Investigating the effect of phosphodiesterase type 5 inhibitors and selective oestrogen receptor modulators in models of Peyronie's disease

Introduction: Peyronie’s disease (PD) is characterised by fibrosis in the penile tunica albuginea (TA) leading to pain, curvature, and erectile dysfunction, with myofibroblasts being the key cells in the pathogenesis. Current treatment options are limited, highlighting the need for novel medication. Material & Methods: An In-Cell ELISA based assay measuring TGF-β1-induced myofibroblast transformation of cells derived from human TA was utilised to investigate drugs from two classes, selective oestrogen receptor modulators (SERMs) and phosphodiesterase type 5 inhibitors (PDE5i). Furthermore, functional assays measuring contraction and extracellular matrix (ECM) formation were used. The drugs and their combination were investigated in vivo using an animal model of PD where Sprague-Dawley rats were divided in 5 groups: 1) TGF-β1 injection in the TA (TGI) 2) vehicle injection, 3) TGI plus daily PDE5i (vardenafil), 4) TGI plus daily SERM (tamoxifen), 5) TGI plus daily combination of PDE5i and SERM. Five weeks after injection with or without treatments, the rats were subjected to erectile function measurement with subsequent molecular analysis of the penis. Results: Three PDE5i and two SERMs significantly inhibited TGF-β1-induced myofibroblast transformation in a concentration dependent manner but could not reverse it. The drugs decreased TGF-β1-induced collagen lattice contraction, as well as ECM formation. A synergy between the two classes in inhibiting TGF-β1-induced myofibroblast transformation and collagen contraction was observed. In vivo experiments revealed that TGF-β1 injection caused penile fibrosis in rats resulting in erectile dysfunction, ECM changes and smooth muscle loss, which was prevented in the groups receiving treatment. The drug combination exerted a synergistic effect on various fibrotic markers in vivo. Discussion: An anti-fibrotic effect was confirmed for PDE5i, SERM and their combination in in vitro and in vivo models of PD on a functional, histological and molecular level. The previously undescribed synergy of the drugs at both in vitro and in vivo levels, suggests a novel potential combination therapy approach for the early phases of PD