Reproduction and Fertility
First Impact Factor: 2.1



Professor Andrew Horne
Professor of Gynaecology and Reproductive
MRC Centre for Reproductive Health,
University of Edinburgh, UK
Professor Norah Spears
Norah Spears, D Phil
Professor of Reproductive Physiology,
Centre for Integrative Physiology,
University of Edinburgh, UK
Meet the Editorial Board

Endometriosis is a chronic inflammatory condition affecting one in 10 women and those assigned female at birth, defined by the presence of endometrial-like tissue outside the uterus. It is commonly associated with pain, infertility, and mood disorders, and often comorbid with other chronic pain conditions, such as irritable bowel syndrome. Recent research has identified a key role for the microbiota-gut-brain axis in health and a range of inflammatory and neurological disorders, prompting an exploration of its potential mechanistic role in endometriosis. Increased awareness of the impact of the gut microbiota within the patient community, combined with the often-detrimental side effects of current therapies, has motivated many to utilise self-management strategies, such as dietary modification and supplements, despite a lack of robust clinical evidence. Current research has characterised the gut microbiota in endometriosis patients and animal models. However, small cohorts and differing methodology has resulted in little consensus in the data. In this narrative review, we summarise research studies that have investigated the role of gut microbiota and their metabolic products in the development and progression of endometriosis lesions, before summarising insights from research into co-morbid conditions and discussing the reported impact of self-management strategies on symptoms of endometriosis. Finally, we suggest ways in which this promising field of research could be expanded to explore the role of specific bacteria, improve access to ‘microbial’ phenotyping, and to develop personalised patient advice for reduction of symptoms such as chronic pain and bloating.

Chronic endometritis (CE) in humans is asymptomatic inflammation of the endometrium, associated with poor reproductive outcomes. Similarly asymptomatic endometrial inflammation in cows, termed subclinical endometritis (SCE), is associated with adverse reproductive outcomes. While the pathophysiology and treatment options for CE in humans remains poorly defined, the financial implications of SCE in dairy cows mean it has been intensively researched. We performed a systematic review with an emergent theme thematic analysis of studies of SCE in cows, to determine potential areas of interest in human CE research. A literature search for studies of subclinical endometritis in cows published between 1990 and November 2021 was performed across Embase, Medline, Scopus and CINAHL. Studies of symptomatic or clinical endometritis were excluded. Thematic analysis across two broad themes were explored: diagnostic methods and pathophysiology of SCE. In total, 44 bovine studies were included. 12 studies reported on diagnostic methodology. The primary emergent theme was the use of cytology for the diagnosis of SCE. This method has a lower sensitivity than histopathology but is less invasive and more specific than alternative techniques of ultrasound, vaginoscopy, or metabolic markers. The subthemes related to pathophysiology were identified as type of endometritis, metabolic stress, artificial insemination, infective causes, and altered cellular pathways. Despite the lack of symptoms, cellular pathways of inflammation including NFkB, MAPK, and inflammasomes were found to be activated. The key themes related to the diagnosis and pathophysiology of SCE in cows identified in this systematic review highlight potential areas for future research into human CE.

Currently, the optimal treatment to increase the chance of pregnancy and live births in patients with colorectal endometriosis and subfertility is unknown. Evidence suggests that that both surgery and in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) are effective in improving the live birth rate (LBR) among these women. However, the available evidence is of low quality, reports highly heterogeneous results, lacks direct comparison between both treatment options, and does not assess whether a combination strategy results in a higher LBR compared to IVF/ICSI-only treatment. Additionally, the optimal timing of surgery within the treatment trajectory remains unclear. The primary objective of the TOSCA study is to assess the effectiveness of surgical treatment (potentially combined with IVF/ICSI) compared to IVF-/ICSI-only treatment to increase the chance of an ongoing pregnancy resulting in a live birth in patients with colorectal endometriosis and subfertility, measured by cumulative LBR. Secondary objectives are to assess and compare quality of life and cost-effectiveness in both groups. Patients will be followed for 40 months after inclusion or until live birth. The TOSCA study is expected to be completed in 6 years.

Trial registration number

The TOSCA trial is registered as ‘Cost-Effectiveness of Surgical Excision of Colorectal Endometriosis Compared to ART Treatment Trajectory (TOSCA)’ in the Clinical Trials Register (NCT No. NCT05677269,

Date of first patient enrolment

The first patient was included in February 2023.

Lay summary

Treating bowel endometriosis in people with fertility problems is difficult, and at the moment, there is no consensus on the best way to increase the chances of pregnancy. This makes it hard for gynaecologists to advise people when to have either IVF/ICSI or surgery, particularly in patients with fewer pain symptoms, as the benefits of surgery to enhance fertility have to be balanced against the potential risk of side effects. Surgery can improve fertility and pain symptoms, but it may delay people trying to conceive which means the reserve of eggs in the ovaries will reduce with time. IVF/ICSI also seems a viable option, but having the surgery first may increase the chances of conception (both naturally and/or after IVF/ICSI). The TOSCA study aims to determine whether surgery for bowel endometriosis leads to an increased birth rate and better patient reported outcome measures compared to IVF/ICSI alone.

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