Effectiveness of laparoscopic removal of isolated superficial peritoneal endometriosis for the management of chronic pelvic pain in women (ESPriT2): protocol for a multi-centre randomised controlled trial.

BACKGROUND: Endometriosis affects 190 million women and those assigned female at birth worldwide. For some, it is associated with debilitating chronic pelvic pain. Diagnosis of endometriosis is often achieved through diagnostic laparoscopy. However, when isolated superficial peritoneal endometriosis (SPE), the most common endometriosis subtype, is identified during laparoscopy, limited evidence exists to support the common decision to surgically remove it via excision or ablation. Improved understanding of the impact of surgical removal of isolated SPE for the management of chronic pelvic pain in women is required. Here, we describe our protocol for a multi-centre trial to determine the effectiveness of surgical removal of isolated SPE for the management of endometriosis-associated pain. METHODS: We plan to undertake a multi-centre participant-blind parallel-group randomised controlled clinical and cost-effectiveness trial with internal pilot. We plan to randomise 400 participants from up to 70 National Health Service Hospitals in the UK. Participants with chronic pelvic pain awaiting diagnostic laparoscopy for suspected endometriosis will be consented by the clinical research team. If isolated SPE is identified at laparoscopy, and deep or ovarian endometriosis is not seen, participants will be randomised intraoperatively (1:1) to surgical removal (by excision or ablation or both, according to surgeons' preference) versus diagnostic laparoscopy alone. Randomisation with block-stratification will be used. Participants will be given a diagnosis but will not be informed of the procedure they received until 12 months post-randomisation, unless required. Post-operative medical treatment will be according to participants' preference. Participants will be asked to complete validated pain and quality of life questionnaires at 3, 6 and 12 months after randomisation. Our primary outcome is the pain domain of the Endometriosis Health Profile-30 (EHP-30), via a between randomised group comparison of adjusted means at 12 months. Assuming a standard deviation of 22 points around the pain score, 90% power, 5% significance and 20% missing data, 400 participants are required to be randomised to detect an 8-point pain score difference. DISCUSSION: This trial aims to provide high quality evidence of the clinical and cost-effectiveness of surgical removal of isolated SPE. TRIAL REGISTRATION: ISRCTN registry ISRCTN27244948. Registered 6 April 2021.

Longitudinal Changes in Body Composition and Resting Metabolic Rate in Male Professional Flat Jockeys: Preliminary Outcomes and Implications for Future Research Directions.

Jockeys are unique given that they make weight daily and, therefore, often resort to fasting and dehydration. Through increasing daily food frequency (during energy deficit), we have reported short-term improvements in jockey's body composition. While these changes were observed over 6-12 weeks with food provided, it is unclear whether such improvements can be maintained over an extended period during free-living conditions. We, therefore, assessed jockeys over 5 years using dual X-ray absorptiometry, resting metabolic rate, and hydration measurements. Following dietary and exercise advice, jockeys reduced fat mass from baseline of 7.1 ± 1.4 kg to 6.1 ± 0.7 kg and 6.1 ± 0.6 kg (p < .001) at Years 1 and 5, respectively. In addition, fat-free mass was maintained with resting metabolic rate increasing significantly from 1,500 ± 51 kcal/day at baseline to 1,612 ± 95 kcal/day and 1,620 ± 92 kcal/day (p < .001) at Years 1 and 5, respectively. Urine osmolality reduced from 816 ± 236 mOsmol/L at baseline to 564 ± 175 mOsmol/L and 524 ± 156 mOsmol/L (p < .001) at Years 1 and 5, respectively. The percent of jockeys consuming a regular breakfast significantly increased from 48% at baseline to 83% (p = .009) and 87% (p = .003) at Years 1 and 5, alongside regular lunch from 35% to 92% (p < .001) and 96% (p < .001) from baseline to Years 1 and 5, respectively. In conclusion, we report that improved body composition can be maintained in free-living jockeys over a 5-year period when appropriate guidance has been provided.

Peritoneal fluid progesterone and progesterone resistance in superficial endometriosis lesions.

