If you have questions

[Meso]

There are several types of anti-depression drugs. Widely used are SSRIs (Selective serotonin reuptake inhibitors) and SNRIs (Serotonin-norepinephrine reuptake inhibitors). Usually, anti-depression drugs lead to excessive chronic prolactin production – a condition called Hyperprolactinemia (can best be described as a functional disorder). Excessive prolactin in the bloodstream reduces the testosterone and DHT release from the testicles, resulting in bone and muscle weakness.

This is correct, although recent studies (2002-2017) have found that the prolactin elevation is usually not significant [Link]. The prolactin should return to normal after withdrawal, so it doesn't explain PSSD.

SSRIs tend to block dopamine nervous functions in the hypothalamus-pituitary axis, which are responsible for the release of oxytocin, known as the emotional and orgasm hormone. The drugs also tend to indirectly interfere with all the neurotransmitter systems and the production of various hormones, usually by overloading the liver P450 detoxification system. They also block the spinal nervous transmissions in the synapses with a flooding of serotonin through a reuptaking inhibition. The gene expressions of D2 dopamine receptors, acetylcholine receptors, and 5-HT (Serotonin) 2C receptors are also being alternated.

That's right. Desensitization of 5HT1A receptors on oxytocin neurons is believed to be what causes SSRI-induced delayed orgasm. This is all reversible, though.

SSRIs will destroy the pituitary and liver functioning, burdening your endocrine system. SSRIs not only inhibit the reuptaking of serotonin, but actually lower the natural levels of serotonin due to the destructive effects on the liver P450. SSRIs drugs usually reduce the serotonin nervous action in the neuromuscular ending receptors all over the body.

This is complete BS. The liver's P450 enzymes that are sometimes inhibited by SSRIs are neither permanently destroyed nor depleted. Nor are the ones that are used to metabolize the drug. The liver will keep making them normally since SSRIs are not hepatotoxic.

Neuronal serotonin synthesis occurs within the CNS by tryptophan hydoxylase. It's ridiculous saying that "they actually lower the natural level of serotonin due to the destructive effects on the liver P450".

The blocking of dopamine and acetylcholine transduction, accompanied with the high level prolactin (being dumpled into the bloodstream), disables the nervous function in the penis and seminal production, and if taken systematically, can completely desensitize the penile nerves, prostate and seminal vesicles. Furthermore, SSRIs drugs tend to block hypothalamic/adrenal – dopamine – norepinephrine conversion and oxytocin release (essential to activation of orgasmic contractions).

SSRIs don't inhibit dopamine beta-hydroxylase (DBH), so they don't affect dopamine-NE conversion. SSRIs don't inhibit cholinergic receptors (with the exception of Paroxetine). Penile nerves are desensitized by disrupting glutamatergic function, TRP channels, spinal neurons, and sex hormones, to name a few.

SSRIs anti-depression drugs cause neuroplasticity, a term used in this particular context to describe deformation of synapses and outgrowth of serotonin neurons. This neuroplasticity is known to cause addiction and severe withdrawal symptoms.

Neuroplasticity is an adaptive mechanism by the brain to change continuously throughout an individual's life. So, it's a normal response to any substance intake as much as it's normal in memory formation mechanisms.

SSRIs will inhibit the reputaking of serotonin in the nervous synapses by blocking the serotonin transporter, thus allowing the serotonin neurotransmitter to continue influencing the postsynaptic neurons. However, SSRIs are not increasing neurotransmitter synthesis, on the contrary – they are cutting down the natural serotonin release from the nervous terminals, it is just that SSRIs stimulate more serotonin neurons.

Since SSRIs inhibit SERT, the brain's adaptive mechanisms slow down serotonin release. In part through autoreceptor activation.

SSRIs antidepressants also tend to alter the relationship between dopamine and serotonin signaling in the striatum, which will receive moderate serotonergic and rich dopaminergic innervation. This can be extremely harmful and may lead to irreversible damage. Due to the inhibition of serotonin transporters, the dense striatal Dopamine Transporters may uptake serotonin into the dopamine terminals, which will destroy the dopamine nervous function...

