Serotonin regulates prostate growth through androgen receptor modulation

#1

Recently I reviewed @Rb26dett’s case after he shared his experience. Considering a demonstrable property of antiandrogenic action amongst substances causing members to experience PFS, I had a look for evidence that 5-HT is capable of a notable downregulatory effect on the AR.

The following 2017 study explored this in detail, with strong evidence both in vitro and in vivo:

https://www.nature.com/articles/s41598-017-15832-5

Serotonin regulates prostate growth through androgen receptor modulation

Abstract:

Aging and testosterone almost inexorably cause benign prostatic hyperplasia (BPH) in Human males. However, etiology of BPH is largely unknown. Serotonin (5-HT) is produced by neuroendocrine prostatic cells and presents in high concentration in normal prostatic transition zone, but its function in prostate physiology is unknown. Previous evidence demonstrated that neuroendocrine cells and 5-HT are decreased in BPH compared to normal prostate. Here, we show that 5-HT is a strong negative regulator of prostate growth. In vitro , 5-HT inhibits rat prostate branching through down-regulation of androgen receptor (AR). This 5-HT’s inhibitory mechanism is also present in human cells of normal prostate and BPH, namely in cell lines expressing AR when treated with testosterone. In both models, 5-HT’s inhibitory mechanism was replicated by specific agonists of 5-Htr1a and 5-Htr1b . Since peripheral 5-HT production is specifically regulated by tryptophan hydroxylase 1(Tph1), we showed that Tph1 knockout mice present higher prostate mass and up-regulation of AR when compared to wild-type, whereas 5-HT treatment restored the prostate weight and AR levels. As 5-HT is decreased in BPH, we present here evidence that links 5-HT depletion to BPH etiology through modulation of AR. Serotoninergic prostate pathway should be explored as a new therapeutic target for BPH.

Key extracts from my notes:

Several reports have documented an up-regulation of the androgen receptor (AR) in BPH tissue, unveiling a potential role for AR in BPH etiopathogenesis.

We hypothesized that 5-HT had an inhibitory function over benign prostate growth and that suppression of prostatic 5-HT production could be responsible for benign prostatic growth. The aim of this study was to define the role of 5-HT in the regulation of benign prostatic growth and to test the pharmacologic modulation of the prostatic serotoninergic system as a new pharmacological target for BPH.

We asked if the 5-HT inhibitory effect was related to the AR stimulatory pathway. By western blot analysis we showed that testosterone supplementation induced AR up-regulation, but 5-HT treatment significantly decreased AR expression either with or without testosterone supplementation (Fig. 2a and b) suggesting that the inhibitory function of 5-HT could be related to inhibition of the AR pathway. Similarly, both the selective 5-Htr1a agonist 8-OH-DPAT, (Fig. 2a and c) and the selective 5-Htr1b agonist, anpirtoline, (Fig. 2a and d) induced a significant AR down-regulation, more evident in anpirtoline treated VPs. Taken together these results indicate that in vitro 5-HT inhibits rat prostate growth through 5-Htr1a and 5-Htr1b, by down-regulating AR.

Remarkably, the absence of inhibitory action of 5-HT, 5-Htr1a and 5-Htr1b specific agonists on PNT1A cells viability and proliferation, even in presence of testosterone, co-existed with a complete absence of AR expression in these cells (Fig. 5a). These data strongly argue that 5-HT’s inhibitory function on growth of benign human prostate cells is related with the suppression of the AR pathway.

In vivo ablation of peripheral 5-HT synthesis in mice induces benign prostatic growth

Based on our in vitro findings which suggest that 5-HT has a strong inhibitory action on prostate growth through down-regulation of AR, we used Tph1-/- mice to evaluate the effect of peripheral 5-HT depletion on mouse prostate gland growth. Remarkably, Tph1-/- mice exhibited a significantly 37% higher prostate-to-body weight ratio compared to wild-type at 20 weeks (p<0.001) (Fig. 6a and b) without changes in body weight (Supplementary Fig. 3a). Interestingly, histology of the prostate gland revealed that Tph1-/- mice exhibit areas of hyperplasia in epithelium and stroma (Fig. 6a, lower panel). To determine if 5-HT treatment could revert higher prostate mass in Tph1-/- mice, we performed intraperitoneal injections of 5-HT at 10 consecutive days. 5-HT treatment resulted in significant mass reduction in prostate gland compared to levels similar to the wild-type (Fig. 6c and d) again without affecting animal weight (Supplementary Fig. 3b). Next, we asked if the higher prostate mass in Tph1-/-mice was associated with different expression of AR

