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Sources of Funding: Surgical Sciences Research Domain, Life and Health Sciences Research Institute, ICVS/3B’s - PT Government Associate Laboratory

Introduction

Ageing and testosterone cause almost inexorably benign prostatic hyperplasia (BPH) in Human males, however the etiology of BPH is unknown. Serotonin (5-HT) is produced by neuroendocrine prostatic cells and is present in high concentration in normal prostatic transition zone. In BPH neuroendocrine cells and 5-HT are significantly decreased comparatively to normal prostatic transition zone. Previously, we have demonstrated in several in vitro models that 5-HT inhibitis non-malignant prostatic growth through androgen receptor down-regulation and we suggested a new Neuroendocrine Theory for BPH etiology. Here, we investigated in vivo the effects of peripheral inhibition of 5-HT synthesis on mice prostate gland.

Methods

peripheral 5-HT synthesis is critical dependent of the presence of TPH1, so we used transgenic mice depleted from TPH1 (Tph1-/-) to study the in vivo effect of peripheral serotonin depletion. Male wild-type and Tph1-/- mice were sacrificed at different time points: 7, 12, 16 and 20 weeks-old. For pharmacological studies, wild-type and Tph1-/- mice with 19 week-old were treated with daily intraperitoneal injections of 0,9% saline or 5-HT (100 mg/Kg) during 10 consecutive days._x000D_ Prostate gland mass was determined and proceeded for histology, western blotting, immunofluorescence and qRT-PCR of AR expression._x000D_

Results

We showed that Tph1 knockout mice depleted from peripheral 5-HT have significant higher prostate mass comparatively to wild-type (p < 0,001) and 5-HT treatment of Tph1 knockout mice restores prostate mass to levels of wild-type (p < 0,001) (figure A and B). We demonstrated also that the benign prostatic growth in Tph1 knockout mice is associated with up-regulation of AR and 5-HT treatment restores de expression of AR (p<0,05)(Figure C and D)._x000D_

Conclusions

In vivo, 5-HT depletion induces benign prostatic growth in mice trough AR up-regulation. 5-HT depletion in transition zone of aging human male could be the etiologic factor for BPH etiology.

Funding

Surgical Sciences Research Domain, Life and Health Sciences Research Institute, ICVS/3B’s - PT Government Associate Laboratory