. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Comparing endometriotic lesions with eutopic endometrium: time to shift focus? Eliza M. Colgrave 1 , Janet R. Keast 2 , Sophie Bittinger 3 , Martin Healey 1 , Peter A.W. Rogers 1 , Sarah J. Holdsworth-Carson 1,† , and Jane E. Girling 1,4, * ,† 1 Department of Obstetrics and Gynaecology, University of Melbourne and Gynaecology Research Centre, Royal Women’s Hospital, Melbourne, Australia 2 Department of Anatomy and Physiology, University of Melbourne, Melbourne, Australia 3 Department of Pathology, Royal Women’s Hospital, Melbourne, Australia 4 Department of Anatomy, University of Otago, Dunedin, New Zealand *Correspondence address. Department of Anatomy, University of Otago, 270 Great King Street, Dunedin 9016, New Zealand. Tel: þ64-3- 479-7346. E-mail: jane.girling@otago.ac.nz https://orcid.org/ 0000-0002-8154-2068 Submitted on March 11, 2021; resubmitted on August 2, 2021; editorial decision on September 1, 2021 ABSTRACT: Endometriosis is a heterogeneous disease in terms of patient symptoms, treatment responsiveness and the presentation of endometriotic lesions. This article explores the histological features of endometriotic lesions, highlighting their sometimes underappreci- ated heterogeneity. We note the variability in evidence for and against the menstrual cycle responsiveness of lesions and consider the utility of drawing parallels between endometriotic lesions and eutopic endometrium. We ask whether histopathologic features beyond just the presence/absence of endometrial-like glands and/or stroma could help improve disease stratification. At the same time, we acknowledge the desire of many clinicians and patients to avoid invasive surgery thereby limiting the ability to histologically phenotype lesions. The ability to derive clinically useful histological information from endometriotic lesions, in association with patient data, would be invaluable to clinicians to help improve treatment options in such a diverse group of patients. However, in suggesting that a shift in focus may enable the development of a better patient stratification system, we recognise that our wish for a single comprehensive stratification system may be beyond reach for a disease of such diverse presentation. Key words: endometriosis / menstrual cycle / endometriotic lesion / endometrium / histology / classification Introduction Endometriosis is a common gynaecological disease that imposes a significant physical, emotional and financial burden on patients, their families and the community (Culley et al., 2013; Armour et al., 2019). The disease is characterised by the presence of endometrial-like lesions outside of the uterus (Giudice and Kao, 2004). We argue that continued investigations focused on these lesions, and incorporation of findings into disease classification, should be a priority for improving patient stratification and ulti- mately patient outcomes. This research should be conducted in parallel with comprehensive studies that address the mechanisms responsible for pain symptoms and other aspects of disease patho- physiology. Research advancements are essential as not all patients respond to current surgical and medical treatments and side effects are problematic (Giudice and Kao, 2004; Bedaiwy et al., 2017). If Sampson’s frequently cited theory of retrograde menstruation is correct, the origin of endometriotic lesions is the eutopic endome- trium (Sampson, 1927). On this basis, the biology of lesions is often equated with endometrial physiology including the hormonal and mor- phological changes associated with the menstrual cycle. While numer- ous studies still make direct comparisons, robust evidence supporting equivalent menstrual cycle-associated changes in lesions versus eutopic endometrium is lacking; our recent work further substantiates this dif- ference (Colgrave et al., 2020). The purpose of this article is to high- light the evidence suggesting that only a subset of endometriotic lesions follow menstrual cycle-related changes in morphology and ste- roid hormone responsiveness, and that these changes are largely inde- pendent of changes in the eutopic endometrium. † The last two authors shared senior authorship. V C The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com Human Reproduction, Vol.00, No.0, pp. 1–10, 2021 doi:10.1093/humrep/deab208 OPINION Downloaded from https://academic.oup.com/humrep/advance-article/doi/10.1093/humrep/deab208/6372199 by guest on 19 September 2021