Peritoneal fluid in ovulatory women is an ovarian exudate with higher estrogen and progesterone concentrations than in plasma. In the follicular phase, progesterone concentrations are as high as plasma concentrations in the luteal phase. After ovulation, estrogen and progesterone concentrations in the peritoneal fluid are 5-10 times higher than in plasma, both in women with and without endometriosis. The histologically proliferative aspect without secretory changes of most superficial subtle lesions is not compatible with the progesterone concentrations in the peritoneal fluid. Therefore, we have to postulate a strong progesterone resistance in these lesions. The mechanism is unclear and might be a peritoneal fluid effect in women with predisposing defects in the endometrium, or isolated endometrial glands with progesterone resistance, or subtle lesions originating from the basal endometrium: the latter hypothesis is attractive since in basal endometrium progesterone does not induce secretory changes while progesterone withdrawal, not occurring in peritoneal fluid, is required to resume mitotic activity and proliferation. Hormone concentrations in the peritoneal fluid are an important factor in understanding the medical therapy of endometriosis. The effect of oestro-progestin therapy on superficial endometriosis lesions seems to be a consequence of the decreased estrogen concentrations rather than a direct progestin effect. In conclusion, the peritoneal fluid, being a secretion product of the ovarian follicule, deserves more attention in the pathophysiology and treatment of endometriosis.

Corrigendum: Injury Incidence Across the Menstrual Cycle in International Footballers.

[This corrects the article DOI: 10.3389/fspor.2021.616999.].

Prevalence of Endometriosis and Peritoneal Pockets in Women with Infertility and/or Pelvic Pain.

OBJECTIVE: To evaluate the prevalence of endometriosis and peritoneal pockets and to analyze whether these pockets are associated with pain. METHODS: Analysis of prospectively registered data of all women undergoing laparoscopy for infertility or pelvic pain between 1988 and 2011 at KU Leuven University Hospital. RESULTS: Of 4497 women, 191 had 238 pockets, with a prevalence of 4.7% in women with infertility only, 4.9% in women with infertility and pelvic pain, and 3.5% in women with pelvic pain only (P = 0.045 for all infertility vs. pelvic pain only). Prevalence did not vary by age. Pockets were associated with endometriosis (P < 0.0001), which was found in 77% of women with pockets. Among women with infertility only, the prevalence of endometriosis was higher in women with pockets (P = 0.0001) than in women without. The prevalence of endometriosis was similar in women with infertility and pelvic pain or pelvic pain only. Pelvic pain as an indication for surgery was associated simultaneously (through logistic regression) with endometriosis (P < 0.0001) and pockets (P = 0.040). Pelvic pain severity was associated simultaneously with pockets (P = 0.0026) and the severity of subtle (P = 0.001), typical (P = 0.030), cystic ovarian (P = 0.051), and deep endometriosis (P < 0.0001). Pelvic pain severity was not associated with endometriosis in the pockets or the diameter or location of pockets. CONCLUSIONS: The prevalence of pockets was low, at between 3.5% and 5%. Women with infertility only and pockets had more endometriosis than women without. Severe pelvic pain and pelvic pain as an indication for surgery were associated with the presence of pockets as well as the presence and severity of endometriosis.

Injury Incidence Across the Menstrual Cycle in International Footballers.

Objectives: This study aimed to assess how menstrual cycle phase and extended menstrual cycle length influence the incidence of injuries in international footballers. Methods: Over a 4-year period, injuries from England international footballers at training camps or matches were recorded, alongside self-reported information on menstrual cycle characteristics at the point of injury. Injuries in eumenorrheic players were categorized into early follicular, late follicular, or luteal phase. Frequencies were also compared between injuries recorded during the typical cycle and those that occurred after the cycle would be expected to have finished. Injury incidence rates (per 1,000 person days) and injury incidence rate ratios were calculated for each phase for all injuries and injuries stratified by type. Results: One hundred fifty-six injuries from 113 players were eligible for analysis. Injury incidence rates per 1,000 person-days were 31.9 in the follicular, 46.8 in the late follicular, and 35.4 in the luteal phase, resulting in injury incidence rate ratios of 1.47 (Late follicular:Follicular), 1.11 (Luteal:Follicular), and 0.76 (Luteal:Late follicular). Injury incident rate ratios showed that muscle and tendon injury rates were 88% greater in the late follicular phase compared to the follicular phase, with muscle rupture/tear/strain/cramps and tendon injuries/ruptures occurring over twice as often during the late follicular phase compared to other phases 20% of injuries were reported as occurring when athletes were "overdue" menses. Conclusion: Muscle and tendon injuries occurred almost twice as often in the late follicular phase compared to the early follicular or luteal phase. Injury risk may be elevated in typically eumenorrheic women in the days after their next menstruation was expected to start.

