Introduction: There is a well-established inverse relationship between body mass index and frequency of endometriosis. However, these population-based studies have relied mostly on self-reported cases of endometriosis, rather than surgically confirmed endometriosis where disease severity has been objectively assessed. The aim of the current retrospective study was to establish whether the established relationship between endometriosis and low body mass index was independent of disease severity. Methods: Women with menstrual and/or pelvic pain undergoing laparoscopy for suspected endometriosis were recruited for this retrospective study (n = 509). Women were grouped by body mass index (kg/m 2) according to World Health Organization criteria: underweight (<18.5), normal (18.5-24.99), pre-obese (25-29.99) or obese (≥30). Endometriosis was scored according to the revised American Fertility Society system. Data were analysed based on body mass index and endometriosis status to identify any relationship between body mass index and disease. Results: The average body mass index of women with endometriosis was 25.0 kg/m 2. The body mass index distribution of women with endometriosis differed relative to women in the general population. As expected, fewer obese women had endometriosis than in the lower body mass index categories. However, the obese women who did have endometriosis had significantly higher revised American Fertility Society scores compared to women with normal and pre-obese body mass indices. Discussion: Our results are consistent with the established finding of an inverse relationship between body mass index and endometriosis. The novel finding from this study is that obesity is associated with increased disease severity and reduced frequency of stage I endometriosis. It remains unclear what role body mass index has in the cause or effect of endometriosis; we speculate that body mass index may be useful for sub-classifying the disease.

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STUDY QUESTION Do menstrual cycle-dependent changes occur in the histological appearance of superficial peritoneal endometriotic lesions, and are they equivalent to those observed in the eutopic endometrium? SUMMARY ANSWER Only a small subset of superficial peritoneal endometriotic lesions exhibits some histological features in phase with menstrual cycle-related changes observed in eutopic endometrium. WHAT IS KNOWN ALREADY Endometriotic lesions are frequently described as implants that follow menstrual cycle-related changes in morphology, as per the eutopic endometrium. This concept has been widely accepted despite the lack of conclusive published evidence. STUDY DESIGN, SIZE, DURATION This was a retrospective cohort study of 42 patients, from across the menstrual cycle, with surgically and histologically confirmed endometriosis. Patients were a subset selected from a larger endometriosis study being conducted at the Royal Women’s Hospital, Melbourne since 2012. PARTICIPANTS/MATERIALS, SETTING, METHODS Histological features of epithelium, stroma and gland morphology were examined in haematoxylin and eosin stained sections of superficial peritoneal endometriotic lesions and matched eutopic endometrium (menstrual: n = 4, proliferative: n = 11, secretory: n = 17, hormone-treated: n = 10). At least two biopsies (average = 4, range = 2–8 biopsies) and a matched endometrial sample were analysed for each patient and results were presented per endometriotic gland profile (n = 1051). Data were analysed using mixed effects logistic regression to account for multiple patients and multiple endometriotic biopsies, each with multiple endometriotic gland profiles. This model also enabled analysis of endometriotic lesions versus eutopic endometrium. MAIN RESULTS AND THE ROLE OF CHANCE There was considerable inter- and intra-patient variability in the morphology of superficial peritoneal endometriotic lesions. Menstrual cycle-associated changes were only observed for some features in a subset of endometriotic gland profiles. The proportion of endometriotic gland profiles with epithelial mitoses significantly increased in the proliferative phase (18% of gland profiles) relative to the menstrual phase (0% of endometriotic gland profiles) (odds ratios (OR) 9.30; 95% confidence intervals (CI) = 3.71–23.32; P &lt; 0.001). Fewer blood-filled gland lumens were observed in the secretory phase (45% of endometriotic gland profiles) compared to the menstrual phase (67% of endometriotic gland profiles) (OR, 0.30; 95% CI = 0.11–0.79; P = 0.015). The features of the eutopic endometrium analysed in this study did not reflect the results in matched endometriotic lesions (P &gt; 0.05). LARGE SCALE DATA Not applicable. LIMITATIONS, REASONS FOR CAUTION This study focused on features observed in sections of superficial peritoneal lesions and these may differ from features of deep infiltrating endometriosis or ovarian endometriomas. Cycle phases were limited to menstrual, proliferative and secretory phases to allow appropriate statistical modelling. WIDER IMPLICATIONS OF THE FINDINGS This study highlights heterogeneity in the histological characteristics of superficial peritoneal lesions. It challenges the assumption that lesion morphology consistently reflects menstrual cycle-associated changes. STUDY FUNDING/COMPETING INTEREST(S) Research reported in this publication was supported in part by National Health and Medical Research Council (NHMRC) project grants GNT1012245, GNT1105321 and GNT1026033 (P.A.W.R., J.E.G. and S.J.H.-C.). There are no competing interests.

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 underappreciated 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.

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