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Qian Feng Oxford Endometriosis CaRe Centre, Nuffield Department of Women’s and Reproductive Health, University of Oxford, John Radcliffe Hospital, Women’s Centre, Oxford, United Kingdom
Department of Obstetrics and Gynaecology, Monash University, Melbourne, Clayton, Victoria, Australia

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Nina Shigesi Oxford Endometriosis CaRe Centre, Nuffield Department of Women’s and Reproductive Health, University of Oxford, John Radcliffe Hospital, Women’s Centre, Oxford, United Kingdom

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Jun Guan Department of Gynaecology, Obstetrics and Gynaecology Hospital of Fudan University, Shanghai, China

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Nilufer Rahmioglu Oxford Endometriosis CaRe Centre, Nuffield Department of Women’s and Reproductive Health, University of Oxford, John Radcliffe Hospital, Women’s Centre, Oxford, United Kingdom
Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom

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Mona Bafadhel School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, Guy’s Campus, King’s College London, United Kingdom

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Kevin Paddon Laboratory Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom

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Carol Hubbard Oxford Endometriosis CaRe Centre, Nuffield Department of Women’s and Reproductive Health, University of Oxford, John Radcliffe Hospital, Women’s Centre, Oxford, United Kingdom

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Krina T Zondervan Oxford Endometriosis CaRe Centre, Nuffield Department of Women’s and Reproductive Health, University of Oxford, John Radcliffe Hospital, Women’s Centre, Oxford, United Kingdom
Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom

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Christian M Becker Oxford Endometriosis CaRe Centre, Nuffield Department of Women’s and Reproductive Health, University of Oxford, John Radcliffe Hospital, Women’s Centre, Oxford, United Kingdom

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Karin Hellner Oxford Endometriosis CaRe Centre, Nuffield Department of Women’s and Reproductive Health, University of Oxford, John Radcliffe Hospital, Women’s Centre, Oxford, United Kingdom

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Graphical abstract

Abstract

Immunological dysregulation plays a fundamental role in the inflammatory aspects of endometriosis. Circulating blood leukocytes, one of the most abundant immune cell populations in the human body, have been shown diagnostic significance in some diseases. Nevertheless, the association between peripheral blood leukocyte counts and endometriosis remains unexplored to date.

We analyzed two targeted study cohorts: a tertiary center cohort (Endometriosis at Oxford University (ENDOX) Study: 325 cases/177 controls) and a large-scale population study (UK Biobank (UKBB): 1537 cases/6331 controls). In both datasets, peripheral venous blood sample results were retrieved, and counts of leukocyte subpopulations, including neutrophils, lymphocytes, monocytes, eosinophils, and basophils, were analyzed. Logistic regression models were used to investigate the association of leukocyte subtype alterations with endometriosis status, adjusting for confounding factors. We demonstrate that a higher blood basophil level is associated with increased odds of endometriosis. This association was first discovered in the ENDOX cohort (basophils >0.04 × 109/L: OR 1.65 (95% CI: 1.06–2.57), P trend = 0.025) and replicated in the UKBB dataset (basophils >0.04 × 109/L: OR 1.26 (95% CI: 1.09–1.45), P trend = 0.001). Notably, women with basophil counts in the upper tercile had significantly increased odds of having stage III/IV endometriosis (ENDOX study: OR = 2.30, 95% CI (1.25–4.22), P trend = 0.007; UKBB study (OR = 1.40, 95% CI (1.07–1.85), P trend = 0.015). None of the other leukocyte subtypes showed an association. Our findings suggest an association between inflammatory responses and the pathogenesis of endometriosis; future studies are warranted to investigate whether the association is causal.

Lay summary

Endometriosis is a long-term disease affecting approximately 10% of women during their fertile age. It happens when the tissue similar to the lining of the womb grows in other parts of the body, commonly causing pelvic pain and subfertility. Most diagnostic tests for endometriosis are neither accurate nor reliable, leading to a long wait before a correct diagnosis. Looking for changes in blood cell counts could guide doctors for further testing to confirm diagnosis. Our study shows that a higher number of basophils, a specialized type of white cells, commonly measured in a simple blood test, are positively linked with a higher likelihood of endometriosis. The link becomes stronger in severe endometriosis cases. Although we are showing a robust link, whether this can be used to find endometriosis sooner needs to be tested in future studies.