Bone metabolic marker concentrations across the menstrual cycle and phases of combined oral contraceptive use.

There is a need to further understand the impact of the menstrual cycle and phase of combined oral contraceptive (COC) use on the pre-analytical variability of markers of bone metabolism in order to improve standardisation procedures for clinical practice and research. The aim of this study was to assess bone metabolism marker concentrations across the menstrual cycle and phases of COC use. Carboxy-terminal cross-linking telopeptide of type I collagen (ß-CTX), procollagen type 1 N propeptide (P1NP) and Bone alkaline phosphatase (Bone ALP) concentrations were assessed in eumenorrheic women (n = 14) during the early follicular, ovulatory and mid-luteal phases of the menstrual cycle and in COC (Microgynon®) (n = 14) users on day 2-3 of pill consumption (PC1), day 15-16 pill consumption (PC2) and day 3-4 of the pill free interval (PFI). ß-CTX was significantly (-16%) lower at PC2 compared to PC1 (P = 0.015) in COC users and was not affected by menstrual cycle phase (P > 0.05). P1NP and Bone ALP were not significantly different across either menstrual cycle phase or phase of COC use (all P > 0.05). There was no difference in pooled bone marker concentrations between eumenorrheic women and COC users (P > 0.05). In contrast to some previous studies, this study showed that bone marker concentrations do not significantly fluctuate across the menstrual cycle. Furthermore, bone resorption markers are significantly affected by phase of COC use, although bone formation markers do not significantly vary by COC phase. Therefore, the phase of COC use should be considered in clinical practice and research when assessing markers of bone metabolism as this can impact circulating concentrations of bone metabolic markers yet is not currently considered in existing guidelines for best practice.

The epidemiology of endometriosis is poorly known as the pathophysiology and diagnosis are unclear.

As the diagnosis requires a laparoscopy, we only have data in women with pain and/or infertility. Endometriosis has been considered to be a single disease defined as 'endometrium like glands and stroma outside the uterus'. However, subtle, typical, cystic ovarian and deep endometriosis lesions should be considered to be different pathologies which occur in all combinations and with different severities. All large datasets, especially those based on hospital discharge records, consider endometriosis to be a single disease without taking into account severity. In particular, the variable prevalence and recognition of subtle lesions is problematic. Reliable surgical data are small series not permitting multivariate analysis. Endometriosis is a hereditary disease. The oxidative stress of heavy menstrual bleeding with retrograde menstruation and an altered pelvic microbiome are probably associated with increasingly severe endometriosis. Whether the prevalence is increasing, or whether endometriosis is associated with fat intake or an increased risk of cardiovascular disease is unclear.

The Pathogenesis of Endometriosis: Molecular and Cell Biology Insights.

The etiopathogenesis of endometriosis is a multifactorial process resulting in a heterogeneous disease. Considering that endometriosis etiology and pathogenesis are still far from being fully elucidated, the current review aims to offer a comprehensive summary of the available evidence. We performed a narrative review synthesizing the findings of the English literature retrieved from computerized databases from inception to June 2019, using the Medical Subject Headings (MeSH) unique ID term "Endometriosis" (ID:D004715) with "Etiology" (ID:Q000209), "Immunology" (ID:Q000276), "Genetics" (ID:D005823) and "Epigenesis, Genetic" (ID:D044127). Endometriosis may origin from Müllerian or non-Müllerian stem cells including those from the endometrial basal layer, Müllerian remnants, bone marrow, or the peritoneum. The innate ability of endometrial stem cells to regenerate cyclically seems to play a key role, as well as the dysregulated hormonal pathways. The presence of such cells in the peritoneal cavity and what leads to the development of endometriosis is a complex process with a large number of interconnected factors, potentially both inherited and acquired. Genetic predisposition is complex and related to the combined action of several genes with limited influence. The epigenetic mechanisms control many of the processes involved in the immunologic, immunohistochemical, histological, and biological aberrations that characterize the eutopic and ectopic endometrium in affected patients. However, what triggers such alterations is not clear and may be both genetically and epigenetically inherited, or it may be acquired by the particular combination of several elements such as the persistent peritoneal menstrual reflux as well as exogenous factors. The heterogeneity of endometriosis and the different contexts in which it develops suggest that a single etiopathogenetic model is not sufficient to explain its complex pathobiology.

