Phenotyping women with endometriosis pain to improve understanding the preclinical models’ relevance

Background & Aims

Endometriosis-associated pain (EAP) is common. However, there is little relationship between the severity of disease and pain symptoms, with ~ 50% continuing to suffer chronic pain despite optimum treatment of their endometriosis as per current guidance. There is therefore an urgent need for novel therapeutic approaches, frequently necessitating preclinical investigation. It is not currently well understood to what extent preclinical models of endometriosis reflect the phenotype of women with EAP, potentially contributing to failed translational efforts.

Here we use data from the Translational Research in Pelvic Pain (TRiPP) project to explore differences between women with EAP and pain-free controls in a variety of pain-relevant measures. We then consider how well these relate to key relevant assessments of a selection of mouse models of endometriosis. We hypothesised that the preclinical models would only reflect some of the differences observed clinically.

Methods

Women with EAP and pain-free controls were recruited from existing cohorts in Oxford and Boston (EAP (N=43) and Control (N=50)). They completed a set of pain-relevant validated questionnaires and underwent physiological testing including assessments of autonomic nervous system activity, sensory profiling, bladder sensitivity and 24 hour and stress response cortisol profiling. Statistical analysis using parametric testing and Bonferroni correction was performed on SPSS software.

Preclinical mouse models of endometriosis were explored at 4 sites (Edinburgh, Berlin, Valencia and Osong-euo). Assessments were made of both evoked responses and home cage activity. Assessments considered most reflective of those used in the clinical study were selected for comparison.

Results

We found significant differences between the EAP group and pain-free controls in a variety of pain-relevant measures. This included significantly higher levels of pain interference with daily life (p<0.001), fatigue (p<0.001), anxiety (p=0.005) and pain catastrophising (p<0.001) particularly on the helplessness subscales (p<0.001) and worse sleep quality (p=0.002). There were no significant differences in assessments of the autonomic nervous or stress systems (ECG and cortisol respectively). However, QST analysis revealed that the EAP group had significant loss of function for thermal sensory limen at the abdomen (p=0.04) but not in other pain threshold measures. Analysis of preclinical data demonstrates variation in pain-relevant assessments between models. However, both evoked and non-evoked differences could be seen in comparison to sham models. This included reduced locomotor activity and social interactions in the activity phase of the animals during the lights-off time period

Conclusions

Overall, we demonstrate that differences between those with EAP and pain-free controls are broader than just those traditionally considered as endometriosis symptoms. This highlights the need to consider areas such as fatigue and psychological wellbeing in comprehensive treatment plans. Our preclinical analysis, emphasises the need to carefully consider the preclinical model used in translational investigations to ensure it reflects the clinical situation. However, non-evoked data suggests that at least some of these models may have utility in reflecting the impact EAP has on women’s lives in addition to recreation of the pathology.

References

Demetriou, Lysia, et al. “Deep phenotyping of women with endometriosis-associated pain and bladder pain syndrome: the TRiPP (Translational Research in Pelvic Pain) study protocol.” medRxiv (2022): 2022-05.

Demetriou, Lysia, et al. “Clinical profiling of specific diagnostic subgroups of women with chronic pelvic pain.” Frontiers in reproductive health 5 (2023): 1140857.

Presenting Author

Lysia Demetriou

Poster Authors

Lysia Demetriou

PhD

University of Oxford

Lead Author

Phenotyping women with endometriosis pain to improve understanding the preclinical models’ relevance

Background & Aims

Methods

Results

Conclusions

References

Presenting Author

Lysia Demetriou

Poster Authors

Lysia Demetriou

Lydia Coxon

Paulina Nunez-Badinez

Ioannis Simitsidellis

Raul Gomez

Claire E Lunde

Danielle Perro

Michal Krassowski

Kurtis Garbutt

Allison Vitonis

Lars Arendt-Nielsen

Qasim Aziz

Judy Birch

Andrew Horne

Anja Hoffman

Patrick Sweeney

Christian Becker

Francisco Cruz

Stacey Missmer

Krina Zondervan

Christine Sieberg

Philippa Saunders

Jens Nagel

Katy Vincent DPhil BSc MBBS MRCOG

Topics

IASP 2024 World Congress on Pain