Non-scientific conclusion. Uptake of serotonin into the dopaminerigic terminals would cause these neurons to fire both serotonin and dopamine (co-release). This is by no means limited to striatal neurons as this phenomenon is seen with other neurotransmitters co-releasing different neurotransmitters (i.e. nucleus accumben's corelease of glutamate). It's harmless.

What do you think of this Meso? It's suggesting that at least some of the damage is irreversible

Some of the things he said is BS, while some others are correct. All of this is reversible, though. It doesn't explain PSSD.

[AnhedonicApe]

Thanks a lot for Your answer, I hopefully am right if I translate it as I, a PSSD sufferer (although took almost all types of Ssris/Snris/Saris.. over years), I am still more safe around those PFS to-avoid substances compared to true PFS sufferer.. (endless minefield of things to avoid or lottery to better avoid - that ends with almost better do nothing and wait for Baylor study)

Funny thing is that on PFS forum the most strong theory is about that their AR receptors are -overexpressed- so the opposite of Your conclusion, they seem to follow the path trend of effort to reduce their AR receptors.. (But maybe I am understanding it wrong somehow, I did not exactly looked into too much details, I will, but anyway they do tend say their ARs are overexpresses, too much upregulated).

It's possible that they have misinterpreted studies relative to AR expression. These studies show that AR over-expression is tissue-specific, mostly along the human foreskin (stromal and epithelial cells) as well as the cortical regions. Androgen receptors in the normal prostate can be downregulated by Finasteride, while upregulated in the hyperplastic prostate. [link][link2]

When it comes to neural AR expression, androgens can upregulate them while Finasteride can partially block this effect, except for cortical neurons. [link3][link4]

In the penis smooth muscles (not foreskin), T and DHT actually upregulate AR expression. Only when 5-alpha reductase is blocked does testosterone downregulate AR there (through aromatization to estradiol)
[link5].

Finally, it's important to determine which cell types are affected by Finasteride-induced AR over-expression instead of generalizing this to all tissue types. It's also important to take into consideration auto-regulation and cross-regulation of nuclear receptors, especially the interaction between estrogen and androgen receptors (and different interactions across different cell types)

Hey meso, i asked on the propecia forum what they thought about this and got this response:

I didn’t read all of this because I don’t have much time but I am confused by the suggestion “Finasteride can partially block this effect” when the study they cite for this point plainly says this:

In males given T plus FIN, a condition in which 5areductase activity was blocked, increases in AR at the 7-h time point were comparable to those seen with T and DHT alone. This indicates that T up-regulates AR as effectively as DHT, at least within this time frame.

That is notedly not blocking the effect. While I appreciate he appended “except cortical neurons”, nothing else in those studies is at all relevant to his sentence, so why are those studies linked at all? I find acontextual study linking is a big source of confusion to others and invariably a waste of time. I’ve just wasted five minutes looking through completely irrelevant studies. This does not give a good impression.

''When you take Finasteride, you are significantly reducing DHT, so I would expect that AR expression would also be reduced.''

Regardless of what anyone expects, finasteride induces a persistent upregulation of the AR in the cerebral cortex of sub-chronically treated rats. This was an important finding of Giatti et al and involved Roberto Melcangi. The expression of AR was highest at the final period of washout.

''As shown in figure 2 a, after finasteride treatment, we observed a significant upregulation of AR protein levels in the cerebral cortex.

As shown in figure 3 , at the end of the withdrawal period, the protein levels of AR ( fig. 3 a) and
ERα ( fig. 3 c) were upregulated in the cerebral cortex''

This is simply the normal physiological response. It’s important to note that PFS is an aberrant response.

AR expression is significantly increased in symptomatic tissue in PFS, and a key reality we have been telling people endlessly is that while antiandrogens often relieve symptoms in PFS, sometimes transformatively, they can be extremely dangerous and have preceded further crashes and suicide. People often ask for significant warnings to be placed on the forum because of this.

