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ESSM Consensus Statement on the Use of the Cavernous Nerve Injury Rodent Model to Study Postradical Prostatectomy Erectile Dysfunction

Onur Omer Cakir, MD,
Department of Urology, University College London
Hospitals NHS Trust, London, UK,
Division of Surgery and Interventional Science, UCL

Fabio Castiglione,
Department of Urology, University College London
Hospitals NHS Trust, London, UK

Hussain M. Alnajjar,
Department of Urology, University College London
Hospitals NHS Trust, London, UK

Asif Muneer,
Department of Urology, University College London
Hospitals NHS Trust, London, UK,
Division of Surgery and Interventional Science, UCL
NIHR Biomedical Research Centre University
College London Hospital

The advent of prostate specific antigen(PSA) screening has led to the early detection of prostate cancer (PCa). As a result, an increasing number of patients will have good long-term oncologic outcomes following radical prostatectomy (RP). In contrast, it has been reported that only 23- 30% of men younger than 60 years regain their complete erectile function (EF) after bilateral nerve-sparing RP (NSRP). This scenario is further complicated by the widespread use of penile rehabilitation therapy despite the absence of solid clinical evidence to back up this practice. The in vivo models mimicking this CN injury (CNI) have played a role in the advancement of the field of penile rehabilitation. However, despite the numerous studies published in the last 20 years, there is still a discrepancy between negative clinical data and positive basic science results.

In the recent paper from the European Society for Sexual Medicine Consensus Statement committee, the group of Castiglione et al. [1] aimed to review the current state of the art, highlight possible pitfalls, and provide statements for the rodent model of RP in order to better clarify the reason for this discrepancy.

In the study, available as open access at https://www.ncbi.nlm.nih.gov/pmc/ articles/PMC7471127/pdf/main.pdf, several technical statements were proposed in order to standardize the experimental methods with the intent to increase comparability between reports which could advance the field as a whole. More importantly, to increase the value of research methodology with animals, the authors emphasize the concept that the ARRIVE (Animal Research Reporting In Vivo Experiments) guidelines and recommendations should be followed. In particular, the ARRIVE guidelines were developed to improve standards of reporting and ensure that the data from animal experiments can be fully evaluated and used. They consist of a 20-point checklist (https://www.nc3rs.org.uk/sites/ default/files/documents/Guidelines/ NC3Rs%20ARRIVE%20Guidelines%20 Checklist%20(fillable).pdf) of the essential information that should be included in publications reporting animal research.

Interestingly, Castiglione et al. [1] reported several limitations of the rat model of RP which could be one of the possible reasons of the discrepancy between the clinical and basic science data. Firstly, the erectile function evaluation in rats is performed by an objective method (Intracavernous pressure measurement) and, on the other hand, in the clinical practice the evaluation is performed via validated questionnaires. Secondly, the rat model of RP mimics a “perfect “bilateral intrafacial nervesparing procedure which is difficult to perform in patients in the clinical setting. Thirdly, the basic science studies in this field use healthy young rats without any baseline ED. This does not reflect the current clinical landscape. Patients with PCa are commonly older than 50 years of age and may be suffering from different comorbidities (diabetes, cardiovascular disease) which impair baseline ED and can limit nerve repair mechanisms after the NSRP.

More importantly, the spontaneous recovery of EF in the rat model has an important scientific-translational consequence. The rats recover the normal EF after 6 months from the injury of the cavernous nerves (CNI). Indeed, this model can only be used to assess if a treatment can modify the time to return of EF recovery. Conversely, this model cannot be used to test if there is an absolute variation in terms of EF recovery rate between 2 or several treatments. The spontaneous recovery of EF in the CNI rat model should be considered as one of the major limitations of this model.

Today, the rat is commonly used as an animal model to mimic post-RP ED. In this paper, the authors provided ESSM statements for the correct and reproducible use of this model. This also reported the main pitfalls of the model. This may help clinicians and non- basic science experts to better understand the real results and possible limitations of the basic science studies using this animal model.

[1] European Society for Sexual Medicine Consensus Statement on the Use of the Cavernous Nerve Injury Rodent Model to Study Postradical Prostatectomy Erectile Dysfunction. Weyne E, Ilg MM, Cakir OO, Muneer A, Roussel DB, Albersen M, Angulo J, Corona G, Bettocchi C, Reisman Y, Castiglione F. Sex Med. 2020 Sep;8(3):327-337.

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