Typically, patients with PD present in the acute (early) phase usually within 6 months of the first symptoms such as pain during erection with or without a palpable penile mass. During this phase, it is thought that the repetitive microtrauma triggers inflammation which activates the fibrotic process. The fibrotic process is centered around the transformation of resident fibroblasts in TA to pro-fibrotic myofibroblasts which have increased proliferation, enhanced capacity, and ability to produce high amounts of extracellular matrix (ECM) proteins and gained the ability to contract. In this acute phase, there is no efficacious treatment available to patients. The chronic (late) phase of PD is characterised by the continuing excessive production of ECM proteins and tissue contraction and subsequent calcification of the fibrotic plaque which leads to curvature. In this phase, patients are offered collagenase injection and/or surgery to physically correct the curvature. There is therefore an urgent unmet need to develop novel therapeutic approaches that can halt the progression of fibrosis in the acute phase and that can reverse fibrosis in the late phase.
In our efforts to find novel drugs that can be given in acute PD, we discovered a synergy between phosphodiesterase type 5 inhibitors (PDE5i) and selective estrogen receptor modulators (SERM) in preventing the transformation of fibroblasts to myofibroblasts in in vitro experiments and in in vivo animal models of PD.1,2 When a combination of a PDE5i and tamoxifen (most commonly used SERM) was given to patients with acute PD, the progression of the disease was halted.3-5 These pre-clinical and clinical observations made us investigate how PDE5i are inhibiting or preventing myofibroblast transformation. This investigation has led to the current publication where we first investigated which isoforms of phosphodiesterases are expressed in TA fibroblasts. We found that PDE1A, 1C, 4, 5A, 7B, and 8B were expressed and their selective inhibitors prevented myofibroblast transformation in a concentration-dependent manner. This is the first demonstration of the expression of PDE1,7, and 8 isoforms, and the function of PDE1 and PDE4 in human TA fibroblasts. Further research will be required to develop novel PDE1 and/or 4 inhibitors for the treatment of acute PD.
Written by: Selim Cellek, Professor of Health and Biomedicine, Fibrosis Research Group, Anglia Ruskin University, UK
References:
- Ilg, M. M., Lapthorn, A. R., Ralph, D. J. and Cellek, S. (2022) 'Phenotypic screening of 1,953 FDA-approved drugs reveals 26 hits with potential for repurposing for Peyronie's disease', PLOS One, 17 (12), e0277646.
- Ilg, M. M., Mateus, M., Stebbeds, W. J., Milenkovic, U., Christopher, N., Muneer, A., Albersen, M., Ralph, D. J. and Cellek, S. (2019) 'Antifibrotic Synergy Between Phosphodiesterase Type 5 Inhibitors and Selective Oestrogen Receptor Modulators in Peyronie's Disease Models', Eur Urol, 75 (2), pp. 329-340.
- Cellek, S., Megson, M., Ilg, M. M. and Ralph, D. J. (2023) 'A combination of phosphodiesterase type 5 inhibitor and tamoxifen for acute Peyronie's disease: the first clinical signals', The Journal of Sexual Medicine, 20 (8), pp. 1057-1059.
- Megson, M., Merrett, C., Ilg, M. M., Cellek, S., Ralph, D. J. (2022). ‘Can tamoxifen and a PDE5 inhibitor slow the progression of Peyronie’s disease?’ The Journal of Sexual Medicine, 19 (Suppl 4), pp. S15-16.
- Geelhoed JP, de Jong IJ, Beck JJ. (2023) ‘Treatment of acute phase of Peyronie’s disease with tamoxifen and tadalafil off label.’ The Journal of Sexual Medicine, 20 (Suppl 4), qdad062.122.