Di Loreto et al. reported 2x AR expression vs controls across measured cell lines in PFS patients with penile atrophy and pain averagely 5 years after cessation. La Marra, co-author of the study, expanded on this in his thesis noting the following:

''The percentages of AR positive cells are always higher in the cases than in the controls. Statistical analysis showed positive correlations between:

The increase of AR levels in the epithelial and stromal cells and the decrease in ability/frequency to perform sexually per the AMS
The increase of AR in the vessels cells and the intensification of ASEX sexual dysfunction and physical exhaustion
The increase of AR in the epithelial cells and the worsening of muscular weakness and feeling “burnt out” (per AMS)
Of course, CRPC is the most well studied cellular adaptation to androgen deprivation, and histone modifications occur following an initial downregulation that significantly and persistently increase AR expression as a result. It is highly unlikely this adaptive mechanism is cancer specific and upregulation in response to low androgens can be demonstrated elsewhere in nature.''

With regards to the effect of serotonin on the AR, I’ve written about this in detail already here.'( https://forum.propeciahelp.com/t/seroto ... tion/35533 )

The regulation of the AR is complex, tissue-specific, and responses strictly depend on epigenetic status. @Awor and I are putting together relevant information and will seek to publish it in some form.

I would suggest as always that anyone with ideas they think are credible take them to a scientist in an appropriate field for feedback.

Best

_____________________
EDIT by Jaxx: Original propeciahelp link: https://forum.propeciahelp.com/t/opinio ... on/37870/5

[Fred]

Does PSSD effect testosterone or androgens?

[AnhedonicApe]

Btw this is their theory in a large written form: http://www.protocol-online.org/forums/u ... 061244.ipb

[FML-PSSD]

What can I do about genital numbness? Does genital numbness cause weak orgasms?

[Meso]

I didn’t read all of this because I don’t have much time but I am confused by the suggestion “Finasteride can partially block this effect” when the study they cite for this point plainly says this:

In males given T plus FIN, a condition in which 5areductase activity was blocked, increases in AR at the 7-h time point were comparable to those seen with T and DHT alone. This indicates that T up-regulates AR as effectively as DHT, at least within this time frame.

That is notedly not blocking the effect.

The study also noted:
Treatment with T or DHT significantly augmented AR 3 and 7 h after hormone administration, but only DHT sustained this increase for 21 h. This difference also was observed when males were given T plus finasteride (FIN, a 5alpha reductase inhibitor). The findings demonstrate that the two endogenous ligands have differential time course effects on neural AR

While I appreciate he appended “except cortical neurons”, nothing else in those studies is at all relevant to his sentence, so why are those studies linked at all? I find acontextual study linking is a big source of confusion to others and invariably a waste of time. I’ve just wasted five minutes looking through completely irrelevant studies. This does not give a good impression.

Sorry for the confusion. Since I mentioned the cortical region in the opening statement, I wrote it again to remind the reader that these two studies that I linked regarding neuronal AR exclude this region.

I'm also short on time, so I don't provide reference links to everything I post on the forum since it's too time-consuming. However, if a member wants to confirm something I said, they can for example literally search for "androgen receptor cortex finasteride pubmed" and it's the first result of the search. It takes less than 1 minute.

''When you take Finasteride, you are significantly reducing DHT, so I would expect that AR expression would also be reduced.''

Regardless of what anyone expects, finasteride induces a persistent upregulation of the AR in the cerebral cortex of sub-chronically treated rats. This was an important finding of Giatti et al and involved Roberto Melcangi. The expression of AR was highest at the final period of washout.

This is simply the normal physiological response. It’s important to note that PFS is an aberrant response.

What I'm pointing out that although AR upregulation is found in some tissue types, AR downregulation is also found in others. My point is: since the burden of evidence falls upon the research reviewer, it's important to look into all angles relative to the topic at hand.

In this particular case, the cerebral cortex isn't the only tissue type or region in the body. As I mentioned before, in the penis smooth muscles, T and DHT actually upregulate AR expression. In the normal prostate, Finasteride also downregulates AR expression. These are also important symptomatic tissue in PFS, aren't they?

