posted on 2023-08-30, 20:18authored byMarcus M. Ilg
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
History
Institution
Anglia Ruskin University
File version
Accepted version
Language
eng
Thesis name
PhD
Thesis type
Doctoral
Legacy posted date
2022-10-18
Legacy creation date
2022-10-18
Legacy Faculty/School/Department
Faculty of Health, Education, Medicine & Social Care