Immunofluorescence dorsolateral prostate of Tph1-/- mice appeared to express more AR (Fig. 6e, lower panel). So, we investigated and demonstrated by qRT-PCR that the dorsolateral prostate of Tph1-/- mice has increased levels of AR mRNA expression, while 5-HT treatment partially restores it to levels to wild-type mice (Fig. 6e, upper panel), reinforcing our hypothesis. It is well established that castration induces a strong reduction in size of the prostate gland as well as in seminal vesicles, while testosterone supplementation makes both organs return to normal size27,28. Interestingly, also seminal vesicles of Tph1-/- mice were significantly larger than the ones of wild-type (Fig. 6f) suggesting that 5-HT could regulate androgen sensitivity not only in prostate gland but also in seminal vesicles. Again, we observed that the mass of seminal vesicles was partially restored by 5-HT treatment in Tph1-/- mice.

The increased mass of Tph1-/- prostates was associated to an up-regulation of AR in dorso-lateral prostate samples suggesting that, at least in part, the excessive prostatic growth in Tph1-/- could be attributed to AR up-regulation. In conclusion, our findings suggest that 5-HT is a strong negative regulator of prostate growth through AR down-regulation. As 5-HT is decreased in BPH, we present here evidence that links 5-HT-producing neuroendocrine cell depletion to BPH etiology. Therefore, this new described serotoninergic inhibitory pathway over benign prostatic growth should be explored as a new target for BPH treatment.

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#2

Really a great job! This is an important discovery. Another step forward in understanding how PFS and PSSD are connected. Serotonin in high doses has an effect similar to finasteride in interfering with the androgen receptor. We should understand how to restore them.

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#3

Maybe some kind of a serotonin suppresser would work for PSSD patients?

#4

Took MDMA several months off the drug and got a raging boner showering with my girlfriend several hours after consumption. MDMA uses up a lot of serotonin.

#5

Yea? I almost died from a single dose of MDMA because of serotonin depletion syndrome a few years ago no doubt caused by PFS - be very careful

#6

What happened? You think pfs already lowers your serotonin? I know there are many surfers who abuse mdma who have the same symtoms we do. They call it Long Term Comdown (Ltc) LTC=PFS

#7

So do we have too high serotonin or too low? I’m benefitting from Wellbutrin right now that acts on dopamine and norepinephrine l but only in mood and some extra energy. And does marijuana also eat up serotonin similar to mdma? I’ve posted a few times that on days when I smoke ALOT that my libido skyrockets and I get some feeling back but nothing crazy

#8

Do you know how much you took? I took .10mg and then another .10mg 2 hours later.

MDMA uses up a lot of your serotonin, its how it makes you feel high as fuck.

I just looked at her and it went up. It was weird because the head was kinda numb but it was pointing towards the ceiling.

#9

This is very interesting as a month ago I went to a festival and rolled for my first time (MDMA) Two weeks post “roll” I had all the desire to want women. I felt like my mind and penis were connected finally and I could think kinda normal again. After those weeks wore off I am actually more confused than ever. Anxiety is at an all time high right now. I ALSO noticed a slight improvement when I take Advil. I don’t know if its inflammation in our bodies but Advil seems to take some issues away for me at least. PM me and discuss this maybe @Burito101 @Lostinaustin ?

#10

I’ve never done mdma or anything like that but I was just curious if marijuana has a similar effect on serotonin. I’ve never correlated any improvements with taking Advil/Tylenol etc though

#11

I smoke daily along with CBD so I can discuss with you in regards to that. Someone else from a while ago posted about trib + weed works so I gave it a go. It seemed to help but subsided. I still smoke weed daily as I don’t know if that helps or doesn’t lol. The trib I took was from Jarrow and I don’t know if its legit.

#12

I’ve been taking Mediherb tribulus for a week now and also smoke daily but only at nighttime around bed. Hasn’t really done much for me except maybe harder muscles and a little more energy in the day. Also taking dhea right now though

#13

Yeah me too, nights only. PM me so we can have a longer convo? also, isn’t dhea a direct hormone? I hear a lot of people say to be careful in general outside propecia. Let me know how that feels!

#14

Im just taking 5-10mg which is a way smaller dose than most people do. Feel free to pm me with anything you want to talk about.