To clear the misunderstanding regarding AR expression, they should also research nuclear receptors auto-regulation and cross-regulation. For example, estrogen receptor activation can regulate the expression of both androgen receptors and progesterone receptors. This is also tissue-specific, causing downregulation in some tissues and upregulation in others. It's important to find symptomatic relief options for PSF - or even a cure.

PSF deserves more in-depth look into the different angles. It's a complex condition.

Di Loreto et al. reported 2x AR expression vs controls across measured cell lines in PFS patients with penile atrophy and pain averagely 5 years after cessation. La Marra, co-author of the study, expanded on this in his thesis noting the following:

''The percentages of AR positive cells are always higher in the cases than in the controls. Statistical analysis showed positive correlations between:

The increase of AR levels in the epithelial and stromal cells and the decrease in ability/frequency to perform sexually per the AMS
The increase of AR in the vessels cells and the intensification of ASEX sexual dysfunction and physical exhaustion
The increase of AR in the epithelial cells and the worsening of muscular weakness and feeling “burnt out” (per AMS)
Of course, CRPC is the most well studied cellular adaptation to androgen deprivation, and histone modifications occur following an initial downregulation that significantly and persistently increase AR expression as a result. It is highly unlikely this adaptive mechanism is cancer specific and upregulation in response to low androgens can be demonstrated elsewhere in nature.''

If that's indeed the root cause of PFS, then wouldn't chronic supraphysiological TRT downregulate the receptors and be essentially a cure after chronic use, if androgens generally downregulate AR expression?

The regulation of the AR is complex, tissue-specific, and responses strictly depend on epigenetic status.

I would suggest as always that anyone with ideas they think are credible take them to a scientist in an appropriate field for feedback.

Although PFS research review is not my main focus, what I wanted to highlight is the misunderstanding of AR over-expression being generalized. Even in tissue types that are also relevant to PFS symptoms, the opposite effect on AR expression can be seen. One should also take into consideration the cross-regulation of nuclear receptors.

[lookingforacure]

Hi Mesolimbo,

I had extremely severe emotional dysregulation due to my borderline personality disorder and was taking mirtazapine, viibryd 20 mg, and had just started 200 mg of lamictal when I first got PSSD (in the past, every time I stopped any ssri or medication I would promptly regain full sexual functioning, but this time, after taking lamictal, even after I stopped all medications I noticed I still had full sexual dysfunction even after 1 month). I now only need to take viibryd and am much much more emotionally stable, but if I want to take a drug holiday from it for sex like I did in the past it doesn’t work and I still have genital numbness. Only after a night of very heavy drinking does my sexual functioning return in full when I’m hungover the next morning- that’s the only thing that’s made the genital numbness go away temporarily, although I haven’t tried many other drugs to help with this. Could you please recommend what to take to temporarily reduce the genital numbness? It would be extremely appreciated. Thanks for your time!

[finities infinities]

I remember what you mentioned about donepezil.
My acetylcholine appear is involved in my problem. I thinking about muscarinic receptor.
I feel that I must checked my muscarinic from pilocarpine or bethanechol. Your donepezil description in ,,nostalgic" ,,difficult emotion" moment fit to my problem.
I have question to you. Was it the type of "sticky" sentiment that makes you feel sorry for everything and you feel overly concerned about everything? This is popular in old people- excess empathy and characteric anxiety and thinking about time passing. Such people have a lot of lumber in their home, because they leave everything, they do not want to throw it away. I think it also results from the awareness of the evil, aversive state in the present. As if they were waiting for a better future or leaving souvenirs of a magical, beautiful past. People have the same emotions during grief.

[Tree]

Meso

About a year ago, I crashed/(serotonin syndrome) from ginger, a partial 5ht1a agonist, which caused an extreme worsening of cognitive and sexual dysfunction. A year later, there has been very little improvement. Baseline seems to have become permanently worse to the point where it's debilitating.

From research I've done, it seems like protein kinase c is mostly responsible for 5ht1a agonist induced receptor desensitization. My question is do you think it's plausible that a pkc inhibitor could help re sensitize receptors due to 5ht1a agonism?

[kpavel]

I don't know what Meso thinks on the question but I think you're right, and it was actually shown in the 90s.