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Lysia Demetriou Nuffield Department of Women’s and Reproductive Health, University of Oxford, Oxford, UK

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Christian M Becker Nuffield Department of Women’s and Reproductive Health, University of Oxford, Oxford, UK

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Beatriz Martínez-Burgo Nuffield Department of Women’s and Reproductive Health, University of Oxford, Oxford, UK

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Adriana L Invitti Nuffield Department of Women’s and Reproductive Health, University of Oxford, Oxford, UK
Departamento de Ginecologia, Universidade Federal de São Paulo, São Paulo, Brazil

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Marina Kvaskoff Université Paris-Saclay, UVSQ, Univ. Paris-Sud, Inserm, Gustave Roussy, ‘Exposome and Heredity’ Team, CESP, Villejuif, France

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Razneen Shah Nuffield Department of Women’s and Reproductive Health, University of Oxford, Oxford, UK

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Emma Evans Oxford University Hospitals NHS Foundation Trust, Oxford, UK

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Claire E Lunde Nuffield Department of Women’s and Reproductive Health, University of Oxford, Oxford, UK
Biobehavioral Pediatric Pain Lab, Department of Psychiatry, Boston Children’s Hospital, Boston, Massachusetts, USA
Pain and Affective Neuroscience Center, Department of Anesthesiology, Critical Care, and Pain Medicine, Boston Children’s Hospital, Massachusetts, USA

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Emma Cox Endometriosis UK, UK

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Kurtis Garbutt Nuffield Department of Women’s and Reproductive Health, University of Oxford, Oxford, UK

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Krina T Zondervan Nuffield Department of Women’s and Reproductive Health, University of Oxford, Oxford, UK
Wellcome Centre for Human Genetics, University of Oxford, Oxford, UK

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Elaine Fox Department of Experimental Psychology, University of Oxford, Oxford, UK

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Katy Vincent Nuffield Department of Women’s and Reproductive Health, University of Oxford, Oxford, UK

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Endometriosis is a chronic condition that affects ~10% of women globally. Its symptoms include chronic pelvic pain, heavy periods and tiredness/fatigue, which have been associated with poorer quality of life and mental health. We aim to explore the impact of the COVID-19 pandemic on pain and fatigue symptoms and their interactions with the impact on mental health in people with endometriosis. This global cross-sectional online survey study collected data from 4717 adults with self-reported surgical/radiological diagnosis of endometriosis between May and June 2020. The survey included questions on the current status and changes of endometriosis symptoms (pelvic pain, tiredness/fatigue, and bleeding patterns), mental health, pain catastrophising, and the impact of the COVID-19 pandemic on the respondents’ lives. Compared to 6 months earlier, Respondents reported a marked worsening of their endometriosis symptoms (endometriosis-associated pain (39.3%; 95% CI: 37.7, 40.5), tiredness/fatigue (49.9%; 95% CI: 48.4, 51.2) and bleeding patterns (39.6%; 95% CI: 38.2, 41)) and mental health (38.6%; 95% CI: 37.2, 39.9). Those with a pre-existing mental health diagnosis (38.8%) were more likely to report their symptoms worsening. Worsening of pain and tiredness/fatigue was significantly correlated with worsening of mental health (P < 0.001). The relationship between changes in mental health and (a) change in pain and (b) change in fatigue was found to be weakly mediated by pain catastrophising scores (pain: B = 0.071, lower limit of confidence interval (LLCI) = 0.060, upper limit of confidence interval (ULCI) = 0.082, tiredness/fatigue: B = 0.050, LLCI = 0.040, ULCI = 0.060). This study demonstrates that stressful experiences impact the physical and mental health of people with endometriosis. The findings highlight the need to consider psychological approaches in the holistic management of people with endometriosis.

Lay summary

Endometriosis is a chronic condition in which tissue similar to that of the lining of the womb grows outside it. It affects around 10% of women globally, and the symptoms often include persistent pelvic pain, heavy periods and tiredness/fatigue. These symptoms are associated with impaired mental health and life quality. This study used an online questionnaire to assess the experiences of people with endometriosis during the first months of the pandemic. Results from 4717 adults revealed that pelvic pain, tiredness/fatigue and bleeding worsened in more than 39% of the participants. Poor mental health was also exacerbated and associated with worsening in tiredness/fatigue. Further analysis revealed that this relationship could be partially explained by ‘pain catastrophising’, which measures how participants think about their pain. Our results suggest that stressful experiences like the pandemic negatively impact the already burdened mental health of people with endometriosis, who could benefit from psychological interventions.

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