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:
Serotonin regulates prostate growth through androgen receptor modulation
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.