcription. It turns out that PGC-1a can bind to AR and cause downstream genetic effects even in the absence of androgen hormones. More interestingly, if there is a lack of PGC-1a, then androgens have less of an effect. This could be one mechanism of androgen insensitivity that is postulated in PFS, PSSD, etc. In PSSD and PFS, androgen levels are often unchanged, yet people feel less of an effect from them. If PGC-1a production is somehow lowered, it could explain that. The problem with this theory is, low PGC-1a would probably have many effects on cellular metabolism that are not typical symptoms of PFS, PSSD. Also, PGC-1a expression is increased by exercise, hot and cold exposure, and NO, among other things.

Anyway so IMO what is "new" here is the protein PGC-1a and how it's reduction might effect androgen signalling. It is not clear if the PPARy receptor is involved in PSSD symptoms.
Cured | PSSD 2012-2020 | Log thread
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JayR
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Re: FOUND THE CAUSE OF PSSD!!! SEROTONIN - PPARy - nNOS *REVEALED*

Unread post by JayR »

TalkingAntColony wrote:Interesting studies, thanks. But I don't think you have interpreted them correctly.

PPARy is a nuclear receptor (on surface of cell nucleus) with many ligands. It is basically a "nutrient detector" because it binds to various fats, etc, and influences cellular metabolism. What that one study found is that 5-HT receptor activation reduces a protein kinase GSK-3B. GSK-3B normally degrades a protein β-catenin involved in gene transcription. Without β-catenin degradation, it builds up. This build up reduces the number of PPARy receptors. So the effect is something like:
Too much 5HT -> Too little GSK-3B -> increased β-catenin -> reduced PPARy
With less PPARy, cell proliferation of cancer is a bigger risk. As far as the relevance to PSSD, it could mean that if serotonin levels are consistently elevated throughout the body, the risk of cancer is higher. It is not clear how high serotonin levels have to be to have this effect. This study blasts heart muscle cells with tons of serotonin so it might not be clinically relevant in the body or brain.

In another study you posted, they show "PPARy coactivator 1a" aka PGC-1a is also a coactivator of the androgen receptor. PGC-1a is not the same as PPARy. PPARy is a receptor, while PGC-1a is a coactivator (similar to a ligand). PGC-1a can bind to PPARy in a certain way that effects gene transcription. It turns out that PGC-1a can bind to AR and cause downstream genetic effects even in the absence of androgen hormones. More interestingly, if there is a lack of PGC-1a, then androgens have less of an effect. This could be one mechanism of androgen insensitivity that is postulated in PFS, PSSD, etc. In PSSD and PFS, androgen levels are often unchanged, yet people feel less of an effect from them. If PGC-1a production is somehow lowered, it could explain that. The problem with this theory is, low PGC-1a would probably have many effects on cellular metabolism that are not typical symptoms of PFS, PSSD. Also, PGC-1a expression is increased by exercise, hot and cold exposure, and NO, among other things.

Anyway so IMO what is "new" here is the protein PGC-1a and how it's reduction might effect androgen signalling. It is not clear if the PPARy receptor is involved in PSSD symptoms.
Good point! But still stands as a direct connection for the same reasons you stated...
tonyareias
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Re: FOUND THE CAUSE OF PSSD!!! SEROTONIN - PPARy - nNOS *REVEALED*

Unread post by tonyareias »

Differential effects of serotonin reuptake inhibitors on erectile responses, NO-production, and neuronal NO synthase expression in rat corpus cavernosum tissue.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1573043/
While high levels of dopamine are related to promoting sexual function, high levels of serotonin, in general, are thought to inhibit sexual behaviour
The interference of paroxetine with the catalytic activity of NOS could be related to the reported ability of this agent to inhibit, potently, the activity of cytochrome P450 isozymes
nNOS has many other physiological functions, including regulation of cardiac function and peristalsis and sexual arousal in males and females
Image

Paroxetine is a novel nitric oxide synthase inhibitor.
https://www.ncbi.nlm.nih.gov/pubmed/8993087
PsychoGenesis
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Re: FOUND THE CAUSE OF PSSD!!! SEROTONIN - PPARy - nNOS *REVEALED*

Unread post by PsychoGenesis »

must be easy to test with a PPARy agonist like pioglitazone

PPARa agonist fenofibrate seems to have the opposite effect on AR in prostate cells

https://www.ncbi.nlm.nih.gov/pubmed/23399562

if the same applies to penis tissue and going by this study on finasteride showing doubled AR expression in the penis
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4069023/

may be that could reverse androgen insensitivity?
if not at least it' can prevent someone with PFS from getting prostate cancer
Halan
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Re: FOUND THE CAUSE OF PSSD!!! SEROTONIN - PPARy - nNOS *REVEALED*

Unread post by Halan »

This is an underlooked thread.
So, how can we activate PPARy?
PPARy agonists generally are drugs with lots of side effects.
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kpavel
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Re: FOUND THE CAUSE OF PSSD!!! SEROTONIN - PPARy - nNOS *REVEALED*

Unread post by kpavel »

Halan wrote: Thu Jun 11, 2020 10:04 pm This is an underlooked thread.
So, how can we activate PPARy?
PPARy agonists generally are drugs with lots of side effects.
Linolenic acid (omega-3), pomegranate extracts, red oak bark extracts (high in ellagic acid). I tried to choose potent stuff, but there are lots of other options and pathways I'd found.
https://pubmed.ncbi.nlm.nih.gov/24362249/
https://pubmed.ncbi.nlm.nih.gov/23684435/
https://pubmed.ncbi.nlm.nih.gov/26116231/
https://pubmed.ncbi.nlm.nih.gov/21736821/
https://pubmed.ncbi.nlm.nih.gov/19828904/
https://pubmed.ncbi.nlm.nih.gov/29103827/
https://pubmed.ncbi.nlm.nih.gov/27845788/
https://pubmed.ncbi.nlm.nih.gov/25579987/

Direct connection of carnitine with blood flow and tissue quality through ppar gamma. Carnitine plays a serious role I guess.
https://pubmed.ncbi.nlm.nih.gov/22962578/
https://pubmed.ncbi.nlm.nih.gov/26452216/
https://pubmed.ncbi.nlm.nih.gov/24413708/
https://pubmed.ncbi.nlm.nih.gov/23295156/
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