The perioperative period: a critical yet neglected time window for reducing the recurrence risk of endometriosis?

While surgery is commonly the management of symptomatic endometriosis when patients do not respond to medical or supportive therapy, recurrence after surgery poses a serious challenge, and repeat surgery increases the risk of premature ovarian failure, adhesion and organ injury. Conceivably, the recurrent endometriotic lesions could arise from minimal residual lesions (MRLs) or from de novo lesions. However, several lines of evidence suggest that the former is more likely. So far, most, if not all, efforts to combat recurrence have been focused on postoperative medication of hormonal drugs to reduce recurrence risk through lesional dormancy and possibly atrophy. However, the perioperative period may exert a disproportionally high impact on the risk of recurrence; it is likely to be amendable for possible intervention but has been generally neglected. Indeed, many perioperative factors are known to or conceivably could facilitate the recurrence of endometriosis through the suppression of cell-mediated immunity due to the activation of adrenergic signaling and the release of prostaglandins. Perioperative use of ß-blockers and/or nuclear factor κB/jCycloxygenase 2 (NF-κB/COX-2) inhibitors may boost the cell-mediated immunity suppressed by surgery, resulting in the partial or even complete removal of MRLs and reduced recurrence risk. This is both biologically plausible and supported by a recent experimental study. We call for more research on possible perioperative interventions to reduce the recurrence risk of endometriosis. The potential payoff might be a substantial reduction in the risk of recurrence and cost when compared with the traditional approach of postoperative intervention.

Joint European Society of Paediatric Radiology (ESPR) and International Society for Forensic Radiology and Imaging (ISFRI) guidelines: paediatric postmortem computed tomography imaging protocol.

Postmortem CT for investigating childhood deaths is increasingly utilised as a noninvasive adjunct or alternative to standard autopsy; however there are no standardised published imaging protocols. This article describes a standardised imaging protocol that has been developed based on current practices of international postmortem imaging practitioners and experts. This recommendation is expected to be useful for postmortem imaging centres wishing to update their existing practices and for those starting paediatric postmortem CT as a new service.

Pathogenesis of endometriosis: the genetic/epigenetic theory.

OBJECTIVE: To study the pathophysiology of endometriosis. DESIGN: Overview of observations on endometriosis. SETTING: Not applicable. PATIENT(S): None. INTERVENTIONS(S): None. MAIN OUTCOME MEASURE(S): The hypothesis is compatible with all observations. RESULT(S): Endometriosis, endometrium-like tissue outside the uterus, has a variable macroscopic appearance and a poorly understood natural history. It is a hereditary and heterogeneous disease with many biochemical changes in the lesions, which are clonal in origin. It is associated with pain, infertility, adenomyosis, and changes in the junctional zone, placentation, immunology, plasma, peritoneal fluid, and chronic inflammation of the peritoneal cavity. The Sampson hypothesis of implanted endometrial cells following retrograde menstruation, angiogenic spread, lymphogenic spread, or the metaplasia theory cannot explain all observations if metaplasia is defined as cells with reversible changes and an abnormal behavior/morphology due to the abnormal environment. We propose a polygenetic/polyepigenetic mechanism. The set of genetic and epigenetic incidents transmitted at birth could explain the hereditary aspects, the predisposition, and the endometriosis-associated changes in the endometrium, immunology, and placentation. To develop typical, cystic ovarian or deep endometriosis lesions, a variable series of additional transmissible genetic and epigenetic incidents are required to occur in a cell which may vary from endometrial to stem cells. Subtle lesions are viewed as endometrium in a different environment until additional incidents occur. Typical cystic ovarian or deep endometriosis lesions are heterogeneous and represent three different diseases. CONCLUSION(S): The genetic epigenetic theory is compatible with all observations on endometriosis. Implications for treatment and prevention are discussed.